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Zhang L, Xiong Z, Chen Z, Xu M, Zhao S, Liu X, Jiang K, Hu Y, Liu S, Sun X, Wu Z, Shen J, Wang LF. Periplakin Attenuates Liver Fibrosis Via Reprogramming CD44 Low Cells into CD44 High Liver Progenitor Cells. Cell Mol Gastroenterol Hepatol 2025:101498. [PMID: 40107450 DOI: 10.1016/j.jcmgh.2025.101498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 03/08/2025] [Accepted: 03/11/2025] [Indexed: 03/22/2025]
Abstract
BACKGROUND & AIMS Liver progenitor cells (LPCs) contribute significantly to the restoration of injured liver parenchyma and promote liver regeneration, thereby ameliorating liver fibrosis. However, the mechanism of the derivation of LPCs remains poorly understood. METHODS We first examined the expression of periplakin (PPL) in patients and mouse models with liver fibrosis. Adenovirus overexpressing PPL was injected into the tail vein of mouse models to detect the regulatory effect of PPL on liver fibrosis. Single-cell sequencing explored how PPL influences liver fibrosis progression. Additionally, PPL+CD44Low cells and PPL+CD44High LPCs were transplanted into 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced mouse models to assess their therapeutic efficacy in treating liver fibrosis. RESULTS The expression of PPL is upregulated in fibrotic livers in human and mouse models of liver fibrosis. Functionally, we found that PPL overexpression significantly attenuated liver fibrosis. Mechanistically, PPL was specifically expressed in LPCs and promoted LPC expansion. Moreover, we observed that PPL+ cells could be categorized into PPL+CD44Low and PPL+CD44High subsets, and PPL+CD44Low cells were found to redifferentiate into PPL+CD44High LPCs during liver fibrosis. Furthermore, transplantation of PPL+CD44High LPCs notably suppressed liver fibrosis. CONCLUSIONS These findings demonstrate that PPL+CD44Low cells can be reprogrammed into PPL+CD44High LPCs, which ameliorate liver fibrosis, suggesting a potential application of PPL for the treatment of liver fibrosis.
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Affiliation(s)
- Lichao Zhang
- Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangdong, China
| | - Zhiyong Xiong
- Department of General Surgery, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Zebin Chen
- Center of Hepato-Pancreatico-Biliary Surgery, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Meiyining Xu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Siyu Zhao
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Xianzhi Liu
- Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Kefeng Jiang
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Yunyi Hu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Shurui Liu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - Xi Sun
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
| | - Zhongdao Wu
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
| | - Jia Shen
- Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China.
| | - Lifu F Wang
- Guangzhou Key Laboratory for Clinical Rapid Diagnosis and Early Warning of Infectious Diseases, KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, China.
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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Defamie V, Aliar K, Sarkar S, Vyas F, Shetty R, Reddy Narala S, Fang H, Saw S, Tharmapalan P, Sanchez O, Knox JJ, Waterhouse PD, Khokha R. Metalloproteinase inhibitors regulate biliary progenitor cells through sDLK1 in organoid models of liver injury. J Clin Invest 2024; 135:e164997. [PMID: 39699962 PMCID: PMC11785925 DOI: 10.1172/jci164997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/10/2024] [Indexed: 12/21/2024] Open
Abstract
Understanding cell fate regulation in the liver is necessary to advance cell therapies for hepatic disease. Liver progenitor cells (LPCs) contribute to tissue regeneration after severe hepatic injury, yet signals instructing progenitor cell dynamics and fate are largely unknown. Tissue inhibitor of metalloproteinases 1 (TIMP1) and TIMP3 control the sheddases ADAM10 and ADAM17, key for NOTCH activation. Here we uncover the role of the TIMP/ADAM/NOTCH/DLK1 axis in LPC maintenance and cholangiocyte specification. Combined TIMP1/TIMP3 loss in vivo caused abnormal portal triad stoichiometry accompanied by collagen deposits, dysregulated Notch signaling, and increased soluble DLK1. The MIC1-1C3+CD133+CD26- biliary progenitor population was reduced following acute CCl4 or chronic DDC liver injury and in aged TIMP-deficient livers. Single-cell RNA sequencing data interrogation and RNAscope identified portal mesenchymal cells coexpressing ADAM17/DLK1 as enzymatically equipped to process DLK1 and direct LPC differentiation. Specifically, TIMP-deficient biliary fragment-derived organoids displayed increased propensity for cholangiocyte differentiation. ADAM17 inhibition reduced Sox9-mediated cholangiocyte differentiation, prolonging organoid growth and survival, whereas WT organoids treated with soluble DLK1 triggered Sox9 expression and cholangiocyte specification in mouse and patient-derived liver organoids. Thus, metalloproteinase inhibitors regulate instructive signals for biliary cell differentiation and LPC preservation within the portal niche, providing a new basis for cell therapy strategies.
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Affiliation(s)
- Virginie Defamie
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Kazeera Aliar
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Soumili Sarkar
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Foram Vyas
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Ronak Shetty
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Swami Reddy Narala
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Hui Fang
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Sanjay Saw
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | | | - Otto Sanchez
- Ontario Tech University, Oshawa, Ontario, Canada
| | - Jennifer J. Knox
- Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada
| | - Paul D. Waterhouse
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Rama Khokha
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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Liu Z, Ren J, Qiu C, Wang Y, Zhang T. Application of mesenchymal stem cells in liver fibrosis and regeneration. LIVER RESEARCH 2024; 8:246-258. [PMID: 39958916 PMCID: PMC11771278 DOI: 10.1016/j.livres.2024.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/20/2024] [Accepted: 11/22/2024] [Indexed: 02/18/2025]
Abstract
Liver transplantation remains the most effective treatment for end-stage liver disease (ESLD), but it is fraught with challenges such as immunosuppression, high risk and cost, and donor shortage. In recent years, stem cell transplantation has emerged as a promising new strategy for ESLD treatment, with mesenchymal stem cells (MSCs) gaining significant attention because of their unique properties. MSCs can regulate signaling pathways, including hepatocyte growth factor/c-Met, Wnt/beta (β)-catenin, Notch, transforming growth factor-β1/Smad, interleukin-6/Janus kinase/signal transducer and activator of transcription 3, and phosphatidylinositol 3-kinase/PDK/Akt, thereby influencing the progression of liver fibrosis and regeneration. As a promising stem cell type, MSCs offer numerous advantages in liver disease treatment, including low immunogenicity; ease of acquisition; unlimited proliferative ability; pluripotent differentiation potential; immunomodulatory function; and anti-inflammatory, antifibrotic, and antiapoptotic biological characteristics. This review outlines the mechanisms by which MSCs reverse liver fibrosis and promote liver regeneration. MSCs are crucial in reversing liver fibrosis and repairing liver damage through the secretion of growth factors, regulation of signaling pathways, and modulation of immune responses. MSCs have shown good therapeutic effects in preclinical and clinical studies, providing new strategies for liver disease treatment. However, challenges still exist in the clinical application of MSCs, including low differentiation efficiency and limited sources. This review provides a reference for MSC application in liver disease treatment. With the continuous progress in MSC research, MSCs are expected to achieve breakthroughs in liver disease treatment, thereby improving patient treatment outcomes.
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Affiliation(s)
- Zhenyu Liu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Junkai Ren
- Department of Hepatobiliary Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Cheng Qiu
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Ying Wang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Tong Zhang
- Organ Transplantation Clinical Medical Center of Xiamen University, Department of General Surgery, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
- Organ Transplantation Institute of Xiamen University, Xiamen Human Organ Transplantation Quality Control Center, Xiamen Key Laboratory of Regeneration Medicine, Fujian Provincial Key Laboratory of Organ and Tissue Regeneration, School of Medicine, Xiamen University, Xiamen, Fujian, China
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van Luyk ME, Krotenberg Garcia A, Lamprou M, Suijkerbuijk SJE. Cell competition in primary and metastatic colorectal cancer. Oncogenesis 2024; 13:28. [PMID: 39060237 PMCID: PMC11282291 DOI: 10.1038/s41389-024-00530-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 07/05/2024] [Accepted: 07/16/2024] [Indexed: 07/28/2024] Open
Abstract
Adult tissues set the scene for a continuous battle between cells, where a comparison of cellular fitness results in the elimination of weaker "loser" cells. This phenomenon, named cell competition, is beneficial for tissue integrity and homeostasis. In fact, cell competition plays a crucial role in tumor suppression, through elimination of early malignant cells, as part of Epithelial Defense Against Cancer. However, it is increasingly apparent that cell competition doubles as a tumor-promoting mechanism. The comparative nature of cell competition means that mutational background, proliferation rate and polarity all factor in to determine the outcome of these processes. In this review, we explore the intricate and context-dependent involvement of cell competition in homeostasis and regeneration, as well as during initiation and progression of primary and metastasized colorectal cancer. We provide a comprehensive overview of molecular and cellular mechanisms governing cell competition and its parallels with regeneration.
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Affiliation(s)
- Merel Elise van Luyk
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Ana Krotenberg Garcia
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Maria Lamprou
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Saskia Jacoba Elisabeth Suijkerbuijk
- Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
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6
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Nishikawa Y. Aberrant differentiation and proliferation of hepatocytes in chronic liver injury and liver tumors. Pathol Int 2024; 74:361-378. [PMID: 38837539 PMCID: PMC11551836 DOI: 10.1111/pin.13441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 04/29/2024] [Accepted: 05/12/2024] [Indexed: 06/07/2024]
Abstract
Chronic liver injury induces liver cirrhosis and facilitates hepatocarcinogenesis. However, the effects of this condition on hepatocyte proliferation and differentiation are unclear. We showed that rodent hepatocytes display a ductular phenotype when they are cultured within a collagenous matrix. This process involves transdifferentiation without the emergence of hepatoblastic features and is at least partially reversible. During the ductular reaction in chronic liver diseases with progressive fibrosis, some hepatocytes, especially those adjacent to ectopic ductules, demonstrate ductular transdifferentiation, but the majority of increased ductules originate from the existing bile ductular system that undergoes extensive remodeling. In chronic injury, hepatocyte proliferation is weak but sustained, and most regenerative nodules in liver cirrhosis are composed of clonally proliferating hepatocytes, suggesting that a small fraction of hepatocytes maintain their proliferative capacity in chronic injury. In mouse hepatocarcinogenesis models, hepatocytes activate the expression of various fetal/neonatal genes, indicating that these cells undergo dedifferentiation. Hepatocyte-specific somatic integration of various oncogenes in mice demonstrated that hepatocytes may be the cells of origin for a broad spectrum of liver tumors through transdifferentiation and dedifferentiation. In conclusion, the phenotypic plasticity and heterogeneity of mature hepatocytes are important for understanding the pathogenesis of chronic liver diseases and liver tumors.
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Affiliation(s)
- Yuji Nishikawa
- President's OfficeAsahikawa Medical UniversityAsahikawaHokkaidoJapan
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7
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Xu C, Fang X, Song Y, Xiang Z, Xu X, Wei X. Transcriptional Control: A Directional Sign at the Crossroads of Adult Hepatic Progenitor Cells' Fates. Int J Biol Sci 2024; 20:3544-3556. [PMID: 38993564 PMCID: PMC11234216 DOI: 10.7150/ijbs.93739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 05/31/2024] [Indexed: 07/13/2024] Open
Abstract
Hepatic progenitor cells (HPCs) have a bidirectional potential to differentiate into hepatocytes and bile duct epithelial cells and constitute a second barrier to liver regeneration in the adult liver. They are usually located in the Hering duct in the portal vein region where various cells, extracellular matrix, cytokines, and communication signals together constitute the niche of HPCs in homeostasis to maintain cellular plasticity. In various types of liver injury, different cellular signaling streams crosstalk with each other and point to the inducible transcription factor set, including FoxA1/2/3, YB-1, Foxl1, Sox9, HNF4α, HNF1α, and HNF1β. These transcription factors exert different functions by binding to specific target genes, and their products often interact with each other, with diverse cascades of regulation in different molecular events that are essential for homeostatic regulation, self-renewal, proliferation, and selective differentiation of HPCs. Furthermore, the tumor predisposition of adult HPCs is found to be significantly increased under transcriptional factor dysregulation in transcriptional analysis, and the altered initial commitment of the differentiation pathway of HPCs may be one of the sources of intrahepatic tumors. Related transcription factors such as HNF4α and HNF1 are expected to be future targets for tumor treatment.
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Affiliation(s)
- Chenhao Xu
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xixi Fang
- Hangzhou Normal University, Hangzhou 310006, China
| | - Yisu Song
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou 310058, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
| | - Xuyong Wei
- Zhejiang University School of Medicine, Hangzhou First People's Hospital, Hangzhou 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou 310006, China
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8
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Nita A, Moroishi T. Hippo pathway in cell-cell communication: emerging roles in development and regeneration. Inflamm Regen 2024; 44:18. [PMID: 38566194 PMCID: PMC10986044 DOI: 10.1186/s41232-024-00331-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/24/2024] [Indexed: 04/04/2024] Open
Abstract
The Hippo pathway is a central regulator of tissue growth that has been widely studied in mammalian organ development, regeneration, and cancer biology. Although previous studies have convincingly revealed its cell-autonomous functions in controlling cell fate, such as cell proliferation, survival, and differentiation, accumulating evidence in recent years has revealed its non-cell-autonomous functions. This pathway regulates cell-cell communication through direct interactions, soluble factors, extracellular vesicles, and the extracellular matrix, providing a range of options for controlling diverse biological processes. Consequently, the Hippo pathway not only dictates the fate of individual cells but also triggers multicellular responses involving both tissue-resident cells and infiltrating immune cells. Here, we have highlighted the recent understanding of the molecular mechanisms by which the Hippo pathway controls cell-cell communication and discuss its importance in tissue homeostasis, especially in development and regeneration.
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Affiliation(s)
- Akihiro Nita
- Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Toshiro Moroishi
- Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
- Center for Metabolic Regulation of Healthy Aging, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
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Li Z, Yang W, Wu P, Shan Y, Zhang X, Chen F, Yang J, Yang JR. Reconstructing cell lineage trees with genomic barcoding: approaches and applications. J Genet Genomics 2024; 51:35-47. [PMID: 37269980 DOI: 10.1016/j.jgg.2023.05.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/19/2023] [Accepted: 05/20/2023] [Indexed: 06/05/2023]
Abstract
In multicellular organisms, developmental history of cell divisions and functional annotation of terminal cells can be organized into a cell lineage tree (CLT). The reconstruction of the CLT has long been a major goal in developmental biology and other related fields. Recent technological advancements, especially those in editable genomic barcodes and single-cell high-throughput sequencing, have sparked a new wave of experimental methods for reconstructing CLTs. Here we review the existing experimental approaches to the reconstruction of CLT, which are broadly categorized as either image-based or DNA barcode-based methods. In addition, we present a summary of the related literature based on the biological insight provided by the obtained CLTs. Moreover, we discuss the challenges that will arise as more and better CLT data become available in the near future. Genomic barcoding-based CLT reconstructions and analyses, due to their wide applicability and high scalability, offer the potential for novel biological discoveries, especially those related to general and systemic properties of the developmental process.
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Affiliation(s)
- Zizhang Li
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Department of Genetics and Biomedical Informatics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Wenjing Yang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Peng Wu
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Yuyan Shan
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Xiaoyu Zhang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Feng Chen
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Department of Genetics and Biomedical Informatics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Junnan Yang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China
| | - Jian-Rong Yang
- Advanced Medical Technology Center, The First Affiliated Hospital, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Department of Genetics and Biomedical Informatics, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510080, China; Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
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10
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Rizvi F, Lee YR, Diaz-Aragon R, Bawa PS, So J, Florentino RM, Wu S, Sarjoo A, Truong E, Smith AR, Wang F, Everton E, Ostrowska A, Jung K, Tam Y, Muramatsu H, Pardi N, Weissman D, Soto-Gutierrez A, Shin D, Gouon-Evans V. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. Cell Stem Cell 2023; 30:1640-1657.e8. [PMID: 38029740 PMCID: PMC10843608 DOI: 10.1016/j.stem.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/07/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023]
Abstract
The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial-cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via nonintegrative and safe nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNPs) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and elimination of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This work defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals unexpected therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases.
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Affiliation(s)
- Fatima Rizvi
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Yu-Ri Lee
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Ricardo Diaz-Aragon
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Pushpinder S Bawa
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Juhoon So
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Rodrigo M Florentino
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Susan Wu
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Arianna Sarjoo
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Emily Truong
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Anna R Smith
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Feiya Wang
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Elissa Everton
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Alina Ostrowska
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Kyounghwa Jung
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Ying Tam
- Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada
| | - Hiromi Muramatsu
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Norbert Pardi
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Drew Weissman
- Department of Medicine, Infectious Diseases Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 10104, USA
| | - Alejandro Soto-Gutierrez
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Donghun Shin
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Valerie Gouon-Evans
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
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11
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Karpova Y, Orlicky DJ, Schmidt EE, Tulin AV. Disrupting Poly(ADP-ribosyl)ating Pathway Creates Premalignant Conditions in Mammalian Liver. Int J Mol Sci 2023; 24:17205. [PMID: 38139034 PMCID: PMC10743425 DOI: 10.3390/ijms242417205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 12/24/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a major global health concern, representing one of the leading causes of cancer-related deaths. Despite various treatment options, the prognosis for HCC patients remains poor, emphasizing the need for a deeper understanding of the factors contributing to HCC development. This study investigates the role of poly(ADP-ribosyl)ation in hepatocyte maturation and its impact on hepatobiliary carcinogenesis. A conditional Parg knockout mouse model was employed, utilizing Cre recombinase under the albumin promoter to target Parg depletion specifically in hepatocytes. The disruption of the poly(ADP-ribosyl)ating pathway in hepatocytes affects the early postnatal liver development. The inability of hepatocytes to finish the late maturation step that occurs early after birth causes intensive apoptosis and acute inflammation, resulting in hypertrophic liver tissue with enlarged hepatocytes. Regeneration nodes with proliferative hepatocytes eventually replace the liver tissue and successfully fulfill the liver function. However, early developmental changes predispose these types of liver to develop pathologies, including with a malignant nature, later in life. In a chemically induced liver cancer model, Parg-depleted livers displayed a higher tendency for hepatocellular carcinoma development. This study underscores the critical role of the poly(ADP-ribosyl)ating pathway in hepatocyte maturation and highlights its involvement in liver pathologies and hepatobiliary carcinogenesis. Understanding these processes may provide valuable insights into liver biology and liver-related diseases, including cancer.
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Affiliation(s)
- Yaroslava Karpova
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 501 North Columbia Road, Grand Forks, ND 58202, USA;
- Koltzov Institute of Developmental Biology of Russian Academy of Sciences, 119334 Moscow, Russia
| | - David J. Orlicky
- Department of Pathology, University of Colorado School of Medicine, Aurora, CO 80045, USA;
| | - Edward E. Schmidt
- Microbiology & Cell Biology, Montana State University, Bozeman, MT 59718, USA;
- Department of Microbiology & Immunology, Lewis Hall, Bozeman, MT 59718, USA
- Redox Biology Laboratory, University of Veterinary Medicine, 1078 Budapest, Hungary
| | - Alexei V. Tulin
- Department of Biomedical Sciences, School of Medicine and Health Sciences, University of North Dakota, 501 North Columbia Road, Grand Forks, ND 58202, USA;
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12
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Jiang M, Ren J, Belmonte JCI, Liu GH. Hepatocyte reprogramming in liver regeneration: Biological mechanisms and applications. FEBS J 2023; 290:5674-5688. [PMID: 37556833 DOI: 10.1111/febs.16930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/17/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023]
Abstract
The liver is one of the few organs that retain the capability to regenerate in adult mammals. This regeneration process is mainly facilitated by the dynamic behavior of hepatocytes, which are the major functional constituents in the liver. In response to liver injury, hepatocytes undergo remarkable alterations, such as reprogramming, wherein they lose their original identity and acquire properties from other cells. This phenomenon of hepatocyte reprogramming, coupled with hepatocyte expansion, plays a central role in liver regeneration, and its underlying mechanisms are complex and multifaceted. Understanding the fate of reprogrammed hepatocytes and the mechanisms of their conversion has significant implications for the development of innovative therapeutics for liver diseases. Herein, we review the plasticity of hepatocytes in response to various forms of liver injury, with a focus on injury-induced hepatocyte reprogramming. We provide a comprehensive summary of current knowledge on the molecular and cellular mechanisms governing hepatocyte reprogramming, specifically in the context of liver regeneration, providing insight into potential applications of this process in the treatment of liver disorders, including chronic liver diseases and liver cancer.
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Affiliation(s)
- Mengmeng Jiang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Jie Ren
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- School of Future Technology, University of Chinese Academy of Sciences, Beijing, China
| | | | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China
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13
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Liang J, Wei J, Cao J, Qian J, Gao R, Li X, Wang D, Gu Y, Dong L, Yu J, Zhao B, Wang X. In-organoid single-cell CRISPR screening reveals determinants of hepatocyte differentiation and maturation. Genome Biol 2023; 24:251. [PMID: 37907970 PMCID: PMC10617096 DOI: 10.1186/s13059-023-03084-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 10/06/2023] [Indexed: 11/02/2023] Open
Abstract
BACKGROUND Harnessing hepatocytes for basic research and regenerative medicine demands a complete understanding of the genetic determinants underlying hepatocyte differentiation and maturation. Single-cell CRISPR screens in organoids could link genetic perturbations with parallel transcriptomic readout in single cells, providing a powerful method to delineate roles of cell fate regulators. However, a big challenge for identifying key regulators during data analysis is the low expression levels of transcription factors (TFs), which are difficult to accurately estimate due to noise and dropouts in single-cell sequencing. Also, it is often the changes in TF activities in the transcriptional cascade rather than the expression levels of TFs that are relevant to the cell fate transition. RESULTS Here, we develop Organoid-based Single-cell CRISPR screening Analyzed with Regulons (OSCAR), a framework using regulon activities as readouts to dissect gene knockout effects in organoids. In adult-stem-cell-derived liver organoids, we map transcriptomes in 80,576 cells upon 246 perturbations associated with transcriptional regulation of hepatocyte formation. Using OSCAR, we identify known and novel positive and negative regulators, among which Fos and Ubr5 are the top-ranked ones. Further single-gene loss-of-function assays demonstrate that Fos depletion in mouse and human liver organoids promote hepatocyte differentiation by specific upregulation of liver metabolic genes and pathways, and conditional knockout of Ubr5 in mouse liver delays hepatocyte maturation. CONCLUSIONS Altogether, we provide a framework to explore lineage specifiers in a rapid and systematic manner, and identify hepatocyte determinators with potential clinical applications.
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Affiliation(s)
- Junbo Liang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, 100005, China
| | - Jinsong Wei
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Jun Cao
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, 100005, China
- Institute of Clinical Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Translational Medicine Center, Peking Union Medical College Hospital, Beijing, 100730, China
| | - Jun Qian
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, 100005, China
| | - Ran Gao
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, 100005, China
| | - Xiaoyu Li
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, 200438, China
| | - Dingding Wang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, 100005, China
| | - Yani Gu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, 100005, China
| | - Lei Dong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Chemistry and Biomedicine Innovative Center, Nanjing University, Nanjing, 210023, China
| | - Jia Yu
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, 100005, China
| | - Bing Zhao
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
- Institute of Respiratory Disease, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
- Institute of Organoid Technology, Kunming Medical University, Kunming, 650500, China.
| | - Xiaoyue Wang
- State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Union Medical College, Beijing, 100005, China.
- Institute of Clinical Medicine, Peking Union Medical College and Chinese Academy of Medical Sciences, Translational Medicine Center, Peking Union Medical College Hospital, Beijing, 100730, China.
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14
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Su D, Li Y, Zhang W, Gao H, Cheng Y, Hou Y, Li J, Ye Y, Lai Z, Li Z, Huang H, Li J, Li J, Cheng M, Nian C, Wu N, Zhou Z, Xing Y, Zhao Y, Liu H, Tang J, Chen Q, Hong L, Li W, Peng Z, Zhao B, Johnson RL, Liu P, Hong W, Chen L, Zhou D. SPTAN1/NUMB axis senses cell density to restrain cell growth and oncogenesis through Hippo signaling. J Clin Invest 2023; 133:e168888. [PMID: 37843276 PMCID: PMC10575737 DOI: 10.1172/jci168888] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Accepted: 08/22/2023] [Indexed: 10/17/2023] Open
Abstract
The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and MST2 (MST1/2). WW45 interaction with MST1/2 was thereby enhanced, resulting in the activation of Hippo signaling to block YAP activity for cell contact inhibition. Importantly, low cell density led to SPTAN1 dephosphorylation and NUMB cytoplasmic location, along with MST1/2 inhibition and, consequently, YAP activation. Moreover, double KO of NUMB and WW45 in the liver led to appreciable organ enlargement and rapid tumorigenesis. Interestingly, NUMB isoforms 3 and 4, which have a truncated phosphotyrosine-binding (PTB) domain and are thus unable to interact with phosphorylated SPTAN1 and activate MST1/2, were selectively upregulated in liver cancer, which correlated with YAP activation. We have thus revealed a SPTAN1/NUMB1/2 axis that acts as a cell density sensor to restrain cell growth and oncogenesis by coupling external cell-cell contact signals to intracellular Hippo signaling.
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Affiliation(s)
- Dongxue Su
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Yuxi Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Weiji Zhang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Huan Gao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Yao Cheng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Yongqiang Hou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Junhong Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Yi Ye
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Zhangjian Lai
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Zhe Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Haitao Huang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Jiaxin Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Jinhuan Li
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Mengyu Cheng
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Cheng Nian
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Na Wu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Zhien Zhou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Yunzhi Xing
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Yu Zhao
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - He Liu
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Jiayu Tang
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Qinghua Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Lixin Hong
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
| | - Wengang Li
- Department of Hepatobiliary and Pancreatic and Organ Transplantation Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Zhihai Peng
- Department of Hepatobiliary and Pancreatic and Organ Transplantation Surgery, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Bin Zhao
- The MOE Key Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China
| | - Randy L. Johnson
- Department of Cancer Biology, University of Texas, M.D. Anderson Cancer Center, Houston, Texas, USA
| | - Pingguo Liu
- Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Department of Hepatobiliary Surgery, Zhongshan Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Wanjin Hong
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Lanfen Chen
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (ASTAR), Singapore, Singapore
| | - Dawang Zhou
- State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University and
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15
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Aguilar-Bravo B, Ariño S, Blaya D, Pose E, Martinez García de la Torre RA, Latasa MU, Martínez-Sánchez C, Zanatto L, Sererols-Viñas L, Cantallops-Vilà P, Affo S, Coll M, Thillen X, Dubuquoy L, Avila MA, Argemi J, Paz AL, Nevzorova YA, Cubero FJ, Bataller R, Lozano JJ, Ginès P, Mathurin P, Sancho-Bru P. Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 as a driver of cell reprogramming. J Hepatol 2023; 79:728-740. [PMID: 37088308 PMCID: PMC10540088 DOI: 10.1016/j.jhep.2023.04.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 03/17/2023] [Accepted: 04/08/2023] [Indexed: 04/25/2023]
Abstract
BACKGROUND & AIMS Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood. METHODS HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. RESULTS Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. CONCLUSIONS This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. IMPACT AND IMPLICATIONS Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair.
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Affiliation(s)
- Beatriz Aguilar-Bravo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Silvia Ariño
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Delia Blaya
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Elisa Pose
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Liver Unit, Hospital Clínic, Barcelona, Spain
| | | | - María U Latasa
- Hepatology Program, Liver Unit, Instituto de Investigación de Navarra (IdisNA), Clínica Universidad de Navarra and Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Celia Martínez-Sánchez
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Laura Zanatto
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laura Sererols-Viñas
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Paula Cantallops-Vilà
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Silvia Affo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Mar Coll
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Xavier Thillen
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laurent Dubuquoy
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Matías A Avila
- Hepatology Program, Liver Unit, Instituto de Investigación de Navarra (IdisNA), Clínica Universidad de Navarra and Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Josepmaria Argemi
- Hepatology Program, Liver Unit, Instituto de Investigación de Navarra (IdisNA), Clínica Universidad de Navarra and Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Arantza Lamas Paz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Yulia A Nevzorova
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Francisco Javier Cubero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Ramon Bataller
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Liver Unit, Hospital Clínic, Barcelona, Spain; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Juan José Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Pere Ginès
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Liver Unit, Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Philippe Mathurin
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Pau Sancho-Bru
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain.
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16
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Lotto J, Stephan TL, Hoodless PA. Fetal liver development and implications for liver disease pathogenesis. Nat Rev Gastroenterol Hepatol 2023; 20:561-581. [PMID: 37208503 DOI: 10.1038/s41575-023-00775-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2023] [Indexed: 05/21/2023]
Abstract
The metabolic, digestive and homeostatic roles of the liver are dependent on proper crosstalk and organization of hepatic cell lineages. These hepatic cell lineages are derived from their respective progenitors early in organogenesis in a spatiotemporally controlled manner, contributing to the liver's specialized and diverse microarchitecture. Advances in genomics, lineage tracing and microscopy have led to seminal discoveries in the past decade that have elucidated liver cell lineage hierarchies. In particular, single-cell genomics has enabled researchers to explore diversity within the liver, especially early in development when the application of bulk genomics was previously constrained due to the organ's small scale, resulting in low cell numbers. These discoveries have substantially advanced our understanding of cell differentiation trajectories, cell fate decisions, cell lineage plasticity and the signalling microenvironment underlying the formation of the liver. In addition, they have provided insights into the pathogenesis of liver disease and cancer, in which developmental processes participate in disease emergence and regeneration. Future work will focus on the translation of this knowledge to optimize in vitro models of liver development and fine-tune regenerative medicine strategies to treat liver disease. In this Review, we discuss the emergence of hepatic parenchymal and non-parenchymal cells, advances that have been made in in vitro modelling of liver development and draw parallels between developmental and pathological processes.
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Affiliation(s)
- Jeremy Lotto
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada
| | - Tabea L Stephan
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada
| | - Pamela A Hoodless
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada.
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada.
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17
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Ayers M, Kosar K, Xue Y, Goel C, Carson M, Lee E, Liu S, Brooks E, Cornuet P, Oertel M, Bhushan B, Nejak-Bowen K. Inhibiting Wnt Signaling Reduces Cholestatic Injury by Disrupting the Inflammatory Axis. Cell Mol Gastroenterol Hepatol 2023; 16:895-921. [PMID: 37579970 PMCID: PMC10616556 DOI: 10.1016/j.jcmgh.2023.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 08/01/2023] [Accepted: 08/04/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND & AIMS β-Catenin, the effector molecule of the Wnt signaling pathway, has been shown to play a crucial role in bile acid homeostasis through direct inhibition of farnesoid X receptor (FXR), which has pleiotropic effects on bile acid homeostasis. We hypothesize that simultaneous suppression of β-catenin signaling and activation of FXR in a mouse model of cholestasis will reduce injury and biliary fibrosis through inhibition of bile acid synthesis. METHODS To induce cholestasis, we performed bile duct ligation (BDL) on wild-type male mice. Eight hours after surgery, mice received FXR agonists obeticholic acid, tropifexor, or GW-4064 or Wnt inhibitor Wnt-C59. Severity of cholestatic liver disease and expression of target genes were evaluated after either 5 days or 12 days of treatment. RESULTS We found that although the FXR agonists worsened BDL-induced injury and necrosis after 5 days, Wnt-C59 did not. After 12 days of BDL, Wnt-C59 treatment, but not GW-4064 treatment, reduced both the number of infarcts and the number of inflammatory cells in liver. RNA sequencing analysis of whole livers revealed a notable suppression of nuclear factor kappa B signaling when Wnt signaling is inhibited. We then analyzed transcriptomic data to identify a cholangiocyte-specific signature in our model and demonstrated that Wnt-C59-treated livers were enriched for genes expressed in quiescent cholangiocytes, whereas genes expressed in activated cholangiocytes were enriched in BDL alone. A similar decrease in biliary injury and inflammation occurred in Mdr2 KO mice treated with Wnt-C59. CONCLUSIONS Inhibiting Wnt signaling suppresses cholangiocyte activation and disrupts the nuclear factor kappa B-dependent inflammatory axis, reducing cholestatic-induced injury.
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Affiliation(s)
- Mary Ayers
- Department of Pediatric Gastroenterology, Hepatology, and Nutrition, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Karis Kosar
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Yuhua Xue
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Chhavi Goel
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Matthew Carson
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Elizabeth Lee
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Silvia Liu
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Eva Brooks
- Duquesne University, Pittsburgh, Pennsylvania
| | - Pamela Cornuet
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Michael Oertel
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Bharat Bhushan
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Kari Nejak-Bowen
- Department of Experimental Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania.
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18
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Chen F, Schönberger K, Tchorz JS. Distinct hepatocyte identities in liver homeostasis and regeneration. JHEP Rep 2023; 5:100779. [PMID: 37456678 PMCID: PMC10339260 DOI: 10.1016/j.jhepr.2023.100779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/27/2023] [Accepted: 04/07/2023] [Indexed: 07/18/2023] Open
Abstract
The process of metabolic liver zonation is spontaneously established by assigning distributed tasks to hepatocytes along the porto-central blood flow. Hepatocytes fulfil critical metabolic functions, while also maintaining hepatocyte mass by replication when needed. Recent technological advances have enabled us to fine-tune our understanding of hepatocyte identity during homeostasis and regeneration. Subsets of hepatocytes have been identified to be more regenerative and some have even been proposed to function like stem cells, challenging the long-standing view that all hepatocytes are similarly capable of regeneration. The latest data show that hepatocyte renewal during homeostasis and regeneration after liver injury is not limited to rare hepatocytes; however, hepatocytes are not exactly the same. Herein, we review the known differences that give individual hepatocytes distinct identities, recent findings demonstrating how these distinct identities correspond to differences in hepatocyte regenerative capacity, and how the plasticity of hepatocyte identity allows for division of labour among hepatocytes. We further discuss how these distinct hepatocyte identities may play a role during liver disease.
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Affiliation(s)
- Feng Chen
- Novartis Institutes for BioMedical Research, Cambridge, MA, United States
| | | | - Jan S. Tchorz
- Novartis Institutes for BioMedical Research, Basel, Switzerland
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19
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Barkin JM, Jin-Smith B, Torok K, Pi L. Significance of CCNs in liver regeneration. J Cell Commun Signal 2023:10.1007/s12079-023-00762-x. [PMID: 37202628 DOI: 10.1007/s12079-023-00762-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/01/2023] [Indexed: 05/20/2023] Open
Abstract
The liver has an inherent regenerative capacity via hepatocyte proliferation after mild-to-modest damage. When hepatocytes exhaust their replicative ability during chronic or severe liver damage, liver progenitor cells (LPC), also termed oval cells (OC) in rodents, are activated in the form of ductular reaction (DR) as an alternative pathway. LPC is often intimately associated with hepatic stellate cells (HSC) activation to promote liver fibrosis. The Cyr61/CTGF/Nov (CCN) protein family consists of six extracellular signaling modulators (CCN1-CCN6) with affinity to a repertoire of receptors, growth factors, and extracellular matrix proteins. Through these interactions, CCN proteins organize microenvironments and modulate cell signalings in a diverse variety of physiopathological processes. In particular, their binding to subtypes of integrin (αvβ5, αvβ3, α6β1, αvβ6, etc.) influences the motility and mobility of macrophages, hepatocytes, HSC, and LPC/OC during liver injury. This paper summarizes the current understanding of the significance of CCN genes in liver regeneration in relation to hepatocyte-driven or LPC/OC-mediated pathways. Publicly available datasets were also searched to compare dynamic levels of CCNs in developing and regenerating livers. These insights not only add to our understanding of the regenerative capability of the liver but also provide potential targets for the pharmacological management of liver repair in the clinical setting. Ccns in liver regeneration Restoring damaged or lost tissues requires robust cell growth and dynamic matrix remodeling. Ccns are matricellular proteins highly capable of influencing cell state and matrix production. Current studies have identified Ccns as active players in liver regeneration. Cell types, modes of action, and mechanisms of Ccn induction may vary depending on liver injuries. Hepatocyte proliferation is a default pathway for liver regeneration following mild-to-modest damages, working in parallel with the transient activation of stromal cells, such as macrophages and hepatic stellate cells (HSC). Liver progenitor cells (LPC), also termed oval cells (OC) in rodents, are activated in the form of ductular reaction (DR) and are associated with sustained fibrosis when hepatocytes lose their proliferative ability in severe or chronic liver damage. Ccns may facilitate both hepatocyte regeneration and LPC/OC repair via various mediators (growth factors, matrix proteins, integrins, etc.) for cell-specific and context-dependent functions.
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Affiliation(s)
- Joshua M Barkin
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Brady Jin-Smith
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Kendle Torok
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Liya Pi
- Department of Pathology, Tulane University, New Orleans, LA, USA.
- Department of Pathology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA.
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20
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Cai X, Tacke F, Guillot A, Liu H. Cholangiokines: undervalued modulators in the hepatic microenvironment. Front Immunol 2023; 14:1192840. [PMID: 37261338 PMCID: PMC10229055 DOI: 10.3389/fimmu.2023.1192840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 05/02/2023] [Indexed: 06/02/2023] Open
Abstract
The biliary epithelial cells, also known as cholangiocytes, line the intra- and extrahepatic bile ducts, forming a barrier between intra- and extra-ductal environments. Cholangiocytes are mostly known to modulate bile composition and transportation. In hepatobiliary diseases, bile duct injury leads to drastic alterations in cholangiocyte phenotypes and their release of soluble mediators, which can vary depending on the original insult and cellular states (quiescence, senescence, or proliferation). The cholangiocyte-secreted cytokines (also termed cholangiokines) drive ductular cell proliferation, portal inflammation and fibrosis, and carcinogenesis. Hence, despite the previous consensus that cholangiocytes are bystanders in liver diseases, their diverse secretome plays critical roles in modulating the intrahepatic microenvironment. This review summarizes recent insights into the cholangiokines under both physiological and pathological conditions, especially as they occur during liver injury-regeneration, inflammation, fibrosis and malignant transformation processes.
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Affiliation(s)
- Xiurong Cai
- Department of Hematology, Oncology and Tumor Immunology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Hanyang Liu
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
- Center of Gastrointestinal Diseases, Changzhou Second People's Hospital, Changzhou Medical Center, Nanjing Medical University, Changzhou, China
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21
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Rüland L, Andreatta F, Massalini S, Chuva de Sousa Lopes S, Clevers H, Hendriks D, Artegiani B. Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss. Nat Commun 2023; 14:2377. [PMID: 37137901 PMCID: PMC10156813 DOI: 10.1038/s41467-023-37951-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 04/06/2023] [Indexed: 05/05/2023] Open
Abstract
Fibrolamellar carcinoma (FLC) is a lethal primary liver cancer, affecting young patients in absence of chronic liver disease. Molecular understanding of FLC tumorigenesis is limited, partly due to the scarcity of experimental models. Here, we CRISPR-engineer human hepatocyte organoids to recreate different FLC backgrounds, including the predominant genetic alteration, the DNAJB1-PRKACA fusion, as well as a recently reported background of FLC-like tumors, encompassing inactivating mutations of BAP1 and PRKAR2A. Phenotypic characterizations and comparisons with primary FLC tumor samples revealed mutant organoid-tumor similarities. All FLC mutations caused hepatocyte dedifferentiation, yet only combined loss of BAP1 and PRKAR2A resulted in hepatocyte transdifferentiation into liver ductal/progenitor-like cells that could exclusively grow in a ductal cell environment. BAP1-mutant hepatocytes represent primed cells attempting to proliferate in this cAMP-stimulating environment, but require concomitant PRKAR2A loss to overcome cell cycle arrest. In all analyses, DNAJB1-PRKACAfus organoids presented with milder phenotypes, suggesting differences between FLC genetic backgrounds, or for example the need for additional mutations, interactions with niche cells, or a different cell-of-origin. These engineered human organoid models facilitate the study of FLC.
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Affiliation(s)
- Laura Rüland
- The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | | | - Simone Massalini
- The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
| | | | - Hans Clevers
- The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands
- Oncode Institute, Utrecht, The Netherlands
- University Medical Center Utrecht, Utrecht, The Netherlands
- Pharma, Research and Early Development (pRED) of F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Delilah Hendriks
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, Utrecht, The Netherlands.
- Oncode Institute, Utrecht, The Netherlands.
| | - Benedetta Artegiani
- The Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands.
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22
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Rizvi F, Lee YR, Diaz-Aragon R, So J, Florentino RM, Smith AR, Everton E, Ostrowska A, Jung K, Tam Y, Muramatsu H, Pardi N, Weissman D, Soto-Gutierrez A, Shin D, Gouon-Evans V. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.17.537186. [PMID: 37131823 PMCID: PMC10153196 DOI: 10.1101/2023.04.17.537186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via non-integrative and safe nucleoside-modified mRNA encapsulated into lipid-nanoparticles (mRNA-LNP) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and reversion of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals novel therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases. Highlights Complementary mouse and zebrafish models of liver injury demonstrate the therapeutic impact of VEGFA-KDR axis activation to harness BEC-driven liver regeneration.VEGFA mRNA LNPs restore two key features of the chronic liver disease in humans such as steatosis and fibrosis.Identification in human cirrhotic ESLD livers of KDR-expressing BECs adjacent to clusters of KDR+ hepatocytes suggesting their BEC origin.KDR-expressing BECs may represent facultative adult progenitor cells, a unique BEC population that has yet been uncovered.
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23
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Aguilar-Bravo B, Ariño S, Blaya D, Pose E, Martinez García de la Torre RA, Latasa MU, Martínez-Sánchez C, Zanatto L, Sererols-Viñas L, Cantallops P, Affo S, Coll M, Thillen X, Dubuquoy L, Avila MA, Argemi JM, Paz AL, Nevzorova YA, Cubero J, Bataller R, Lozano JJ, Ginès P, Mathurin P, Sancho-Bru P. Hepatocyte Dedifferentiation Profiling In Alcohol-Related Liver Disease Identifies CXCR4 As A Driver Of Cell Reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.04.535566. [PMID: 37066245 PMCID: PMC10104068 DOI: 10.1101/2023.04.04.535566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Background and Aims Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocytes markers and showing immature features. However, the mechanisms and the impact of hepatocyte dedifferentiation in liver disease are poorly understood. Methods HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ALD). Hepatocyte- specific overexpression or deletion of CXCR4, and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. Results Here we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness and cancer gene programs. CXCR4 pathway was highly enriched in HB cells, and correlated with disease severity and hepatocyte dedifferentiation. In vitro , CXCR4 was associated with biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. Conclusions This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. Lay summary Here we describe that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis.
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24
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Pu W, Zhu H, Zhang M, Pikiolek M, Ercan C, Li J, Huang X, Han X, Zhang Z, Lv Z, Li Y, Liu K, He L, Liu X, Heim MH, Terracciano LM, Tchorz JS, Zhou B. Bipotent transitional liver progenitor cells contribute to liver regeneration. Nat Genet 2023; 55:651-664. [PMID: 36914834 PMCID: PMC10101857 DOI: 10.1038/s41588-023-01335-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 02/07/2023] [Indexed: 03/16/2023]
Abstract
Following severe liver injury, when hepatocyte-mediated regeneration is impaired, biliary epithelial cells (BECs) can transdifferentiate into functional hepatocytes. However, the subset of BECs with such facultative tissue stem cell potential, as well as the mechanisms enabling transdifferentiation, remains elusive. Here we identify a transitional liver progenitor cell (TLPC), which originates from BECs and differentiates into hepatocytes during regeneration from severe liver injury. By applying a dual genetic lineage tracing approach, we specifically labeled TLPCs and found that they are bipotent, as they either differentiate into hepatocytes or re-adopt BEC fate. Mechanistically, Notch and Wnt/β-catenin signaling orchestrate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively. Together, our study provides functional and mechanistic insights into transdifferentiation-assisted liver regeneration.
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Affiliation(s)
- Wenjuan Pu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Huan Zhu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Mingjun Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Monika Pikiolek
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Caner Ercan
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Jie Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiuzhen Huang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Ximeng Han
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Zhenqian Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Zan Lv
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yan Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Kuo Liu
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Lingjuan He
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Xiuxiu Liu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Markus H Heim
- Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.,Clarunis University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Luigi M Terracciano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IRCCS Humanitas Research Hospital, Milan, Italy
| | - Jan S Tchorz
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. .,Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. .,School of Life Science and Technology, ShanghaiTech University, Shanghai, China. .,New Cornerstone Science Laboratory, Shenzhen, China.
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25
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Yildiz E, El Alam G, Perino A, Jalil A, Denechaud PD, Huber K, Fajas L, Auwerx J, Sorrentino G, Schoonjans K. Hepatic lipid overload triggers biliary epithelial cell activation via E2Fs. eLife 2023; 12:81926. [PMID: 36876915 PMCID: PMC10030116 DOI: 10.7554/elife.81926] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 03/03/2023] [Indexed: 03/07/2023] Open
Abstract
During severe or chronic hepatic injury, biliary epithelial cells (BECs) undergo rapid activation into proliferating progenitors, a crucial step required to establish a regenerative process known as ductular reaction (DR). While DR is a hallmark of chronic liver diseases, including advanced stages of non-alcoholic fatty liver disease (NAFLD), the early events underlying BEC activation are largely unknown. Here, we demonstrate that BECs readily accumulate lipids during high-fat diet feeding in mice and upon fatty acid treatment in BEC-derived organoids. Lipid overload induces metabolic rewiring to support the conversion of adult cholangiocytes into reactive BECs. Mechanistically, we found that lipid overload activates the E2F transcription factors in BECs, which drive cell cycle progression while promoting glycolytic metabolism. These findings demonstrate that fat overload is sufficient to reprogram BECs into progenitor cells in the early stages of NAFLD and provide new insights into the mechanistic basis of this process, revealing unexpected connections between lipid metabolism, stemness, and regeneration.
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Affiliation(s)
- Ece Yildiz
- Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Gaby El Alam
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Alessia Perino
- Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Antoine Jalil
- Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | | | - Katharina Huber
- Center for Integrative Genomics, Université de Lausanne, Lausanne, Switzerland
| | - Lluis Fajas
- Center for Integrative Genomics, Université de Lausanne, Lausanne, Switzerland
- INSERM, Occitanie, Montpellier, France
| | - Johan Auwerx
- Laboratory of Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Giovanni Sorrentino
- Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Kristina Schoonjans
- Laboratory of Metabolic Signaling, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
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26
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Yan ZJ, Chen L, Wang HY. To be or not to be: The double-edged sword roles of liver progenitor cells. Biochim Biophys Acta Rev Cancer 2023; 1878:188870. [PMID: 36842766 DOI: 10.1016/j.bbcan.2023.188870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/11/2023] [Accepted: 01/28/2023] [Indexed: 02/28/2023]
Abstract
Given the liver's remarkable and unique regenerative capacity, researchers have long focused on liver progenitor cells (LPCs) and liver cancer stem cells (LCSCs). LPCs can differentiate into both hepatocytes and cholangiocytes. However, the mechanism underlying cell conversion and its distinct contribution to liver homeostasis and tumorigenesis remain unclear. In this review, we discuss the complicated conversions involving LPCs and LCSCs. As the critical intermediate state in malignant transformation, LPCs play double-edged sword roles. LPCs are not only involved in hepatic wound-healing responses by supplementing liver cells and bile duct cells in the damaged liver but may transform into LCSCs under dysregulation of key signaling pathways, resulting in refractory malignant liver tumors. Because LPC lineages are temporally and spatially dynamic, we discuss crucial LPC subgroups and summarize regulatory factors correlating with the trajectories of LPCs and LCSCs in the liver tumor microenvironment. This review elaborates on the double-edged sword roles of LPCs to help understand the liver's regenerative potential and tumor heterogeneity. Understanding the sources and transformations of LPCs is essential in determining how to exploit their regenerative capacity in the future.
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Affiliation(s)
- Zi-Jun Yan
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China
| | - Lei Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
| | - Hong-Yang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital/National Center for Liver Cancer, Shanghai 200438, PR China; Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer (SMMU), Ministry of Education, Shanghai 200438, PR China; Shanghai Key Laboratory of Hepatobiliary Tumor Biology (EHBH), Shanghai 200438, PR China.
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27
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Huppert SS, Schwartz RE. Multiple Facets of Cellular Homeostasis and Regeneration of the Mammalian Liver. Annu Rev Physiol 2023; 85:469-493. [PMID: 36270290 PMCID: PMC9918695 DOI: 10.1146/annurev-physiol-032822-094134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Liver regeneration occurs in response to diverse injuries and is capable of functionally reestablishing the lost parenchyma. This phenomenon has been known since antiquity, encapsulated in the Greek myth where Prometheus was to be punished by Zeus for sharing the gift of fire with humanity by having an eagle eat his liver daily, only to have the liver regrow back, thus ensuring eternal suffering and punishment. Today, this process is actively leveraged clinically during living donor liver transplantation whereby up to a two-thirds hepatectomy (resection or removal of part of the liver) on a donor is used for transplant to a recipient. The donor liver rapidly regenerates to recover the lost parenchymal mass to form a functional tissue. This astonishing regenerative process and unique capacity of the liver are examined in further detail in this review.
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Affiliation(s)
- Stacey S Huppert
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA;
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Robert E Schwartz
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, USA;
- Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY, USA
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28
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Rezvani M, Vallier L, Guillot A. Modeling Nonalcoholic Fatty Liver Disease in the Dish Using Human-Specific Platforms: Strategies and Limitations. Cell Mol Gastroenterol Hepatol 2023; 15:1135-1145. [PMID: 36740045 PMCID: PMC10031472 DOI: 10.1016/j.jcmgh.2023.01.014] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/27/2023] [Accepted: 01/30/2023] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease affecting multiple cell types of the human liver. The high prevalence of NAFLD and the lack of approved therapies increase the demand for reliable models for the preclinical discovery of drug targets. In the last decade, multiple proof-of-principle studies have demonstrated human-specific NAFLD modeling in the dish. These systems have included technologies based on human induced pluripotent stem cell derivatives, liver tissue section cultures, intrahepatic cholangiocyte organoids, and liver-on-a-chip. These platforms differ in functional maturity, multicellularity, scalability, and spatial organization. Identifying an appropriate model for a specific NAFLD-related research question is challenging. Therefore, we review different platforms for their strengths and limitations in modeling NAFLD. To define the fidelity of the current human in vitro NAFLD models in depth, we define disease hallmarks within the NAFLD spectrum that range from steatosis to severe fibroinflammatory tissue injury. We discuss how the most common methods are efficacious in modeling genetic contributions and aspects of the early NAFLD-related tissue response. We also highlight the shortcoming of current models to recapitulate the complexity of inter-organ crosstalk and the chronic process of liver fibrosis-to-cirrhosis that usually takes decades in patients. Importantly, we provide methodological overviews and discuss implementation hurdles (eg, reproducibility or costs) to help choose the most appropriate NAFLD model for the individual research focus: hepatocyte injury, ductular reaction, cellular crosstalk, or other applications. In sum, we highlight current strategies and deficiencies to model NAFLD in the dish and propose a framework for the next generation of human-specific investigations.
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Affiliation(s)
- Milad Rezvani
- Charité Universitätsmedizin Berlin, Department of Pediatric Gastroenterology, Nephrology and Metabolic Medicine, Berlin, Germany; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Berlin Institute of Health, Center for Regenerative Therapies (BCRT), Berlin, Germany; Berlin Institute of Health, Clinician-Scientist Program, Berlin, Germany
| | - Ludovic Vallier
- Berlin Institute of Health, Center for Regenerative Therapies (BCRT), Berlin, Germany; Max Planck Institute for Molecular Genetics, Berlin, Germany
| | - Adrien Guillot
- Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Department of Hepatology & Gastroenterology, Berlin, Germany.
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29
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Rigual MDM, Sánchez Sánchez P, Djouder N. Is liver regeneration key in hepatocellular carcinoma development? Trends Cancer 2023; 9:140-157. [PMID: 36347768 DOI: 10.1016/j.trecan.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 11/08/2022]
Abstract
The liver is the largest organ of the mammalian body and has the remarkable ability to fully regenerate in order to maintain tissue homeostasis. The adult liver consists of hexagonal lobules, each with a central vein surrounded by six portal triads localized in the lobule border containing distinct parenchymal and nonparenchymal cells. Because the liver is continuously exposed to diverse stress signals, several sophisticated regenerative processes exist to restore its functional status following impairment. However, these stress signals can affect the liver's capacity to regenerate and may lead to the development of hepatocellular carcinoma (HCC), one of the most aggressive liver cancers. Here, we review the mechanisms of hepatic regeneration and their potential to influence HCC development.
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Affiliation(s)
- María Del Mar Rigual
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Paula Sánchez Sánchez
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain.
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30
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Kim M, Rizvi F, Shin D, Gouon-Evans V. Update on Hepatobiliary Plasticity. Semin Liver Dis 2023; 43:13-23. [PMID: 36764306 PMCID: PMC10005859 DOI: 10.1055/s-0042-1760306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
The liver field has been debating for decades the contribution of the plasticity of the two epithelial compartments in the liver, hepatocytes and biliary epithelial cells (BECs), to derive each other as a repair mechanism. The hepatobiliary plasticity has been first observed in diseased human livers by the presence of biphenotypic cells expressing hepatocyte and BEC markers within bile ducts and regenerative nodules or budding from strings of proliferative BECs in septa. These observations are not surprising as hepatocytes and BECs derive from a common fetal progenitor, the hepatoblast, and, as such, they are expected to compensate for each other's loss in adults. To investigate the cell origin of regenerated cell compartments and associated molecular mechanisms, numerous murine and zebrafish models with ability to trace cell fates have been extensively developed. This short review summarizes the clinical and preclinical studies illustrating the hepatobiliary plasticity and its potential therapeutic application.
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Affiliation(s)
- Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Fatima Rizvi
- Department of Medicine, Gastroenterology Section, Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts
| | - Donghun Shin
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Valerie Gouon-Evans
- Department of Medicine, Gastroenterology Section, Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts
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31
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Oderberg IM, Goessling W. Biliary epithelial cells are facultative liver stem cells during liver regeneration in adult zebrafish. JCI Insight 2023; 8:163929. [PMID: 36625346 PMCID: PMC9870093 DOI: 10.1172/jci.insight.163929] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/22/2022] [Indexed: 01/11/2023] Open
Abstract
The liver is a highly regenerative organ, yet the presence of a dedicated stem cell population remains controversial. Here, we interrogate a severe hepatocyte injury model in adult zebrafish to define that regeneration involves a stem cell population. After near-total hepatocyte ablation, single-cell transcriptomic and high-resolution imaging analyses throughout the entire regenerative timeline reveal that biliary epithelial cells undergo transcriptional and morphological changes to become hepatocytes. As a population, biliary epithelial cells give rise to both hepatocytes and biliary epithelial cells. Biliary epithelial cells proliferate and dedifferentiate to express hepatoblast transcription factors prior to hepatocyte differentiation. This process is characterized by increased MAPK, PI3K, and mTOR signaling, and chemical inhibition of these pathways impairs biliary epithelial cell proliferation and fate conversion. We conclude that, upon severe hepatocyte ablation in the adult liver, biliary epithelial cells act as facultative liver stem cells in an EGFR-PI3K-mTOR-dependent manner.
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Affiliation(s)
- Isaac M. Oderberg
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Wolfram Goessling
- Division of Genetics, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Harvard Stem Cell Institute, Cambridge, Massachusetts USA.,Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts, USA.,Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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32
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Ventura-Cots M, Argemi J, Jones PD, Lackner C, El Hag M, Abraldes JG, Alvarado E, Clemente A, Ravi S, Alves A, Alboraie M, Altamirano J, Barace S, Bosques F, Brown R, Caballeria J, Cabezas J, Carvalhana S, Cortez-Pinto H, Costa A, Degré D, Fernandez-Carrillo C, Ganne-Carrie N, Garcia-Tsao G, Genesca J, Koskinas J, Lanthier N, Louvet A, Lozano JJ, Lucey MR, Masson S, Mathurin P, Mendez-Sanchez N, Miquel R, Moreno C, Mounajjed T, Odena G, Kim W, Sancho-Bru P, Warren Sands R, Szafranska J, Verset L, Schnabl B, Sempoux C, Shah V, Shawcross DL, Stauber RE, Straub BK, Verna E, Tiniakos D, Trépo E, Vargas V, Villanueva C, Woosley JT, Ziol M, Mueller S, Stärkel P, Bataller R. Clinical, histological and molecular profiling of different stages of alcohol-related liver disease. Gut 2022; 71:1856-1866. [PMID: 34992134 PMCID: PMC11034788 DOI: 10.1136/gutjnl-2021-324295] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 12/06/2021] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking. DESIGN Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed. RESULTS Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. CONCLUSIONS Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.
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Affiliation(s)
- Meritxell Ventura-Cots
- Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Josepmaria Argemi
- Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- Liver Unit, Clinica Universitaria de Navarra, Pamplona, Spain
| | - Patricia D Jones
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Carolin Lackner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Mohamed El Hag
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Juan G Abraldes
- Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Edilmar Alvarado
- Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Gastroenterology, Hospital of Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Ana Clemente
- Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- Liver Unit and Digestive Department, H.G.U. Gregorio Marañon, Madrid, Spain
| | - Samhita Ravi
- Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Antonio Alves
- Departament of Pathology, Hospital Prof. Doutor Fernando Fonseca. Instituto de Anatomia Patologica, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal
| | - Mohamed Alboraie
- Department of Internal Medicine, Al-Azhar University, Cairo, Egypt
| | - Jose Altamirano
- Internal Medicine, Hospital Quironsalud Barcelona, Barcelona, Spain
| | - Sergio Barace
- Centro de investigación Médica Aplicada (CIMA), Universidad de Navarra, Hepatology Program, Pamplona, Spain
| | - Francisco Bosques
- Hospital Sant José Tecnológico de Monterrey, Universidad Autonoma de Nuevo Leon, Monterrey, Monterrey, Mexico
| | - Robert Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA
| | - Juan Caballeria
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- Liver Unit, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain
| | - Joaquin Cabezas
- Gastroenterology and Hepatology Department Marques de Valdecilla University Hospital, Valdecilla Research Institute - IDIVAL, Santander, Santander, Spain
| | - Sofia Carvalhana
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Adilia Costa
- Department of Pathology, Hospital Santa Maria, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal
| | - Delphine Degré
- Centre de ressources biologiques (BB-0033-00027) Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Brussels, Belgium
| | - Carlos Fernandez-Carrillo
- Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro, Puerta de Hierro Health Research Institute (IDIPHIM), Madrid, Spain
| | - Nathalie Ganne-Carrie
- Liver Unit, INSERM UMR 1162, Hôpitaux Universitaires Paris Seine Saint-Denis, APHP, Université paris 13 Sorbonne Paris Cité, Paris, France
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University, New Haven, Connecticut. Department of Veterans Affairs Connecticut Healthcare, New Haven, Connecticut, USA
| | - Joan Genesca
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - John Koskinas
- 2nd Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
| | - Nicolas Lanthier
- Service d'Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Bruxelles, Belgium
- Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
| | - Alexandre Louvet
- University of Lille, Inserm, CHU Lille, U1286-INFINITI-Institute for Translational Research in Inflammation, F-590000, Lille, France
| | - Juan José Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Michael R Lucey
- Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Steven Masson
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | - Philippe Mathurin
- University of Lille, Inserm, CHU Lille, U1286-INFINITI-Institute for Translational Research in Inflammation, F-590000, Lille, France
| | - Nahum Mendez-Sanchez
- Liver Research Unit, Medica Sur Clinic & Foundation and Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | - Rosa Miquel
- Liver Histopathology Laboratory, Institute of Liver Studies, Kings College London, London, UK
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme and Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Taofic Mounajjed
- Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota, USA
| | - Gemma Odena
- Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea (the Republic of)
| | - Pau Sancho-Bru
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - R Warren Sands
- Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Justyna Szafranska
- Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Barcelona, Spain
| | - Laurine Verset
- Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
| | - Bern Schnabl
- Medicine, University of California San Diego, La Jolla, California, USA
| | - Christine Sempoux
- Institute of Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Debbie Lindsay Shawcross
- Liver Sciences, James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College, London, UK
| | - Rudolf E Stauber
- Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Beate K Straub
- Institute of Pathology, Universities of Mainz and Heidelberg, Mainz, Germany
| | - Elizabeth Verna
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA
| | - Dina Tiniakos
- Institute of Cellular Medicine, Translational and Clinical Research Institute, Newcastle Univsersity, Newcastle upon Tyne, UK
- Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Eric Trépo
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme and Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Victor Vargas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Càndid Villanueva
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Autonomous University, Barcelona, Spain
| | - John T Woosley
- Pathology Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Marianne Ziol
- Centre de ressources biologiques (BB-0033-00027) Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France
| | - Sebastian Mueller
- Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany
| | - Peter Stärkel
- Service d'Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
| | - Ramon Bataller
- Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Annunziato S, Sun T, Tchorz JS. The RSPO-LGR4/5-ZNRF3/RNF43 module in liver homeostasis, regeneration, and disease. Hepatology 2022; 76:888-899. [PMID: 35006616 DOI: 10.1002/hep.32328] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 12/02/2021] [Accepted: 01/06/2022] [Indexed: 01/05/2023]
Abstract
WNT/β-catenin signaling plays pivotal roles during liver development, homeostasis, and regeneration. Likewise, its deregulation disturbs metabolic liver zonation and is responsible for the development of a large number of hepatic tumors. Liver fibrosis, which has become a major health burden for society and a hallmark of NASH, can also be promoted by WNT/β-catenin signaling. Upstream regulatory mechanisms controlling hepatic WNT/β-catenin activity may constitute targets for the development of novel therapies addressing these life-threatening conditions. The R-spondin (RSPO)-leucine-rich repeat-containing G protein-coupled receptor (LGR) 4/5-zinc and ring finger (ZNRF) 3/ring finger 43 (RNF43) module is fine-tuning WNT/β-catenin signaling in several tissues and is essential for hepatic WNT/β-catenin activity. In this review article, we recapitulate the role of the RSPO-LGR4/5-ZNRF3/RNF43 module during liver development, homeostasis, metabolic zonation, regeneration, and disease. We further discuss the controversy around LGR5 as a liver stem cell marker.
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Affiliation(s)
- Stefano Annunziato
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Tianliang Sun
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Jan S Tchorz
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
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34
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Wang W, Chen D, Wang J, Wen L. Cellular Homeostasis and Repair in the Biliary Tree. Semin Liver Dis 2022; 42:271-282. [PMID: 35672015 DOI: 10.1055/a-1869-7714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
During biliary tree homeostasis, BECs are largely in a quiescent state and their turnover is slow for maintaining normal tissue homeostasis. BTSCs continually replenish new BECs in the luminal surface of EHBDs. In response to various types of biliary injuries, distinct cellular sources, including HPCs, BTSCs, hepatocytes, and BECs, repair or regenerate the injured bile duct. BEC, biliary epithelial cell; BTSC, biliary tree stem/progenitor cell; EHBD, extrahepatic bile ducts; HPC, hepatic progenitor cell.The biliary tree comprises intrahepatic bile ducts and extrahepatic bile ducts lined with epithelial cells known as biliary epithelial cells (BECs). BECs are a common target of various cholangiopathies for which there is an unmet therapeutic need in clinical hepatology. The repair and regeneration of biliary tissue may potentially restore the normal architecture and function of the biliary tree. Hence, the repair and regeneration process in detail, including the replication of existing BECs, expansion and differentiation of the hepatic progenitor cells and biliary tree stem/progenitor cells, and transdifferentiation of the hepatocytes, should be understood. In this paper, we review biliary tree homeostasis, repair, and regeneration and discuss the feasibility of regenerative therapy strategies for cholangiopathy treatment.
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Affiliation(s)
- Wei Wang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Dongfeng Chen
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Jun Wang
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
| | - Liangzhi Wen
- Department of Gastroenterology, Daping Hospital, Army Medical University, Chongqing, China
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35
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Faccioli LA, Dias ML, Paranhos BA, dos Santos Goldenberg RC. Liver cirrhosis: An overview of experimental models in rodents. Life Sci 2022; 301:120615. [DOI: 10.1016/j.lfs.2022.120615] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 02/07/2023]
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Huang R, Zhang X, Gracia-Sancho J, Xie WF. Liver regeneration: Cellular origin and molecular mechanisms. Liver Int 2022; 42:1486-1495. [PMID: 35107210 DOI: 10.1111/liv.15174] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Revised: 12/16/2021] [Accepted: 01/12/2022] [Indexed: 01/11/2023]
Abstract
The liver is known as an organ with high proliferation potential. Clarifying the cellular origin and deepening the understanding of liver regeneration mechanisms will help provide new directions for the treatment of liver disease. With the development and application of lineage tracing technology, the specific distribution and dynamic changes of hepatocyte subpopulations in homeostasis and liver injury have been illustrated. Self-replication of hepatocytes is responsible for the maintenance of liver function and mass under homeostasis. The compensatory proliferation of remaining hepatocytes is the main mechanism of liver regeneration following acute and chronic liver injury. Transdifferentiation between hepatocytes and cholangiocytes has been recognized upon severe chronic liver injury. Wnt/β-catenin, Hippo/YAP and Notch signalling play essential roles in the maintenance of homeostatic liver and hepatocyte-to-cholangiocyte conversion under liver injury. In this review, we summarized the recent studies on cell origin of newly generated hepatocytes and the underlying mechanisms of liver regeneration in homeostasis and liver injury.
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Affiliation(s)
- Ru Huang
- Department of Gastroenterology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xin Zhang
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Unit, IDIBAPS, CIBEREHD, Barcelona, Spain
| | - Wei-Fen Xie
- Department of Gastroenterology, Changzheng Hospital, Naval Medical University, Shanghai, China
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He Q, Cui L, Yuan X, Wang M, Hui L. Cell identity conversion in liver regeneration after injury. Curr Opin Genet Dev 2022; 75:101921. [PMID: 35644120 DOI: 10.1016/j.gde.2022.101921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 04/21/2022] [Accepted: 04/24/2022] [Indexed: 11/03/2022]
Abstract
Cell identity conversion in liver injury is the process that mature cells, specifically hepatocytes or cholangiocytes, convert into cells with other identities, which is found to play a pivotal role in liver regeneration. A better characterization of cell identity conversion will not only facilitate the understanding of liver tissue repair but also the development of novel regenerative therapies. In this review, we discuss the latest advances in cell identity conversion during liver regeneration, including conversions between hepatocytes and cholangiocytes and hepatocyte reprogramming to liver progenitor-like cells. To develop a unified description of cellular states in injury-related liver regeneration, we further propose the quantitative approach to explore cell identity conversion based on the Waddington's landscape.
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Affiliation(s)
- Qiang He
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Lei Cui
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiang Yuan
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China
| | - Mengyao Wang
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Lijian Hui
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China.
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García IC, Villalba JS, Iovino D, Franchi C, Iori V, Pettinato G, Inversini D, Amico F, Ietto G. Liver Trauma: Until When We Have to Delay Surgery? A Review. Life (Basel) 2022; 12:life12050694. [PMID: 35629360 PMCID: PMC9143295 DOI: 10.3390/life12050694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/06/2022] [Accepted: 04/29/2022] [Indexed: 01/09/2023] Open
Abstract
Liver involvement after abdominal blunt trauma must be expected, and in up to 30% of cases, spleen, kidney, and pancreas injuries may coexist. Whenever hemodynamics conditions do not contraindicate the overcoming of the ancient dogma according to which exploratory laparotomy should be performed after every major abdominal trauma, a CT scan has to clarify the liver lesions so as to determine the optimal management strategy. Except for complete vascular avulsion, no liver trauma grade precludes nonoperative management. Every attempt to treat the injured liver by avoiding a strong surgical approach may be considered. Each time, a nonoperative management (NOM) consisting of a basic “wait and see” attitude combined with systemic support and blood replacement are inadequate. Embolization should be considered to stop the bleeding. Percutaneous drainage of collections, endoscopic retrograde cholangiopancreatography (ERCP) with papilla sphincterotomy or stent placement and percutaneous transhepatic biliary drainage (PTBD) may avoid, or at least delay, surgical reconstruction or resection until systemic and hepatic inflammatory remodeling are resolved. The pathophysiological principle sustaining these leanings is based on the opportunity to limit the further release of cell debris fragments acting as damage-associated molecular patterns (DAMPs) and the following stress response associated with the consequent immune suppression after trauma. The main goal will be a faster recovery combined with limited cell death of the liver through the ischemic events that may directly follow the trauma, exacerbated by hemostatic procedures and surgery, in order to reduce the gross distortion of a regenerated liver.
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Affiliation(s)
- Inés Cañas García
- General and Digestive Surgery, Hospital Clínico San Cecilio of Granada, 18002 Granada, Spain;
| | - Julio Santoyo Villalba
- General and Digestive Surgery, Hospital Virgen de Las Nieves of Granada, 18002 Granada, Spain;
| | - Domenico Iovino
- General, Emergency and Transplant Surgery Department, ASST-Settelaghi and University of Insubria, 21100 Varese, Italy; (D.I.); (C.F.); (V.I.); (D.I.)
| | - Caterina Franchi
- General, Emergency and Transplant Surgery Department, ASST-Settelaghi and University of Insubria, 21100 Varese, Italy; (D.I.); (C.F.); (V.I.); (D.I.)
| | - Valentina Iori
- General, Emergency and Transplant Surgery Department, ASST-Settelaghi and University of Insubria, 21100 Varese, Italy; (D.I.); (C.F.); (V.I.); (D.I.)
| | - Giuseppe Pettinato
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA;
| | - Davide Inversini
- General, Emergency and Transplant Surgery Department, ASST-Settelaghi and University of Insubria, 21100 Varese, Italy; (D.I.); (C.F.); (V.I.); (D.I.)
| | - Francesco Amico
- Trauma Service, Department of Surgery, University of Newcastle, Newcastle 2308, Australia;
| | - Giuseppe Ietto
- General, Emergency and Transplant Surgery Department, ASST-Settelaghi and University of Insubria, 21100 Varese, Italy; (D.I.); (C.F.); (V.I.); (D.I.)
- Correspondence: ; Tel.: +39-339-8758024
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Nagao M, Fukuda A, Omatsu M, Namikawa M, Sono M, Fukunaga Y, Masuda T, Araki O, Yoshikawa T, Ogawa S, Masuo K, Goto N, Hiramatsu Y, Muta Y, Tsuda M, Maruno T, Nakanishi Y, Taketo MM, Ferrer J, Tsuruyama T, Nakanuma Y, Taura K, Uemoto S, Seno H. Concurrent Activation of Kras and Canonical Wnt Signaling Induces Premalignant Lesions That Progress to Extrahepatic Biliary Cancer in Mice. Cancer Res 2022; 82:1803-1817. [PMID: 35247892 DOI: 10.1158/0008-5472.can-21-2176] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 12/31/2021] [Accepted: 02/25/2022] [Indexed: 11/16/2022]
Abstract
Biliary cancer has long been known to carry a poor prognosis, yet the molecular pathogenesis of carcinoma of the extrahepatic biliary system and its precursor lesions remains elusive. Here we investigated the role of Kras and canonical Wnt pathways in the tumorigenesis of the extrahepatic bile duct (EHBD) and gall bladder (GB). In mice, concurrent activation of Kras and Wnt pathways induced biliary neoplasms that resembled human intracholecystic papillary-tubular neoplasm (ICPN) and biliary intraepithelial neoplasia (BilIN), putative precursors to invasive biliary cancer. At a low frequency, these lesions progressed to adenocarcinoma in a xenograft model, establishing them as precancerous lesions. Global gene expression analysis revealed increased expression of genes associated with c-Myc and TGFβ pathways in mutant biliary spheroids. Silencing or pharmacologic inhibition of c-Myc suppressed proliferation of mutant biliary spheroids, whereas silencing of Smad4/Tgfbr2 or pharmacologic inhibition of TGFβ signaling increased proliferation of mutant biliary spheroids and cancer formation in vivo. Human ICPNs displayed activated Kras and Wnt signals and c-Myc and TGFβ pathways. Thus, these data provide direct evidence that concurrent activation of the Kras and canonical Wnt pathways results in formation of ICPN and BilIN, which could develop into biliary cancer. SIGNIFICANCE This work shows how dysregulation of canonical cell growth pathways drives precursors to biliary cancers and identifies several molecular vulnerabilities as potential therapeutic targets in these precursors to prevent oncogenic progression.
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Affiliation(s)
- Munemasa Nagao
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Akihisa Fukuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Mayuki Omatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Mio Namikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Makoto Sono
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yuichi Fukunaga
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.,Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Tomonori Masuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Osamu Araki
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Takaaki Yoshikawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Satoshi Ogawa
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Kenji Masuo
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Norihiro Goto
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yukiko Hiramatsu
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yu Muta
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Motoyuki Tsuda
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Takahisa Maruno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Makoto Mark Taketo
- Kitano Hospital, The Tazuke Kofukai Medical Research Institute, Kita-ku, Osaka, Japan.,iACT, Kyoto University Hospital, Sakyo-ku, Kyoto, Japan
| | - Jorge Ferrer
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Spain.,Genetics and Genomics Section, Department of Metabolism, Digestion and Reproduction, National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, Imperial College London, London, United Kingdom
| | - Tatsuaki Tsuruyama
- Department of Drug Discovery Medicine, Medical Innovation Center, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Yasuni Nakanuma
- Department of Diagnostic Pathology, Fukui Prefecture Saiseikai Hospital, Fukui, Japan
| | - Kojiro Taura
- Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepatobiliary Pancreatic Surgery and Transplantation, Department of Surgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
| | - Hiroshi Seno
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan
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Russell JO, Camargo FD. Hippo signalling in the liver: role in development, regeneration and disease. Nat Rev Gastroenterol Hepatol 2022; 19:297-312. [PMID: 35064256 PMCID: PMC9199961 DOI: 10.1038/s41575-021-00571-w] [Citation(s) in RCA: 103] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/14/2021] [Indexed: 02/07/2023]
Abstract
The Hippo signalling pathway has emerged as a major player in many aspects of liver biology, such as development, cell fate determination, homeostatic function and regeneration from injury. The regulation of Hippo signalling is complex, with activation of the pathway by diverse upstream inputs including signals from cellular adhesion, mechanotransduction and crosstalk with other signalling pathways. Pathological activation of the downstream transcriptional co-activators yes-associated protein 1 (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ, encoded by WWTR1), which are negatively regulated by Hippo signalling, has been implicated in multiple aspects of chronic liver disease, such as the development of liver fibrosis and tumorigenesis. Thus, development of pharmacological inhibitors of YAP-TAZ signalling has been an area of great interest. In this Review, we summarize the diverse roles of Hippo signalling in liver biology and highlight areas where outstanding questions remain to be investigated. Greater understanding of the mechanisms of Hippo signalling in liver function should help facilitate the development of novel therapies for the treatment of liver disease.
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Affiliation(s)
- Jacquelyn O Russell
- Stem Cell Program, Boston Children's Hospital, Boston, MA, USA
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA
| | - Fernando D Camargo
- Stem Cell Program, Boston Children's Hospital, Boston, MA, USA.
- Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.
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41
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Holczbauer Á, Wangensteen KJ, Shin S. Cellular origins of regenerating liver and hepatocellular carcinoma. JHEP Rep 2022; 4:100416. [PMID: 35243280 PMCID: PMC8873941 DOI: 10.1016/j.jhepr.2021.100416] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 11/30/2021] [Accepted: 12/02/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant primary cancer arising from the liver and is one of the major causes of cancer-related mortality worldwide. The cellular origin of HCC has been a topic of great interest due to conflicting findings regarding whether it originates in hepatocytes, biliary cells, or facultative stem cells. These cell types all undergo changes during liver injury, and there is controversy about their contribution to regenerative responses in the liver. Most HCCs emerge in the setting of chronic liver injury from viral hepatitis, fatty liver disease, alcohol, and environmental exposures. The injuries are marked by liver parenchymal changes such as hepatocyte regenerative nodules, biliary duct cellular changes, expansion of myofibroblasts that cause fibrosis and cirrhosis, and inflammatory cell infiltration, all of which may contribute to carcinogenesis. Addressing the cellular origin of HCC is the key to identifying the earliest events that trigger it. Herein, we review data on the cells of origin in regenerating liver and HCC and the implications of these findings for prevention and treatment. We also review the origins of childhood liver cancer and other rare cancers of the liver.
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42
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Lin Y, Zhang F, Zhang L, Chen L, Zheng S. Characteristics of SOX9-positive progenitor-like cells during cholestatic liver regeneration in biliary atresia. Stem Cell Res Ther 2022; 13:114. [PMID: 35313986 PMCID: PMC8935712 DOI: 10.1186/s13287-022-02795-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 03/02/2022] [Indexed: 11/16/2022] Open
Abstract
Background The progression of Biliary Atresia (BA) is associated with the number of reactive ductular cells (RDCs) whose heterogeneity in origin and evolution in humans remains unknown. SOX9-positive liver progenitor-like cells (LPLCs) have been shown to participate in RDCs and new hepatocyte formation during cholestatic liver regeneration in an animal model, which implies the possibility that hepatocyte-reprogrammed LPLCs could be a source of RDCs in BA. The present study aimed to elucidate the characteristics of SOX9-positive LPLCs in BA for exploring new possible therapeutic targets by manipulating the bi-differentiation process of LPLCs to prevent disease progression. Methods Twenty-eight patients, including 24 patients with BA and 4 patients with Congenital Choledochal Cyst as the control group, were retrospectively recruited. Liver biopsy samples were classified histologically using a 4-point scale based on fibrosis severity. LPLCs were detected by SOX9 and HNF4A double positive staining. Single immunohistochemistry, double immunohistochemistry, and multiple immunofluorescence staining were used to determine the different cell types and characteristics of LPLCs. Results The prognostic predictors of BA, namely total bile acid (TBA), RDCs, and fibrosis, were correlated to the emergence of LPLCs. SOX9 and HNF4A double-positive LPLCs co-stained rarely with relevant markers of portal hepatic progenitor cells (portal-HPCs), including CK19, CK7, EPCAM, PROM1 (CD133), TROP2, and AFP. Under cholestasis conditions, LPLCs acquired superior proliferation and anti-senescence ability among hepatocytes. Moreover, LPLCs arranged as a pseudo-rosette structure appeared from the periportal parenchyma to the portal region, which implied the differentiation from hepatocyte-reprogrammed LPLCs to RDCs with the progression of cholestasis. Conclusions LPLCs are associated with disease progression and prognostic factors of BA. The bipotent characteristics of LPLCs are different from those of portal-HPCs. As cholestasis progresses, LPLCs appear to gain superior proliferation and anti-senescence ability and continually differentiate to RDCs. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02795-2.
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Affiliation(s)
- Yuting Lin
- Department of Pediatric Surgery, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Fang Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Ludi Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 200031, China
| | - Lian Chen
- Department of Pathology, Children's Hospital of Fudan University, National Children's Medical Center, 399 Wan Yuan Road, Shanghai, 201102, China
| | - Shan Zheng
- Department of Pediatric Surgery, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai Key Laboratory of Birth Defect, and Key Laboratory of Neonatal Disease, Ministry of Health, 399 Wan Yuan Road, Shanghai, 201102, China.
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43
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Hallett JM, Ferreira-Gonzalez S, Man TY, Kilpatrick AM, Esser H, Thirlwell K, Macmillan MT, Rodrigo-Torres D, Dwyer BJ, Gadd VL, Ashmore-Harris C, Lu WY, Thomson JP, Jansen MA, O'Duibhir E, Starkey Lewis PJ, Campana L, Aird RE, Bate TSR, Fraser AR, Campbell JDM, Oniscu GC, Hay DC, Callanan A, Forbes SJ. Human biliary epithelial cells from discarded donor livers rescue bile duct structure and function in a mouse model of biliary disease. Cell Stem Cell 2022; 29:355-371.e10. [PMID: 35245467 PMCID: PMC8900617 DOI: 10.1016/j.stem.2022.02.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 09/20/2021] [Accepted: 02/09/2022] [Indexed: 12/14/2022]
Abstract
Biliary diseases can cause inflammation, fibrosis, bile duct destruction, and eventually liver failure. There are no curative treatments for biliary disease except for liver transplantation. New therapies are urgently required. We have therefore purified human biliary epithelial cells (hBECs) from human livers that were not used for liver transplantation. hBECs were tested as a cell therapy in a mouse model of biliary disease in which the conditional deletion of Mdm2 in cholangiocytes causes senescence, biliary strictures, and fibrosis. hBECs are expandable and phenotypically stable and help restore biliary structure and function, highlighting their regenerative capacity and a potential alternative to liver transplantation for biliary disease.
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Affiliation(s)
- John M Hallett
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Sofia Ferreira-Gonzalez
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Tak Yung Man
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Alastair M Kilpatrick
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Hannah Esser
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Kayleigh Thirlwell
- Tissues, Cells and Advanced Therapeutics Scottish National Blood and Transfusion Service (SNBTS), Research Avenue North, Edinburgh EH14 4BE, UK
| | - Mark T Macmillan
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Daniel Rodrigo-Torres
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Benjamin J Dwyer
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK; Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Kent St., Bentley, Perth 6102, Australia
| | - Victoria L Gadd
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Candice Ashmore-Harris
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Wei-Yu Lu
- Centre for Inflammation Research (CIR), University of Edinburgh, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - John P Thomson
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Cancer, University of Edinburgh, Crewe Road, Edinburgh EH4 2XU, UK
| | - Maurits A Jansen
- Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
| | - Eoghan O'Duibhir
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Philip J Starkey Lewis
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Lara Campana
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Rhona E Aird
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Thomas S R Bate
- Institute or Bioengineering, School of Engineering, University of Edinburgh, Faraday Building Colin Maclaurin Road, Edinburgh EH9 3DW, UK
| | - Alasdair R Fraser
- Tissues, Cells and Advanced Therapeutics Scottish National Blood and Transfusion Service (SNBTS), Research Avenue North, Edinburgh EH14 4BE, UK
| | - John D M Campbell
- Tissues, Cells and Advanced Therapeutics Scottish National Blood and Transfusion Service (SNBTS), Research Avenue North, Edinburgh EH14 4BE, UK
| | - Gabriel C Oniscu
- Edinburgh Transplant Centre, Royal Infirmary of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK; University of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4SA, UK
| | - David C Hay
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK
| | - Anthony Callanan
- Institute or Bioengineering, School of Engineering, University of Edinburgh, Faraday Building Colin Maclaurin Road, Edinburgh EH9 3DW, UK
| | - Stuart J Forbes
- Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK.
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Kou Y, Zheng X, Meng L, Liu M, Xu S, Jing Q, Zhang S, Wang H, Han J, Liu Z, Wei Y, Wang Y. The HVEM-BTLA Immune Checkpoint Restrains Murine Chronic Cholestatic Liver Injury by Regulating the Gut Microbiota. Front Immunol 2022; 13:773341. [PMID: 35185877 PMCID: PMC8854854 DOI: 10.3389/fimmu.2022.773341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 01/18/2022] [Indexed: 11/13/2022] Open
Abstract
The herpes virus entry mediator (HVEM) is an immune checkpoint molecule regulating immune response, but its role in tissue repair remains unclear. Here, we reported that HVEM deficiency aggravated hepatobiliary damage and compromised liver repair after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced injury. A similar phenotype was observed in B and T lymphocyte attenuator (BTLA)-deficient mice. These were correlated with impairment of neutrophil accumulation in the liver after injury. The hepatic neutrophil accumulation was regulated by microbial-derived secondary bile acids. HVEM-deficient mice had reduced ability to deconjugate bile acids during DDC-feeding, suggesting a gut microbiota defect. Consistently, both HVEM and BTLA deficiency had dysregulated intestinal IgA responses targeting the gut microbes. These results suggest that the HVEM-BTLA signaling may restrain liver injury by regulating the gut microbiota.
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Coll M, Ariño S, Mártinez-Sánchez C, Garcia-Pras E, Gallego J, Moles A, Aguilar-Bravo B, Blaya D, Vallverdú J, Rubio-Tomás T, Lozano JJ, Pose E, Graupera I, Fernández-Vidal A, Pol A, Bataller R, Geng JG, Ginès P, Fernandez M, Sancho-Bru P. Ductular reaction promotes intrahepatic angiogenesis through Slit2-Roundabout 1 signaling. Hepatology 2022; 75:353-368. [PMID: 34490644 PMCID: PMC8766889 DOI: 10.1002/hep.32140] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 07/08/2021] [Accepted: 08/06/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND AND AIMS Ductular reaction (DR) expands in chronic liver diseases and correlates with disease severity. Besides its potential role in liver regeneration, DR plays a role in the wound-healing response of the liver, promoting periductular fibrosis and inflammatory cell recruitment. However, there is no information regarding its role in intrahepatic angiogenesis. In the current study we investigated the potential contribution of DR cells to hepatic vascular remodeling during chronic liver disease. APPROACH AND RESULTS In mouse models of liver injury, DR cells express genes involved in angiogenesis. Among angiogenesis-related genes, the expression of Slit2 and its receptor Roundabout 1 (Robo1) was localized in DR cells and neoangiogenic vessels, respectively. The angiogenic role of the Slit2-Robo1 pathway in chronic liver disease was confirmed in ROBO1/2-/+ mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which displayed reduced intrahepatic neovascular density compared to wild-type mice. However, ROBO1/2 deficiency did not affect angiogenesis in partial hepatectomy. In patients with advanced alcohol-associated disease, angiogenesis was associated with DR, and up-regulation of SLIT2-ROBO1 correlated with DR and disease severity. In vitro, human liver-derived organoids produced SLIT2 and induced tube formation of endothelial cells. CONCLUSIONS Overall, our data indicate that DR expansion promotes angiogenesis through the Slit2-Robo1 pathway and recognize DR cells as key players in the liver wound-healing response.
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MESH Headings
- Animals
- Blood Vessels/metabolism
- Chronic Disease
- Disease Progression
- Gene Expression
- Gene Ontology
- Hepatitis, Alcoholic/pathology
- Hepatitis, Alcoholic/physiopathology
- Humans
- Intercellular Signaling Peptides and Proteins/genetics
- Intercellular Signaling Peptides and Proteins/metabolism
- Liver/metabolism
- Liver/physiopathology
- Liver Diseases, Alcoholic/genetics
- Liver Diseases, Alcoholic/metabolism
- Liver Diseases, Alcoholic/pathology
- Liver Diseases, Alcoholic/physiopathology
- Mice
- Neovascularization, Pathologic/genetics
- Neovascularization, Pathologic/pathology
- Neovascularization, Physiologic/genetics
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism
- Organoids
- Patient Acuity
- Receptors, Immunologic/genetics
- Receptors, Immunologic/metabolism
- Signal Transduction/genetics
- Stem Cells
- Up-Regulation
- Vascular Remodeling
- Wound Healing
- Roundabout Proteins
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Affiliation(s)
- Mar Coll
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Silvia Ariño
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Celia Mártinez-Sánchez
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Ester Garcia-Pras
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Javier Gallego
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Anna Moles
- Cell Death and Proliferation, Institute of Biomedical Research of Barcelona, Spanish National Research Council, Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Beatriz Aguilar-Bravo
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Delia Blaya
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Julia Vallverdú
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Teresa Rubio-Tomás
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Juan Jose Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Elisa Pose
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Isabel Graupera
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Andrea Fernández-Vidal
- Cell compartments and Signaling Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
| | - Albert Pol
- Cell compartments and Signaling Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Department of Biomedical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain
| | - Ramón Bataller
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Jian-Guo Geng
- Department of Biologic and Material Sciences, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA
| | - Pere Ginès
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
- Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
| | - Mercedes Fernandez
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
| | - Pau Sancho-Bru
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain
- Medicine department, Faculty of Medicine, University of Barcelona, Barcelona, Catalonia, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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46
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Pu W, Zhou B. Hepatocyte generation in liver homeostasis, repair, and regeneration. CELL REGENERATION (LONDON, ENGLAND) 2022; 11:2. [PMID: 34989894 PMCID: PMC8739411 DOI: 10.1186/s13619-021-00101-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 10/22/2021] [Indexed: 12/29/2022]
Abstract
The liver has remarkable capability to regenerate, employing mechanism to ensure the stable liver-to-bodyweight ratio for body homeostasis. The source of this regenerative capacity has received great attention over the past decade yet still remained controversial currently. Deciphering the sources for hepatocytes provides the basis for understanding tissue regeneration and repair, and also illustrates new potential therapeutic targets for treating liver diseases. In this review, we describe recent advances in genetic lineage tracing studies over liver stem cells, hepatocyte proliferation, and cell lineage conversions or cellular reprogramming. This review will also evaluate the technical strengths and limitations of methods used for studies on hepatocyte generation and cell fate plasticity in liver homeostasis, repair and regeneration.
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Affiliation(s)
- Wenjuan Pu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
- School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
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47
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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48
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Wang J, Hu W, Shen Z, Liu T, Dai W, Shen B, Li X, Wu J, Lu L, Li S, Cai X. Dissecting the single-cell transcriptomeunderlying chronic liver injury. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:1364-1373. [PMID: 34900395 PMCID: PMC8626669 DOI: 10.1016/j.omtn.2021.11.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/17/2021] [Accepted: 11/03/2021] [Indexed: 12/17/2022]
Abstract
Chronic liver disease (CLD) is currently a major health problem worldwide, which is accompanied by chronic liver injury and lack of clinically effective treatment; however, systematic characterization of chronic liver injury procedures at single-cell resolution is lacking. In the present study, we established chronic liver injury mouse models and conducted single-cell RNA sequencing (scRNA-seq), including choline-deficient, ethionine-supplemented (CDE) and 3,5-diethoxycarbonyl 1,4-dihydrocollidinen (DDC) mouse models. We captured in total 16,389 high-quality cells and identified 12 main cell types in scRNA-seq data. Macrophages and endothelial cells are the largest cell populations in our dataset. Transcriptional trajectory analysis revealed different expression patterns of cells between CDE and DDC models and identified potential liver injury markers, such as Ets1, Gda, Itgam, and Sparc. Differential analysis identified 25 and 152 differentially expressed genes in CDE and DDC macrophages, respectively. In addition, 413 genes were detected to exclusively express in specific pseudotime states of macrophages. These genes were found to participate in immune-related biological processes. Further cell-cell communication analysis found extensive receding of cell-cell interactions between different cell types in the liver injury process, especially in the DDC model. Our study characterized the single-cell transcriptional landscape in the process of chronic liver injury, promoting the understanding of the underlying molecular mechanisms and providing candidate clinical strategy for effective intervention of chronic liver diseases.
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Affiliation(s)
- Junjun Wang
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, Chin
| | - Wei Hu
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Zhenyang Shen
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, Chin
| | - Teng Liu
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Weiming Dai
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, Chin
| | - Bo Shen
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, Chin
| | - Xiaoman Li
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, Chin
| | - Jingni Wu
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Lungen Lu
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, Chin
| | - Shengli Li
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
| | - Xiaobo Cai
- Department of Gastroenterology, Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, China
- Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai 201620, Chin
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49
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Campana L, Esser H, Huch M, Forbes S. Liver regeneration and inflammation: from fundamental science to clinical applications. Nat Rev Mol Cell Biol 2021; 22:608-624. [PMID: 34079104 DOI: 10.1038/s41580-021-00373-7] [Citation(s) in RCA: 153] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/20/2021] [Indexed: 02/05/2023]
Abstract
Liver regeneration is a complex process involving the crosstalk of multiple cell types, including hepatocytes, hepatic stellate cells, endothelial cells and inflammatory cells. The healthy liver is mitotically quiescent, but following toxic damage or resection the cells can rapidly enter the cell cycle to restore liver mass and function. During this process of regeneration, epithelial and non-parenchymal cells respond in a tightly coordinated fashion. Recent studies have described the interaction between inflammatory cells and a number of other cell types in the liver. In particular, macrophages can support biliary regeneration, contribute to fibrosis remodelling by repressing hepatic stellate cell activation and improve liver regeneration by scavenging dead or dying cells in situ. In this Review, we describe the mechanisms of tissue repair following damage, highlighting the close relationship between inflammation and liver regeneration, and discuss how recent findings can help design novel therapeutic approaches.
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Affiliation(s)
- Lara Campana
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, The University of Edinburgh, Edinburgh, UK
| | - Hannah Esser
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, The University of Edinburgh, Edinburgh, UK
| | - Meritxell Huch
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Stuart Forbes
- Centre for Regenerative Medicine, Institute of Regeneration and Repair, The University of Edinburgh, Edinburgh, UK.
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50
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Zhou Y, Chen Y, Zhang X, Xu Q, Wu Z, Cao X, Shao M, Shu Y, Lv T, Lu C, Xie M, Wen T, Yang J, Shi Y, Bu H. Brahma-Related Gene 1 Inhibition Prevents Liver Fibrosis and Cholangiocarcinoma by Attenuating Progenitor Expansion. Hepatology 2021; 74:797-815. [PMID: 33650193 DOI: 10.1002/hep.31780] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 01/18/2021] [Accepted: 01/29/2021] [Indexed: 02/05/2023]
Abstract
BACKGROUND AND AIMS Intrahepatic cholangiocarcinoma (iCCA) is closely correlated with hepatic progenitor cell (HPC) expansion and liver fibrosis. Brahma-related gene 1 (Brg1), an enzymatic subunit of the switch/sucrose nonfermentable complex that is critical in stem cell maintenance and tumor promotion, is prominently up-regulated in both HPCs and iCCA; however, its role in this correlation remains undefined. APPROACH AND RESULTS A retrospective cohort study indicated that high Brg1 expression suggests poor prognosis in patients with iCCA. In chronically injured livers induced by a 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet or bile duct ligation surgery, HPCs were dramatically activated, as indicated by their enhanced expression of Brg1 and a subset of stem cell markers; however, Brg1 ablation in HPCs strongly suppressed HPC expansion and liver fibrosis. Furthermore, in a chemically induced iCCA model, inhibition of Brg1 by a specific inhibitor or inducible gene ablation markedly improved histology and suppressed iCCA growth. Mechanistically, in addition to transcriptionally promoting both Wnt receptor genes and target genes, Brg1 was found to bind to the β-catenin/transcription factor 4 transcription complex, suggesting a possible approach for regulation of Wnt/β-catenin signaling. CONCLUSIONS We have demonstrated the function of Brg1 in promoting HPC expansion, liver cirrhosis, and, ultimately, iCCA development in chronically injured livers, which is largely dependent on Wnt/β-catenin signaling. Our data suggest that therapies targeting Brg1-expressing HPCs are promising for the treatment of liver cirrhosis and iCCA.
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Affiliation(s)
- Yongjie Zhou
- Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina.,Laboratory of Liver TransplantationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina
| | - Yuwei Chen
- Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina
| | - Xiaoyun Zhang
- Laboratory of Liver TransplantationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina.,Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Qing Xu
- Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina
| | - Zhenru Wu
- Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina
| | - Xiaoyue Cao
- Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina
| | - Mingyang Shao
- Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina
| | - Yuke Shu
- Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina
| | - Tao Lv
- Laboratory of Liver TransplantationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina.,Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Changli Lu
- Department of PathologyWest China HospitalSichuan UniversityChengduChina
| | - Mingjun Xie
- Department of General SurgeryThe First People's Hospital of YibinYibinChina
| | - Tianfu Wen
- Laboratory of Liver TransplantationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina.,Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Jiayin Yang
- Laboratory of Liver TransplantationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina.,Department of Liver SurgeryWest China HospitalSichuan UniversityChengduChina
| | - Yujun Shi
- Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina.,Laboratory of Liver TransplantationFrontiers Science Center for Disease-Related Molecular NetworkWest China HospitalSichuan UniversityChengduChina
| | - Hong Bu
- Laboratory of PathologyKey Laboratory of Transplant Engineering and ImmunologyNHCWest China HospitalSichuan UniversityChengduChina.,Department of PathologyWest China HospitalSichuan UniversityChengduChina
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