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Sorrentino G. Microenvironmental control of the ductular reaction: balancing repair and disease progression. Cell Death Dis 2025; 16:246. [PMID: 40180915 DOI: 10.1038/s41419-025-07590-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 04/05/2025]
Abstract
The ductular reaction (DR) is a dynamic adaptive cellular response within the liver, triggered by various hepatic insults and characterized by an expansion of dysmorphic biliary epithelial cells and liver progenitors. This complex response presents a dual role, playing a pivotal function in liver regeneration but, paradoxically, contributing to the progression of liver diseases, depending upon specific contextual factors and signaling pathways involved. This comprehensive review aims to offer a holistic perspective on the DR, focusing into its intricate cellular and molecular mechanisms, highlighting its pathological significance, and exploring its potential therapeutic implications. An up-to-date understanding of the DR in the context of different liver injuries is provided, analyzing its contributions to liver regeneration, inflammation, fibrosis, and ultimately carcinogenesis. Moreover, the review highlights the role of multiple microenvironmental factors, including the influence of extracellular matrix, tissue mechanics and the interplay with the intricate hepatic cell ecosystem in shaping the DR's regulation. Finally, in vitro and in vivo experimental models of the DR will be discussed, providing insights into how researchers can study and manipulate this critical cellular response. By comprehensively addressing the multifaceted nature of the DR, this review contributes to a more profound understanding of its pathophysiological role in liver diseases, thus offering potential therapeutic avenues for hepatic disorders and improving patient outcomes.
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Affiliation(s)
- Giovanni Sorrentino
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
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Wang Y, Song W, Feng C, Wu S, Qin Z, Liu T, Ye Y, Huang R, Xie Y, Tang Z, Wang Q, Li T. Multi-omics analysis unveils the predictive value of IGF2BP3/SPHK1 signaling in cancer stem cells for prognosis and immunotherapeutic response in muscle-invasive bladder cancer. J Transl Med 2024; 22:900. [PMID: 39367493 PMCID: PMC11452965 DOI: 10.1186/s12967-024-05685-8] [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: 06/26/2024] [Accepted: 09/06/2024] [Indexed: 10/06/2024] Open
Abstract
BACKGROUND Muscle invasive bladder cancer (MIBC) is a life-threatening malignant tumor characterized by high metastasis rates, poor prognosis, and limited treatment options. Immune checkpoint inhibitors (ICIs) targeting PD-1 and PD-L1 represent an emerging treatment for MIBC immunotherapy. However, the characteristics of patients likely to benefit from immunotherapy remain unclear. METHODS We performed single-cell mass cytometry (CyTOF) analysis of 179,483 single cells to characterize potential immunotherapy-related cancer stem cells (CSCs)-like populations in the tumor microenvironment of 38 MIBC tissues. The upregulated expression of IGF2BP3 in CD274 + ALDH + CSC-like cells, which was associated with poor clinical prognosis, was analyzed by bulk RNA-sequencing data from an in-house cohort. The functional role of IGF2BP3 was determined through cell proliferation, colony formation, cell apoptosis and sphere formation assays. The regulation of SPHK1 expression by IGF2BP3 was investigated using methylated RNA immunoprecipitation sequencing (MeRIP-seq) and bulk RNA-sequencing (bulk RNA-seq). We further utilized single-nucleus RNA sequencing (snRNA-seq) data from 67,988 cells of 25 MIBC tissues and single-cell RNA sequencing (scRNA-seq) data from MIBC patient-derived organoids to characterize the molecular features of bladder cancer cells co-expressing IGF2BP3 and SPHK1. Spatial transcriptomics (ST) and co-detection by indexing (CODEX) analysis were used to describe the spatial distribution and interactions of IGF2BP3 + SPHK1 + bladder cancer cells and immune cells. RESULTS A subset of CD274 + ALDH + CSC-like cells was identified, associating with immunosuppression and low survival rates in MIBC patients. IGF2BP3, an m6A reader gene, was found to be upregulated in the CD274 + ALDH + CSC-like cell population and linked to poor clinical prognosis in MIBC. Knockout of IGF2BP3 dramatically promoted cell apoptosis and reduced cell proliferation in T24 cells. By integrating MeRIP-seq and bulk RNA-seq analyses, we identified SPHK1 served as a substrate for IGF2BP3 in an m6A-dependent manner. Further snRNA-seq, scRNA-seq, ST, and CODEX analysis revealed a closer topographical distance between IGF2BP3 + SPHK1 + bladder cancer cells and exhausted CD8 + T cells, providing one explanation for the superior response to immunotherapy in IGF2BP3 + SPHK1 + bladder cancer cells-enriched patients. Finally, an ICI-associated signature was developed based on the enriched genes of IGF2BP3 + SPHK1 + bladder cancer cells, and its potential ability to predict the response to immunotherapy was validated in two independent immunotherapy cohort. CONCLUSIONS Our study highlighted the critical involvement of the IGF2BP3/SPHK1 signaling in maintaining the stemness of CSCs and promoting MIBC progression. Additionally, these findings suggested that the IGF2BP3/SPHK1 signaling might serve as a biomarker for prognosis and immunotherapy response in MIBC.
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Affiliation(s)
- Yaobang Wang
- Institute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Wuyue Song
- Institute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Chao Feng
- Institute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Shulin Wu
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Zezu Qin
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Tao Liu
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Yu Ye
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Rong Huang
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
| | - Yuanliang Xie
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Department of Urology, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Zhong Tang
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China
- School of Information and Management, Guangxi Medical University, Nanning, Guangxi, China
| | - Qiuyan Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China.
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China.
| | - Tianyu Li
- Institute of Urology and Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
- Department of Urology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
- Guangxi Key Laboratory for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China.
- Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning, Guangxi, China.
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Zhao YX, Zhao HP, Zhao MY, Yu Y, Qi X, Wang JH, Lv J. Latest insights into the global epidemiological features, screening, early diagnosis and prognosis prediction of esophageal squamous cell carcinoma. World J Gastroenterol 2024; 30:2638-2656. [PMID: 38855150 PMCID: PMC11154680 DOI: 10.3748/wjg.v30.i20.2638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 04/26/2024] [Accepted: 05/13/2024] [Indexed: 05/27/2024] Open
Abstract
As a highly invasive carcinoma, esophageal cancer (EC) was the eighth most prevalent malignancy and the sixth leading cause of cancer-related death worldwide in 2020. Esophageal squamous cell carcinoma (ESCC) is the major histological subtype of EC, and its incidence and mortality rates are decreasing globally. Due to the lack of specific early symptoms, ESCC patients are usually diagnosed with advanced-stage disease with a poor prognosis, and the incidence and mortality rates are still high in many countries, especially in China. Therefore, enormous challenges still exist in the management of ESCC, and novel strategies are urgently needed to further decrease the incidence and mortality rates of ESCC. Although the key molecular mechanisms underlying ESCC pathogenesis have not been fully elucidated, certain promising biomarkers are being investigated to facilitate clinical decision-making. With the advent and advancement of high-throughput technologies, such as genomics, proteomics and metabolomics, valuable biomarkers with high sensitivity, specificity and stability could be identified for ESCC. Herein, we aimed to determine the epidemiological features of ESCC in different regions of the world, especially in China, and focused on novel molecular biomarkers associated with ESCC screening, early diagnosis and prognosis prediction.
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Affiliation(s)
- Yi-Xin Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - He-Ping Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Meng-Yao Zhao
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Yan Yu
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Xi Qi
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
| | - Ji-Han Wang
- Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, Shaanxi Province, China
| | - Jing Lv
- Department of Clinical Laboratory, Honghui Hospital, Xi’an Jiaotong University, Xi’an 710054, Shaanxi Province, China
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Faccioli LA, Dias ML, Martins-Santos R, Paredes BD, Takiya CM, dos Santos Goldenberg RC. Resident Liver Stem Cells. RESIDENT STEM CELLS AND REGENERATIVE THERAPY 2024:23-51. [DOI: 10.1016/b978-0-443-15289-4.00015-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Mitaka T, Ichinohe N, Tanimizu N. "Small Hepatocytes" in the Liver. Cells 2023; 12:2718. [PMID: 38067145 PMCID: PMC10705974 DOI: 10.3390/cells12232718] [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: 09/16/2023] [Revised: 11/17/2023] [Accepted: 11/21/2023] [Indexed: 12/18/2023] Open
Abstract
Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I), which are committed progenitor cells that possess a high growth capability and basal hepatocytic functions; type II cells (MH-II), which possess a limited proliferative capability; and type III cells (MH-III), which lose the ability to divide (replicative senescence) and reach the final differentiated state. These subpopulations may explain the liver's development and growth after birth. Generally, small-sized hepatocytes emerge in mammal livers. The cells are characterized by being morphologically identical to hepatocytes except for their size, which is substantially smaller than that of ordinary MHs. We initially discovered small hepatocytes (SHs) in the primary culture of rat hepatocytes. We believe that SHs are derived from MH-I and play a role as hepatocytic progenitors to supply MHs. The population of MH-I (SHs) is distributed in the whole lobules, a part of which possesses a self-renewal capability, and decreases with age. Conversely, injured livers of experimental models and clinical cases showed the emergence of SHs. Studies demonstrate the involvement of SHs in liver regeneration. SHs that appeared in the injured livers are not a pure population but a mixture of two distinct origins, MH-derived and hepatic-stem-cell-derived cells. The predominant cell-derived SHs depend on the proliferative capability of the remaining MHs after the injury. This review will focus on the SHs that appeared in the liver and discuss the significance of SHs in liver regeneration.
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Affiliation(s)
- Toshihiro Mitaka
- Department of Tissue Development and Regeneration, Institute of Regenerative Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (N.I.); (N.T.)
| | - Norihisa Ichinohe
- Department of Tissue Development and Regeneration, Institute of Regenerative Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (N.I.); (N.T.)
| | - Naoki Tanimizu
- Department of Tissue Development and Regeneration, Institute of Regenerative Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan; (N.I.); (N.T.)
- Division of Regenerative Medicine, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
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Liu W, Gao L, Hou X, Feng S, Yan H, Pan H, Zhang S, Yang X, Jiang J, Ye F, Zhao Q, Wei L, Han Z. TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300350. [PMID: 37085918 PMCID: PMC10288241 DOI: 10.1002/advs.202300350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/14/2023] [Indexed: 05/03/2023]
Abstract
The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single-cell RNA (scRNA) sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA sequencing (RNA-seq) and proteomic analyses are also performed on HPC-derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage-derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation-1 (ID1) in HPCs via NF-κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into cancer stem cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC.
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Affiliation(s)
- Wenting Liu
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Lu Gao
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Xiaojuan Hou
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Shiyao Feng
- Department of UrologySecond Affiliated HospitalAnhui Medical UniversityHefei230601P. R. China
| | - Haixin Yan
- Department of UrologySecond Affiliated HospitalAnhui Medical UniversityHefei230601P. R. China
| | - Hongyu Pan
- Department of Hepatic SurgeryThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
| | - Shichao Zhang
- Department of Hepatic SurgeryThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
| | - Xue Yang
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Fei Ye
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
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Meng Q, Wu W, Zhang W, Yuan J, Yang L, Zhang X, Tao K. IL-18BP Improves Early Graft Function and Survival in Lewis-Brown Norway Rat Orthotopic Liver Transplantation Model. Biomolecules 2022; 12:biom12121801. [PMID: 36551229 PMCID: PMC9775331 DOI: 10.3390/biom12121801] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022] Open
Abstract
Interleukin-18 (IL-18) can effectively activate natural killer (NK) cells and induce large concentrations of interferon-γ (IFN-γ). In healthy humans, IL-18 binding protein (IL-18BP) can inhibit the binding of IL-18 to IL-18R and counteract the biological action of IL-18 due to its high concentration and high affinity, thus preventing the production of IFN-γ and inhibiting NK-cell activation. Through previous studies and the phenomena observed by our group in pig-non-human primates (NHPs) liver transplantation experiments, we proposed that the imbalance in IL-18/IL-18BP expression upon transplantation encourages the activation, proliferation, and cytotoxic effects of NK cells, ultimately causing acute vascular rejection of the graft. In this research, we used Lewis-Brown Norway rat orthotopic liver transplantation (OLTx) as a model of acute vascular rejection. AAV8-Il18bp viral vectors as gene delivery vehicles were constructed for gene therapy to overexpress IL-18BP and alleviate NK-cell rejection of the graft after transplantation. The results showed that livers overexpressing IL-18BP had reduced damage and could function longer after transplantation, effectively improving the survival time of the recipients.
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Affiliation(s)
- Qiang Meng
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Weikang Wu
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
- Chinese Education Ministry’s Key Laboratory of Western Resources and Modern Biotechnology, Key Laboratory of Biotechnology Shaanxi Province, College of Life Sciences, Northwest University, Xi’an 710032, China
| | - Juzheng Yuan
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Long Yang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
- Correspondence: (X.Z.); (K.T.)
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
- Correspondence: (X.Z.); (K.T.)
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Lee SH, Yim SY, Jeong YS, Li QX, Kang SH, Sohn BH, Kumar SV, Shin JH, Choi YR, Shim JJ, Kim H, Kim J, Kim S, Guo S, Johnson RL, Kaseb A, Kang KJ, Chun YS, Jang HJ, Lee BG, Woo HG, Ha MJ, Akbani R, Roberts LR, Wheeler DA, Lee JS. Consensus subtypes of hepatocellular carcinoma associated with clinical outcomes and genomic phenotypes. Hepatology 2022; 76:1634-1648. [PMID: 35349735 PMCID: PMC9519807 DOI: 10.1002/hep.32490] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 02/24/2022] [Accepted: 03/12/2022] [Indexed: 01/22/2023]
Abstract
BACKGROUND AND AIMS Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes. APPROACH AND RESULTS By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male predominance) is characterized by prominent β-catenin activation, low miRNA expression, hypomethylation, and high sensitivity to sorafenib. DLP (Differentiated and Low Proliferation) is differentiated with high hepatocyte nuclear factor 4A activity. We also developed and validated a robust predictor of consensus subtype with 100 genes and demonstrated that five subtypes were well conserved in patient-derived xenograft models and cell lines. By analyzing serum proteomic data from the same patients, we further identified potential serum biomarkers that can stratify patients into subtypes. CONCLUSIONS Five HCC subtypes are correlated with genomic phenotypes and clinical outcomes and highly conserved in preclinical models, providing a framework for selecting the most appropriate models for preclinical studies.
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Affiliation(s)
- Sung Hwan Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Yonsei University College of Medicine, Korea
- Division of Hepatobiliary and Pancreas, Department of Surgery, CHA Bundang Medical Center, CHA University, Korea
| | - Sun Young Yim
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Yun Seong Jeong
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Qi-Xiang Li
- Crown Bioscience, Inc., 3375 Scott Blvd, Suite 108, Santa Clara, CA, USA
| | - Sang-Hee Kang
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Surgery, Korea University Guro Hospital, Seoul, Korea
| | - Bo Hwa Sohn
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Shwetha V. Kumar
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ji-Hyun Shin
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - You Rhee Choi
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jae-Jun Shim
- Department of Internal Medicine, School of Medicine, Kyung Hee University, Seoul, Korea
| | - Hayeon Kim
- Department of Pathology, Korea University Guro Hospital, Seoul, Korea
| | - Jihoon Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Shin Kim
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Immunology, School of Medicine, Keimyung University, Daegu, Korea
| | - Sheng Guo
- Crown Bioscience (Suzhou), Inc., 218 Xinhu St, Suzhou, China
| | - Randy L. Johnson
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ahmed Kaseb
- Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Koo Jeong Kang
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Keimyung University Dongsan Medical Center, Daegu, Korea
| | - Yun Shin Chun
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hee Jin Jang
- Division of Thoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
| | - Byoung Gill Lee
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Hyun Goo Woo
- Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea
| | - Min Jin Ha
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Rehan Akbani
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Lewis R. Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - David A. Wheeler
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Ju-Seog Lee
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Wu CC, Lin CJ, Kuo KK, Chen WT, Ker CG, Chai CY, Tsai HP, Yang SF. Correlation between Cancer Stem Cells, Inflammation and Malignant Transformation in a DEN-Induced Model of Hepatic Carcinogenesis. Curr Issues Mol Biol 2022; 44:2879-2886. [PMID: 35877422 PMCID: PMC9324326 DOI: 10.3390/cimb44070198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 06/25/2022] [Accepted: 06/27/2022] [Indexed: 01/10/2023] Open
Abstract
Chronic inflammation and cancer stem cells are known risk factors for tumorigenesis. The aetiology of hepatocellular carcinoma (HCC) involves a multistep pathological process that is characterised by chronic inflammation and hepatocyte damage, but the correlation between HCC, inflammation and cancer stem cells remains unclear. In this study, we examined the role of hepatic progenitor cells in a mouse model of chemical-induced hepatocarcinogenesis to elucidate the relationship between inflammation, malignant transformation and cancer stem cells. We used diethylnitrosamine (DEN) to induce liver tumour and scored for H&E and reticulin staining. We also scored for immunohistochemistry staining for OV-6 expression and analysed the statistical correlation between them. DEN progressively induced inflammation at week 7 (40%, 2/5); week 27 (75%, 6/8); week 33 (62.5%, 5/8); and week 50 (100%, 12/12). DEN progressively induced malignant transformation at week 7 (0%, 0/5); week 27 (87.5%, 7/8); week 33 (100%, 8/8); and week 50 (100%, 12/12). The obtained data showed that DEN progressively induced high-levels of OV-6 expression at week 7 (20%, 1/5); week 27 (37.5%, 3/8); week 33 (50%, 4/8); and week 50 (100%, 12/12). DEN-induced inflammation, malignant transformation and high-level OV-6 expression in hamster liver, as shown above, as well as applying Spearman’s correlation to the data showed that the expression of OV-6 was significantly correlated to inflammation (p = 0.001) and malignant transformation (p < 0.001). There was a significant correlation between the number of cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis in the hamster.
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Affiliation(s)
- Chun-Chieh Wu
- Department of Pathology, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; (C.-C.W.); (C.-Y.C.)
- Department of Pathology, Kaohsiung Medical University Hospital, 100 Tzyou 1st Road, Kaohsiung City 807, Taiwan;
| | - Chien-Ju Lin
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung City 807, Taiwan;
| | - Kong-Kai Kuo
- Division of Hepatobiliary Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan;
| | - Wan-Tzu Chen
- Department of Pathology, Kaohsiung Medical University Hospital, 100 Tzyou 1st Road, Kaohsiung City 807, Taiwan;
| | - Chen-Guo Ker
- Department of Surgery, Yuan’s General Hospital, Kaohsiung City 807, Taiwan;
| | - Chee-Yin Chai
- Department of Pathology, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; (C.-C.W.); (C.-Y.C.)
- Department of Pathology, Kaohsiung Medical University Hospital, 100 Tzyou 1st Road, Kaohsiung City 807, Taiwan;
| | - Hung-Pei Tsai
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung City 807, Taiwan
| | - Sheau-Fang Yang
- Department of Pathology, Faculty of Medicine, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; (C.-C.W.); (C.-Y.C.)
- Department of Pathology, Kaohsiung Medical University Hospital, 100 Tzyou 1st Road, Kaohsiung City 807, Taiwan;
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10
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Qian Y, Shang Z, Gao Y, Wu H, Kong X. Liver Regeneration in Chronic Liver Injuries: Basic and Clinical Applications Focusing on Macrophages and Natural Killer Cells. Cell Mol Gastroenterol Hepatol 2022; 14:971-981. [PMID: 35738473 PMCID: PMC9489753 DOI: 10.1016/j.jcmgh.2022.05.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 04/28/2022] [Accepted: 07/27/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND & AIMS Liver regeneration is a necessary but complex process involving multiple cell types besides hepatocytes. Mechanisms underlying liver regeneration after partial hepatectomy and acute liver injury have been well-described. However, in patients with chronic and severe liver injury, the remnant liver cannot completely restore the liver mass and function, thereby involving liver progenitor-like cells (LPLCs) and various immune cells. RESULTS Macrophages are beneficial to LPLCs proliferation and the differentiation of LPLCs to hepatocytes. Also, cells expressing natural killer (NK) cell markers have been studied in promoting both liver injury and liver regeneration. NK cells can promote LPLC-induced liver regeneration, but the excessive activation of hepatic NK cells may lead to high serum levels of interferon-γ, thus inhibiting liver regeneration. CONCLUSIONS This review summarizes the recent research on 2 important innate immune cells, macrophages and NK cells, in LPLC-induced liver regeneration and the mechanisms of liver regeneration during chronic liver injury, as well as the latest macrophage- and NK cell-based therapies for chronic liver injury. These novel findings can further help identify new treatments for chronic liver injury, saving patients from the pain of liver transplantations.
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Affiliation(s)
- Yihan Qian
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhi Shang
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yueqiu Gao
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hailong Wu
- Shanghai Key Laboratory of Molecular Imaging, Shanghai University of Medicine and Health Sciences, Shanghai, China.
| | - Xiaoni Kong
- Central Laboratory, Department of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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11
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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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12
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Arwinda R, Liem IK, Fatril AE, Oktorina F, Husna FA, Kodariah R, Wuyung PE. CK19 and OV6 Expressions in the Liver of 2-AAF/CCl4 Rat Model. Open Access Maced J Med Sci 2022. [DOI: 10.3889/oamjms.2022.7923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND: Liver regeneration on a chronic liver injury with rat model research is urgent to study the pathology of human chronic diseases. 2-Acetylaminofluorene (2-AAF) and Carbon Tetrachloride (CCl4) can be applied to study about liver regeneration by liver stem cells, known as oval cells. The use of 2-AAF and CCl4 (2-AAF/CCl4) to induce chronic liver injury can lead severe hepatocyte damages and extensive fibrosis.
AIM: to observed the OV6 and CK19 expression in the liver of 2AAF/CCl4 rat model.
METHODS: In this research, a high dose of 2-AAF (10mg/kg) was applied and combined repeatedly with CCl4 (2ml/kg) for 12 weeks. An immunohistochemistry (IHC) procedure by using OV6 and CK19 antibodies was also applied to examine the regeneration of oval cells. Both antibodies expressions were then examined semi-quantitatively according to the expressions percentage of each sample based on the liver zone. We have observed the OV6 and CK19 expressions in every zone, including in portae hepatis area.
RESULTS: The results showed that OV6 and CK19 with the highest expression in the zone I. A significant difference between OV6 and CK19 expressions was revealed in healthy (control group) and 2-AAF/CCl4 groups (both indicating p=0.045). Moreover, a ductular reaction was also found in Zone I and II of the 2-AAF/CCl4.
CONCLUSIONS: We conclude that 2-AAF/CCl4 induced chronic rat liver injury model, could be utilized to investigate the oval cells with OV6 and CK19 expression.
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13
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El-Araby HA, Saber MA, Radwan NM, Taie DM, Adawy NM, Sira AM. SOX9 in biliary atresia: New insight for fibrosis progression. Hepatobiliary Pancreat Dis Int 2021; 20:154-162. [PMID: 33349604 DOI: 10.1016/j.hbpd.2020.12.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 12/01/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Liver fibrosis is a hallmark determinant of morbidity in biliary atresia (BA) even in successfully operated cases. Responsible factors for this rapid progression of fibrosis are not completely defined. Aberrant expression of the transcription factor SOX9 and hepatic progenitor cells (HPCs) proliferation have roles in fibrogenesis in cholestatic disorders. However, they were not investigated sufficiently in BA. We aimed to delineate the relation of SOX9 and HPCs to fibrosis and its progression in BA. METHODS Forty-eight patients with BA who underwent an initial diagnostic liver biopsy (LB) and consequent intraoperative LB were recruited and compared to 28 cases with non-BA cholestasis that had an LB in their diagnostic workup. Liver fibrosis, tissue SOX9 and HPC expressions were studied in both BA and non-BA-cholestasis cases. Liver fibrosis, SOX9, and HPCs' dynamic changes in BA cases were assessed. Relation of fibrosis and its progression to SOX9 and HPCs in BA was assessed. RESULTS SOX9 and HPCs in ductular reaction (DR) form were expressed in 100% of BA and their grades increased significantly in the second biopsy. The rapidly progressive fibrosis in BA, represented by fibrosis grade of the intraoperative LB, correlated significantly to SOX9-DR and HPC-DR at the diagnostic (r = 0.420, P = 0.003 and r = 0.405, P = 0.004, respectively) and the intraoperative (r = 0.460, P = 0.001 and r = 0.467, P = 0.001, respectively) biopsy. On the other hand, fibrosis, SOX9-DR, and HPC-DR were significantly lower in non-BA cases at a comparable age (P < 0.001, P = 0.006, and P = 0.014, respectively). CONCLUSIONS Fibrosis in BA is rapidly progressive within a short time and is significantly correlated to SOX9 and HPCs. Assessment of targeting SOX9 and HPCs on fibrosis progression is warranted.
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Affiliation(s)
- Hanaa Ahmed El-Araby
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Magdy Anwar Saber
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Noha Mohamed Radwan
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Doha Maher Taie
- Department of Pathology, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Nermin Mohamed Adawy
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt
| | - Ahmad Mohamed Sira
- Department of Pediatric Hepatology, Gastroenterology, and Nutrition, National Liver Institute, Menoufia University, 32511 Shebin El-koom, Menoufia, Egypt.
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14
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Wang Z, Faria J, Penning LC, Masereeuw R, Spee B. Tissue-Engineered Bile Ducts for Disease Modeling and Therapy. Tissue Eng Part C Methods 2021; 27:59-76. [PMID: 33267737 DOI: 10.1089/ten.tec.2020.0283] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Recent biotechnical advances in the in vitro culture of cholangiocytes and generation of bioengineered biliary tissue have a high potential for creating biliary tissue to be used for disease modeling, drug screening, and transplantation. For the past few decades, scientists have searched for a source of cholangiocytes, focused on primary cholangiocytes or cholangiocytes derived from hepatocytes or stem cells. At the same time, the development of scaffolds for biliary tissue engineering for transplantation and modeling of cholangiopathies has been explored. In this review, we provide an overview on the current understanding of cholangiocytes sources, the effect of signaling molecules, and transcription factors on cell differentiation, along with the effects of extracellular matrix molecules and scaffolds on bioengineered biliary tissues, and their application in disease modeling and drug screening. Impact statement Over the past few decades, biliary tissue engineering has acquired significant attention, but currently a number of factors hinder this field to eventually generate bioengineered bile ducts that mimic in vivo physiology and are suitable for transplantation. In this review, we present the latest advances with respect to cell source selection, influence of growth factors and scaffolds, and functional characterization, as well as applications in cholangiopathy modeling and drug screening. This review is suited for a broad spectrum of readers, including fundamental liver researchers and clinicians with interest in the current state and application of bile duct engineering and disease modeling.
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Affiliation(s)
- Zhenguo Wang
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.,Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - João Faria
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Louis C Penning
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Rosalinde Masereeuw
- Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands
| | - Bart Spee
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
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15
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16
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Zhou Q, Fan L, Li J. Liver Regeneration and Tissue Engineering. ARTIFICIAL LIVER 2021:73-94. [DOI: 10.1007/978-981-15-5984-6_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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17
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Abstract
Following injury, the liver's epithelial cells regenerate efficiently with rapid proliferation of hepatocytes and biliary cells. However, when proliferation of resident epithelial cells is impaired, alternative regeneration mechanisms can occur. Intricate lineage-tracing strategies and experimental models of regenerative stress have revealed a degree of plasticity between hepatocytes and biliary cells. New technologies such as single-cell omics, in combination with functional studies, will be instrumental to uncover the remaining unknowns in the field. In this review, we evaluate the experimental and clinical evidence for epithelial plasticity in the liver and how this influences the development of therapeutic strategies for chronic liver disease.
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Affiliation(s)
- Victoria L Gadd
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Niya Aleksieva
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Stuart J Forbes
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK.
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18
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So J, Kim A, Lee SH, Shin D. Liver progenitor cell-driven liver regeneration. Exp Mol Med 2020; 52:1230-1238. [PMID: 32796957 PMCID: PMC8080804 DOI: 10.1038/s12276-020-0483-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 06/08/2020] [Accepted: 06/17/2020] [Indexed: 12/28/2022] Open
Abstract
The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver diseases. Hepatocyte-driven liver regeneration that involves the proliferation of preexisting hepatocytes is a primary regeneration mode. On the other hand, liver progenitor cell (LPC)-driven liver regeneration that involves dedifferentiation of biliary epithelial cells or hepatocytes into LPCs, LPC proliferation, and subsequent differentiation of LPCs into hepatocytes is a secondary mode. This secondary mode plays a significant role in liver regeneration when the primary mode does not effectively work, as observed in severe liver injury settings. Thus, promoting LPC-driven liver regeneration may be clinically beneficial to patients with severe liver diseases. In this review, we describe the current understanding of LPC-driven liver regeneration by exploring current knowledge on the activation, origin, and roles of LPCs during regeneration. We also describe animal models used to study LPC-driven liver regeneration, given their potential to further deepen our understanding of the regeneration process. This understanding will eventually contribute to developing strategies to promote LPC-driven liver regeneration in patients with severe liver diseases.
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Affiliation(s)
- Juhoon So
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
| | - Angie Kim
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Seung-Hoon Lee
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Donghun Shin
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
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19
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The Cancer Stem Cell in Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12030684. [PMID: 32183251 PMCID: PMC7140091 DOI: 10.3390/cancers12030684] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 03/11/2020] [Accepted: 03/12/2020] [Indexed: 12/11/2022] Open
Abstract
The recognition of intra-tumoral cellular heterogeneity has given way to the concept of the cancer stem cell (CSC). According to this concept, CSCs are able to self-renew and differentiate into all of the cancer cell lineages present within the tumor, placing the CSC at the top of a hierarchical tree. The observation that these cells—in contrast to bulk tumor cells—are able to exclusively initiate new tumors, initiate metastatic spread and resist chemotherapy implies that CSCs are solely responsible for tumor recurrence and should be therapeutically targeted. Toward this end, dissecting and understanding the biology of CSCs should translate into new clinical therapeutic approaches. In this article, we review the CSC concept in cancer, with a special focus on hepatocellular carcinoma.
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20
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Wu CD, Lee JC, Wu HC, Lee CW, Lin CF, Hsu MC, Lin CT. Preclinical verification of the efficacy by targeting peptide-linked liposomal nanoparticles for hepatocellular carcinoma therapy. Nanobiomedicine (Rij) 2019; 6:1849543519880762. [PMID: 31908670 PMCID: PMC6937529 DOI: 10.1177/1849543519880762] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 09/15/2019] [Indexed: 01/07/2023] Open
Abstract
The purpose of this study was to investigate the efficacy of targeting peptides chemotherapy to overcome adverse event in the conventional chemotherapy for human hepatocellular carcinoma. Previously we reported several cancer-targeting peptides that bind specifically to cancer cells and their vascular endothelia: L-peptide (anti-cancer cell membrane), RLLDTNRPLLPY; SP-94-peptide (anti-hepatoma cell membrane), SFSHHTPILP; PC5-52-peptide (anti-tumor endothelia), SVSVGMKPSPRP; and control peptide, RLLDTNRGGGGG. In this study, these peptides were linked to liposomal iron oxide nanoparticles to localize the targeted tumor cells and endothelia, and to dextran-coated liposomal doxorubicin (L-D) to treat nonobese diabetic severe combined immunodeficient mice bearing hepatoma xenografts. Our results showed that L-peptide-linked liposomal doxorubicin could inhibit tumor growth with very mild adverse events. Use of the control peptide led to a decrease in the xenograft size but also led to marked apoptotic change in the visceral organ. In conclusion, L-peptide-linked liposomal doxorubicin, SP-94-peptide, and PC5-52-peptide can be used for the treatment of hepatoma xenografts in nonobese diabetic severe combined immunodeficient mice with minimal adverse events.
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Affiliation(s)
- Cheng-Der Wu
- Institute and Department of Pathology, National Taiwan University Hospital, Taipei, Republic of China
| | - Jen-Chieh Lee
- Institute and Department of Pathology, National Taiwan University Hospital, Taipei, Republic of China
| | - Hang-Chung Wu
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Republic of China
| | - Chung-Wei Lee
- Department of Medical Imaging and Radiology, National Taiwan University Hospital, Taipei, Republic of China
| | - Chih-Feng Lin
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Republic of China
| | - Ming-Chen Hsu
- Institute and Department of Pathology, National Taiwan University Hospital, Taipei, Republic of China
| | - Chin-Tarng Lin
- Institute and Department of Pathology, National Taiwan University Hospital, Taipei, Republic of China
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21
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Meta-Analysis of Human and Mouse Biliary Epithelial Cell Gene Profiles. Cells 2019; 8:cells8101117. [PMID: 31547151 PMCID: PMC6829476 DOI: 10.3390/cells8101117] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/03/2019] [Accepted: 09/18/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Chronic liver diseases are frequently accompanied with activation of biliary epithelial cells (BECs) that can differentiate into hepatocytes and cholangiocytes, providing an endogenous back-up system. Functional studies on BECs often rely on isolations of an BEC cell population from healthy and/or injured livers. However, a consensus on the characterization of these cells has not yet been reached. The aim of this study was to compare the publicly available transcriptome profiles of human and mouse BECs and to establish gene signatures that can identify quiescent and activated human and mouse BECs. METHODS We used publicly available transcriptome data sets of human and mouse BECs, compared their profiles and analyzed co-expressed genes and pathways. By merging both human and mouse BEC-enriched genes, we obtained a quiescent and activation gene signature and tested them on BEC-like cells and different liver diseases using gene set enrichment analysis. In addition, we identified several genes from both gene signatures to identify BECs in a scRNA sequencing data set. RESULTS Comparison of mouse BEC transcriptome data sets showed that the isolation method and array platform strongly influences their general profile, still most populations are highly enriched in most genes currently associated with BECs. Pathway analysis on human and mouse BECs revealed the KRAS signaling as a new potential pathway in BEC activation. We established a quiescent and activated BEC gene signature that can be used to identify BEC-like cells and detect BEC enrichment in alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) and peribiliary sclerotic livers. Finally, we identified a gene set that can distinguish BECs from other liver cells in mouse and human scRNAseq data. CONCLUSIONS Through a meta-analysis of human and mouse BEC gene profiles we identified new potential pathways in BEC activation and created unique gene signatures for quiescent and activated BECs. These signatures and pathways will help in the further characterization of this progenitor cell type in mouse and human liver development and disease.
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22
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Zhao Y, Zhu J, Shi B, Wang X, Lu Q, Li C, Chen H. The transcription factor LEF1 promotes tumorigenicity and activates the TGF-β signaling pathway in esophageal squamous cell carcinoma. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2019; 38:304. [PMID: 31296250 PMCID: PMC6625065 DOI: 10.1186/s13046-019-1296-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 06/25/2019] [Indexed: 12/28/2022]
Abstract
Background Esophageal squamous cell carcinoma (ESCC) is the most difficult subtype of esophageal cancer to treat due to the paucity of effective targeted therapy. ESCC is believed to arise from cancer stem cells (CSCs) that contribute to metastasis and chemoresistance. Despite advances in diagnosis and treatment, the prognosis of ESCC patients remains poor. Methods In this study, we applied western blot, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry, RNA-Seq analysis, luciferase reporter assay, Chip-qPCR, bioinformatics analysis, and a series of functional assays to show the potential role of LEF1 in regulating esophageal CSCs. Results We found that the overexpression of LEF1 was associated with aberrant clinicopathological characteristics and the poor prognosis of ESCC patients. In addition, the elevated expression of LEF1 and OV6 was significantly associated with aberrant clinicopathological features, and poor patient prognosis. Moreover, the overexpression of LEF1 was observed in esophageal CSCs purified by the magnetic sorting of adherent and spheroidal ESCC cells. The increased level of LEF1 in CSCs facilitated the expression of CSC markers, stem cell-like properties, resistance to chemotherapy, and tumorigenicity and increased the percentage of CSCs in ESCC samples. Conversely, the knockdown of LEF1 significantly diminished the self-renewal properties of ESCC. We showed that LEF1 played an important mechanical role in activating the TGF-β signaling pathway by directly binding to the ID1 gene promoter. A positive association between LEF1 and ID1 expression was also observed in clinical ESCC samples. Conclusion Our results indicate that the overexpression of LEF1 promotes a CSC-like phenotype in and the tumorigenicity of ESCC by activating the TGF-β signaling pathway. The inhibition of LEF1 might therefore be a novel therapeutic target to inactivate CSCs and inhibit tumor progression. Electronic supplementary material The online version of this article (10.1186/s13046-019-1296-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yue Zhao
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Ji Zhu
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Bowen Shi
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Xinyu Wang
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Qijue Lu
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China
| | - Chunguang Li
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
| | - Hezhong Chen
- Department of Thoracic Surgery, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
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Abu Rmilah A, Zhou W, Nelson E, Lin L, Amiot B, Nyberg SL. Understanding the marvels behind liver regeneration. WILEY INTERDISCIPLINARY REVIEWS-DEVELOPMENTAL BIOLOGY 2019; 8:e340. [PMID: 30924280 DOI: 10.1002/wdev.340] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 02/18/2019] [Accepted: 02/22/2019] [Indexed: 02/06/2023]
Abstract
Tissue regeneration is a process by which the remaining cells of an injured organ regrow to offset the missed cells. This field is relatively a new discipline that has been a focus of intense research by clinicians, surgeons, and scientists for decades. It constitutes the cornerstone of tissue engineering, creation of artificial organs, and generation and utilization of therapeutic stem cells to undergo transformation to different types of mature cells. Many medical experts, scientists, biologists, and bioengineers have dedicated their efforts to deeply comprehend the process of liver regeneration, striving for harnessing it to invent new therapies for liver failure. Liver regeneration after partial hepatectomy in rodents has been extensively studied by researchers for many years. It is divided into three important distinctive phases including (a) Initiation or priming phase which includes an overexpression of specific genes to prepare the liver cells for replication, (b) Proliferation phase in which the liver cells undergo a series of cycles of cell division and expansion and finally, (c) termination phase which acts as brake to stop the regenerative process and prevent the liver tissue overgrowth. These events are well controlled by cytokines, growth factors, and signaling pathways. In this review, we describe the function, embryology, and anatomy of human liver, discuss the molecular basis of liver regeneration, elucidate the hepatocyte and cholangiocyte lineages mediating this process, explain the role of hepatic progenitor cells and elaborate the developmental signaling pathways and regulatory molecules required to procure a complete restoration of hepatic lobule. This article is categorized under: Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Signaling Pathways > Global Signaling Mechanisms Gene Expression and Transcriptional Hierarchies > Cellular Differentiation.
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Affiliation(s)
- Anan Abu Rmilah
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Rochester, Minnesota
| | - Wei Zhou
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Rochester, Minnesota
| | - Erek Nelson
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Rochester, Minnesota
| | - Li Lin
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Rochester, Minnesota
| | - Bruce Amiot
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Rochester, Minnesota
| | - Scott L Nyberg
- Department of Surgery, Division of Transplant Surgery, Mayo Clinic, Rochester, Minnesota
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24
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Wang X, Huo B, Liu J, Huang X, Zhang S, Feng T. Hepatitis B virus X reduces hepatocyte apoptosis and promotes cell cycle progression through the Akt/mTOR pathway in vivo. Gene 2019; 691:87-95. [PMID: 30630095 DOI: 10.1016/j.gene.2018.12.054] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/19/2018] [Accepted: 12/27/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis B virus X (HBx), a viral onco-protein encoded by HBV, can promote oncogenesis of HCC. However, the mechanism of HBx in hepatocarcinogenesis is still unclear. In this study, we establish a new mouse model with normal immune system to investigate the role of HBx and its functional mechanisms under normal immune function. The animal model was established by injecting HBx-EGFP-14-19 cells into the hepatic portal vein of KM mice. To verify the mouse model, the expression of HBx in the liver tissue of mice was detected by qRT-PCR, western blotting and immunohistochemistry. The apoptosis index was calculated using the terminal deoxynucleotidyl transferase-dUTP nick-end labeling (TUNEL) assay, and the expression levels of apoptosis-related and cell cycle-related factors were measured. Moreover, expression of proteins in the protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling pathway was detected in HBx-EGFP-14-19 mice with and without use of an Akt inhibitor. The results showed the HBx was successfully overexpressed in liver of KM mice. After overexpressing HBx, the apoptosis index was downregulated in HBx-EGFP-14-19 liver tissue, and the expression levels of caspase-9 and Bad were reduced, but Bcl-xl was increased in HBx-EGFP-14-19 liver tissue. Overexpression of HBx increased the expression of the cyclin-dependent kinase 2 (CDK2), cyclinD1 and cyclinE. Moreover, compared with the low-level HBx group, p-Akt and p-mTOR were increased in the livers of mice with high levels of HBx. However, inactivation of apoptosis by overexpression of HBx was abolished by the treatment with an Akt inhibitor. These results indicate that HBx can induce anti-apoptosis mechanisms in hepatocytes in vivo, which is mediated by the Akt/mTOR signaling pathway.
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Affiliation(s)
- Xue Wang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China; Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China
| | - Bennian Huo
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China; School of Pharmaceutical Science, Chongqing Medical University, Chongqing 400016, China
| | - Jie Liu
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China; School of Pharmaceutical Science, Chongqing Medical University, Chongqing 400016, China
| | - Xin Huang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China; Department of Biochemistry and Molecular Biology, Chongqing Medical University, Chongqing 400016, China
| | - Siyao Zhang
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China; School of Pharmaceutical Science, Chongqing Medical University, Chongqing 400016, China
| | - Tao Feng
- Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing 400016, China; School of Pharmaceutical Science, Chongqing Medical University, Chongqing 400016, China.
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25
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Increased Trimethylation of histone H3K36 associates with biliary differentiation and predicts poor prognosis in resectable hepatocellular carcinoma. PLoS One 2018; 13:e0206261. [PMID: 30356299 PMCID: PMC6200274 DOI: 10.1371/journal.pone.0206261] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 10/09/2018] [Indexed: 12/22/2022] Open
Abstract
INTRODUCTION Trimethylation of histone H3K36 (H3K36me3), an epigenetic marker of transcription-associated histone modification and stem cell regulation, is expressed in a variety of human cancers. This study elucidated the prognostic significance of H3K36me3 in patients with resectable hepatocellular carcinoma (HCC). METHODS Expression of H3K36me3 was retrospectively evaluated through immunohistochemistry in 152 surgically resected primary HCCs. RESULTS In nontumorous liver parenchyma, H3K36Me3 was detected in bile ducts but not in hepatocytes. H3K36me3 was positive in 104 (68.4%) of the HCCs. Positivity for H3K36me3 was associated with high level of serum α-fetoprotein (>200 ng/mL, P = 0.0148), high tumor grade (P = 0.0017), and high tumor stage (P = 0.0008). Patients with H3K36me3-positive tumors were more likely to have lower 5-year disease-free survival and 5-year overall survival than those with H3K36me3-negative tumors (P = 0.0484 and P = 0.0213, respectively). Multivariate analysis showed that H3K36me3 positivity was an independent predictor of high tumor grade (P = 0.0475) and high tumor stage (P = 0.0114) and thus contributed to poor prognosis. Furthermore, H3K36me3 positivity was significantly correlated with the expression of biliary markers cytokeratin 19 (CK19) and hepatocyte nuclear factor 1β (HNF1β) (P < 0.0001 and P = 0.0005, respectively). Combinatorial analysis revealed that CK19 and HNF1β expression individually exerted additive prognostic adverse effects on HCCs with H3K36me3 positivity. CONCLUSIONS Our study indicates that H3K36me3 positivity is associated with the expression of biliary markers and is a crucial predictor of poor prognosis in resectable HCC.
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Rhee H, Kim HY, Choi JH, Woo HG, Yoo JE, Nahm JH, Choi JS, Park YN. Keratin 19 Expression in Hepatocellular Carcinoma Is Regulated by Fibroblast-Derived HGF via a MET-ERK1/2-AP1 and SP1 Axis. Cancer Res 2018; 78:1619-1631. [PMID: 29363547 DOI: 10.1158/0008-5472.can-17-0988] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Revised: 08/12/2017] [Accepted: 01/18/2018] [Indexed: 11/16/2022]
Abstract
Keratin (KRT) 19 is a poor prognostic marker for hepatocellular carcinoma (HCC); however, regulatory mechanisms underlying its expression remain unclear. We have previously reported the presence of fibrous tumor stroma in KRT19-positive HCC, suggesting that cross-talk between cancer-associated fibroblasts (CAF) and tumor epithelial cells could regulate KRT19 expression. This was investigated in this study using an in vitro model of paracrine interaction between HCC cell lines (HepG2, SNU423) and hepatic stellate cells (HSC), a major source of hepatic myofibroblasts. HSCs upregulated transcription and translation of KRT19 in HCC cells via paracrine interactions. Mechanistically, hepatocyte growth factor (HGF) from HSCs activated c-MET and the MEK-ERK1/2 pathway, which upregulated KRT19 expression in HCC cells. Furthermore, AP1 (JUN/FOSL1) and SP1, downstream transcriptional activators of ERK1/2, activated KRT19 expression in HCC cells. In clinical specimens of human HCC (n = 339), HGF and KRT19 protein expression correlated with CAF levels. In addition, HGF or MET protein expression was associated with FOSL1 and KRT19 expression and was found to be a poor prognostic factor. Analysis of data from The Cancer Genome Atlas also revealed KRT19 expression was closely associated with CAF and MET-mediated signaling activities. These results provide insights into the molecular background of KRT19-positive HCC that display an aggressive phenotype.Significance: These findings reveal KRT19 expression in hepatocellular carcinoma is regulated by cross-talk between cancer-associated fibroblasts and HCC cells, illuminating new therapeutic targets for this aggressive disease. Cancer Res; 78(7); 1619-31. ©2018 AACR.
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Affiliation(s)
- Hyungjin Rhee
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Hye-Young Kim
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Ji-Hye Choi
- Department of Physiology, Ajou University School of Medicine, Suwon, Korea
- Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea
| | - Hyun Goo Woo
- Department of Physiology, Ajou University School of Medicine, Suwon, Korea
- Department of Biomedical Science, Graduate School, Ajou University, Suwon, Korea
| | - Jeong Eun Yoo
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Ji Hae Nahm
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea
| | - Jin-Sub Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Korea
| | - Young Nyun Park
- Department of Pathology, Brain Korea 21 PLUS Project for Medical Science, Integrated Genomic Research Center for Metabolic Regulation, Yonsei University College of Medicine, Seoul, Korea.
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
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27
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Kruitwagen HS, Westendorp B, Viebahn CS, Post K, van Wolferen ME, Oosterhoff LA, Egan DA, Delabar JM, Toussaint MJ, Schotanus BA, de Bruin A, Rothuizen J, Penning LC, Spee B. DYRK1A Is a Regulator of S-Phase Entry in Hepatic Progenitor Cells. Stem Cells Dev 2018; 27:133-146. [PMID: 29179659 DOI: 10.1089/scd.2017.0139] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Hepatic progenitor cells (HPCs) are adult liver stem cells that act as second line of defense in liver regeneration. They are normally quiescent, but in case of severe liver damage, HPC proliferation is triggered by external activation mechanisms from their niche. Although several important proproliferative mechanisms have been described, it is not known which key intracellular regulators govern the switch between HPC quiescence and active cell cycle. We performed a high-throughput kinome small interfering RNA (siRNA) screen in HepaRG cells, a HPC-like cell line, and evaluated the effect on proliferation with a 5-ethynyl-2'-deoxyuridine (EdU) incorporation assay. One hit increased the percentage of EdU-positive cells after knockdown: dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A). Although upon DYRK1A silencing, the percentage of EdU- and phosphorylated histone H3 (pH3)-positive cells was increased, and total cell numbers were not increased, possibly through a subsequent delay in cell cycle progression. This phenotype was confirmed with chemical inhibition of DYRK1A using harmine and with primary HPCs cultured as liver organoids. DYRK1A inhibition impaired Dimerization Partner, RB-like, E2F, and multivulva class B (DREAM) complex formation in HPCs and abolished its transcriptional repression on cell cycle progression. To further analyze DYRK1A function in HPC proliferation, liver organoid cultures were established from mBACtgDyrk1A mice, which harbor one extra copy of the murine Dyrk1a gene (Dyrk+++). Dyrk+++ organoids had both a reduced percentage of EdU-positive cells and reduced proliferation compared with wild-type organoids. This study provides evidence for an essential role of DYRK1A as balanced regulator of S-phase entry in HPCs. An exact gene dosage is crucial, as both DYRK1A deficiency and overexpression affect HPC cell cycle progression.
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Affiliation(s)
- Hedwig S Kruitwagen
- 1 Department of Clinical Sciences of Companion Animals, Utrecht University , Utrecht, the Netherlands
| | - Bart Westendorp
- 2 Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University , Utrecht, the Netherlands
| | - Cornelia S Viebahn
- 1 Department of Clinical Sciences of Companion Animals, Utrecht University , Utrecht, the Netherlands
| | - Krista Post
- 1 Department of Clinical Sciences of Companion Animals, Utrecht University , Utrecht, the Netherlands
| | - Monique E van Wolferen
- 1 Department of Clinical Sciences of Companion Animals, Utrecht University , Utrecht, the Netherlands
| | - Loes A Oosterhoff
- 1 Department of Clinical Sciences of Companion Animals, Utrecht University , Utrecht, the Netherlands
| | - David A Egan
- 3 Department of Cell Biology, Centre for Molecular Medicine , UMC Utrecht, Utrecht, the Netherlands
| | - Jean-Maurice Delabar
- 4 Université Paris Diderot , Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205, Paris, France
- 5 Brain & Spine Institute (ICM) CNRS UMR7225 , INSERM UMRS 975, Paris, France
| | - Mathilda J Toussaint
- 2 Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University , Utrecht, the Netherlands
| | - Baukje A Schotanus
- 1 Department of Clinical Sciences of Companion Animals, Utrecht University , Utrecht, the Netherlands
| | - Alain de Bruin
- 2 Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University , Utrecht, the Netherlands
| | - Jan Rothuizen
- 1 Department of Clinical Sciences of Companion Animals, Utrecht University , Utrecht, the Netherlands
| | - Louis C Penning
- 1 Department of Clinical Sciences of Companion Animals, Utrecht University , Utrecht, the Netherlands
| | - Bart Spee
- 1 Department of Clinical Sciences of Companion Animals, Utrecht University , Utrecht, the Netherlands
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28
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Tajul Arifin K, Sulaiman S, Md Saad S, Ahmad Damanhuri H, Wan Ngah WZ, Mohd Yusof YA. Elevation of tumour markers TGF-β, M 2-PK, OV-6 and AFP in hepatocellular carcinoma (HCC)-induced rats and their suppression by microalgae Chlorella vulgaris. BMC Cancer 2017; 17:879. [PMID: 29268718 PMCID: PMC5740965 DOI: 10.1186/s12885-017-3883-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2016] [Accepted: 12/07/2017] [Indexed: 12/24/2022] Open
Abstract
Background Chlorella vulgaris (ChV), a unicellular green algae has been reported to have anticancer and antioxidant effects. The aim of this study was to determine the chemopreventive effect of ChV on liver cancer induced rats by determining the level and expression of several liver tumour markers. Methods Male Wistar rats (200–250 g) were divided into 4 groups according to the diet given: control group (normal diet), ChV group with three different doses (50, 150 and 300 mg/kg body weight), liver cancer- induced group (choline deficient diet + 0.1% ethionine in drinking water or CDE group), and the treatment group (CDE group treated with three different doses of ChV). Rats were killed at 0, 4, 8 and 12 weeks of experiment and blood and tissue samples were taken from all groups for the determination of tumour markers expression alpha-fetoprotein (AFP), transforming growth factor-β (TGF-β), M2-pyruvate kinase (M2-PK) and specific antigen for oval cells (OV-6). Results Serum level of TGF-β increased significantly (p < 0.05) in CDE rats. However, ChV at all doses managed to decrease (p < 0.05) its levels to control values. Expressions of liver tumour markers AFP, TGF-β, M2-PK and OV-6 were significantly higher (p < 0.05) in tissues of CDE rats when compared to control showing an increased number of cancer cells during hepatocarcinogenesis. ChV at all doses reduced their expressions significantly (p < 0.05). Conclusions Chlorella vulgaris has chemopreventive effect by downregulating the expression of tumour markers M2-PK, OV-6, AFP and TGF-β, in HCC-induced rats.
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Affiliation(s)
- Khaizurin Tajul Arifin
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latiff, 56000 Cheras, Kuala Lumpur, Wilayah Persekutuan, Malaysia
| | - Suhaniza Sulaiman
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latiff, 56000 Cheras, Kuala Lumpur, Wilayah Persekutuan, Malaysia
| | - Suhana Md Saad
- Department of Diagnostic & Allied Health Sciences, Faculty of Health & Life Sciences, Management & Science University (MSU), University Drive, Seksyen 13, 40100, Shah Alam, Selangor, Malaysia
| | - Hanafi Ahmad Damanhuri
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latiff, 56000 Cheras, Kuala Lumpur, Wilayah Persekutuan, Malaysia
| | - Wan Zurinah Wan Ngah
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latiff, 56000 Cheras, Kuala Lumpur, Wilayah Persekutuan, Malaysia
| | - Yasmin Anum Mohd Yusof
- Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latiff, 56000 Cheras, Kuala Lumpur, Wilayah Persekutuan, Malaysia.
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Li XF, Chen C, Xiang DM, Qu L, Sun W, Lu XY, Zhou TF, Chen SZ, Ning BF, Cheng Z, Xia MY, Shen WF, Yang W, Wen W, Lee TKW, Cong WM, Wang HY, Ding J. Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance. Hepatology 2017; 66:1934-1951. [PMID: 28714104 DOI: 10.1002/hep.29372] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 06/26/2017] [Accepted: 07/11/2017] [Indexed: 12/11/2022]
Abstract
UNLABELLED The substantial heterogeneity and hierarchical organization in liver cancer support the theory of liver cancer stem cells (LCSCs). However, the relationship between chronic hepatic inflammation and LCSC generation remains obscure. Here, we observed a close correlation between aggravated inflammation and liver progenitor cell (LPC) propagation in the cirrhotic liver of rats exposed to diethylnitrosamine. LPCs isolated from the rat cirrhotic liver initiated subcutaneous liver cancers in nonobese diabetic/severe combined immunodeficient mice, suggesting the malignant transformation of LPCs toward LCSCs. Interestingly, depletion of Kupffer cells in vivo attenuated the LCSC properties of transformed LPCs and suppressed cytokeratin 19/Oval cell 6-positive tumor occurrence. Conversely, LPCs cocultured with macrophages exhibited enhanced LCSC properties. We further demonstrated that macrophage-secreted tumor necrosis factor-α triggered chromosomal instability in LPCs through the deregulation of ubiquitin D and checkpoint kinase 2 and enhanced the self-renewal of LPCs through the tumor necrosis factor receptor 1/Src/signal transducer and activator of transcription 3 pathway, which synergistically contributed to the conversion of LPCs to LCSCs. Clinical investigation revealed that cytokeratin 19/Oval cell 6-positive liver cancer patients displayed a worse prognosis and exhibited superior response to sorafenib treatment. CONCLUSION Our results not only clarify the cellular and molecular mechanisms underlying the inflammation-mediated LCSC generation but also provide a molecular classification for the individualized treatment of liver cancer. (Hepatology 2017;66:1934-1951).
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Affiliation(s)
- Xiao-Feng Li
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Cheng Chen
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Dai-Min Xiang
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,National Center of Liver Cancer, Shanghai, China
| | - Le Qu
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Wen Sun
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Xin-Yuan Lu
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Teng-Fei Zhou
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Shu-Zhen Chen
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Bei-Fang Ning
- Department of Gastroenterology, Changzheng Hospital, Shanghai, China
| | - Zhuo Cheng
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Ming-Yang Xia
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Wei-Feng Shen
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Wen Yang
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Wen Wen
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China
| | - Terence Kin Wah Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong
| | - Wen-Ming Cong
- Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Hong-Yang Wang
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,National Center of Liver Cancer, Shanghai, China
| | - Jin Ding
- The International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai, China.,National Center of Liver Cancer, Shanghai, China
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30
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Bria A, Marda J, Zhou J, Sun X, Cao Q, Petersen BE, Pi L. Hepatic progenitor cell activation in liver repair. LIVER RESEARCH 2017; 1:81-87. [PMID: 29276644 PMCID: PMC5739327 DOI: 10.1016/j.livres.2017.08.002] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The liver possesses an extraordinary ability to regenerate after injury. Hepatocyte-driven liver regeneration is the default pathway in response to mild-to-moderate acute liver damage. When replication of mature hepatocytes is blocked, facultative hepatic progenitor cells (HPCs), also referred to as oval cells (OCs) in rodents, are activated. HPC/OCs have the ability to proliferate clonogenically and differentiate into several lineages including hepatocytes and bile ductal epithelia. This is a conserved liver injury response that has been studied in many species ranging from mammals (rat, mouse, and human) to fish. In addition, improper HPC/OC activation is closely associated with fibrotic responses, characterized by myofibroblast activation and extracellular matrix production, in many chronic liver diseases. Matrix remodeling and metalloprotease activities play an important role in the regulation of HPC/OC proliferation and fibrosis progression. Thus, understanding molecular mechanisms underlying HPC/OC activation has therapeutic implications for rational design of anti-fibrotic therapies.
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Affiliation(s)
| | | | | | | | | | | | - Liya Pi
- Corresponding author. Pediatric Stem Cell Research and Hepatic Disorders, Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA, (L. Pi)
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The Recent Advances on Liver Cancer Stem Cells: Biomarkers, Separation, and Therapy. Anal Cell Pathol (Amst) 2017; 2017:5108653. [PMID: 28819584 PMCID: PMC5551471 DOI: 10.1155/2017/5108653] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 07/05/2017] [Indexed: 12/18/2022] Open
Abstract
As the third major reason of mortality related to cancer in the world, liver cancer is also the fifth most frequent cancer. Unluckily, a majority of patients succumb and relapse though many progresses have been made in detection and therapy of liver cancer. It has been put forward that in liver cancer, cancer stem cells (CSCs) hold main responsibility for the formation, invasion, metastasis, and recurrence of tumor. Strategies that are intended to target liver CSCs are playing a more and more significant role in supervising the development of liver cancer treatment and assessing new therapeutic methods. Herein, a brief review about molecule markers, signal pathways, separation, and treatment on liver cancer stem cells (LCSCs) is provided in this paper.
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Isolation, characterization and cold storage of cells isolated from diseased explanted livers. Int J Artif Organs 2017; 40:294-306. [PMID: 28574111 DOI: 10.5301/ijao.5000594] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2017] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Livers discarded after standard organ retrieval are commonly used as a cell source for hepatocyte transplantation. Due to the scarcity of organ donors, this leads to a shortage of suitable cells for transplantation. Here, the isolation of liver cells from diseased livers removed during liver transplantation is studied and compared to the isolation of cells from liver specimens obtained during partial liver resection. METHODS Hepatocytes from 20 diseased explanted livers (Ex-group) were isolated, cultured and stored at 4°C for up to 48 hours, and compared to hepatocytes isolated from the normal liver tissue of 14 liver lobe resections (Rx-group). The nonparenchymal cell fraction (NPC) was analyzed by flow cytometry to identify potential liver progenitor cells, and OptiPrep™ (Sigma-Aldrich) density gradient centrifugation was used to enrich the progenitor cells for immediate transplantation. RESULTS There were no differences in viability, cell integrity and metabolic activity in cell culture and survival after cold storage when comparing the hepatocytes from the Rx-group and the Ex-group. In some cases, the latter group showed tendencies of increased resistance to isolation and storage procedures. The NPC of the Ex-group livers contained considerably more EpCAM+ and significantly more CD90+ cells than the Rx-group. Progenitor cell enrichment was not sufficient for clinical application. CONCLUSIONS Hepatocytes isolated from diseased explanted livers showed the essential characteristics of being adequate for cell transplantation. Increased numbers of liver progenitor cells can be isolated from diseased explanted livers. These results support the feasibility of using diseased explanted livers as a cell source for liver cell transplantation.
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OV6 + cancer stem cells drive esophageal squamous cell carcinoma progression through ATG7-dependent β-catenin stabilization. Cancer Lett 2017; 391:100-113. [DOI: 10.1016/j.canlet.2017.01.026] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 01/15/2017] [Accepted: 01/17/2017] [Indexed: 12/14/2022]
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Brandi G, De Lorenzo S, Candela M, Pantaleo MA, Bellentani S, Tovoli F, Saccoccio G, Biasco G. Microbiota, NASH, HCC and the potential role of probiotics. Carcinogenesis 2017; 38:231-240. [PMID: 28426878 DOI: 10.1093/carcin/bgx007] [Citation(s) in RCA: 117] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 01/15/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. Clearly identifiable risk factors are lacking in up to 30% of HCC patients and most of these cases are attributed to non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Beyond the known risk factors for NAFLD, the intestinal microbiota, in particular dysbiosis (defined as any change in the composition of the microbiota commonly found in healthy conditions) is emerging as a new factor promoting the development of chronic liver diseases and HCC. Intestinal microbes produce a large array of bioactive molecules from mainly dietary compounds, establishing an intense microbiota-host transgenomic metabolism with a major impact on physiological and pathological conditions. A better knowledge of these 'new' pathways could help unravel the pathogenesis of HCC in NAFLD to devise new prevention strategies. Currently unsettled issues include the relative role of a 'negative microbiota' (in addition to the other known risk factors for NASH) and the putative prevention of NAFLD through modulation of the gut microbiota.
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Affiliation(s)
- Giovanni Brandi
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, Bologna University, 40138 Bologna, Italy
- "G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), Bologna University, via Massarenti 9, 40138 Bologna, Italy
| | - Stefania De Lorenzo
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, Bologna University, 40138 Bologna, Italy
| | - Marco Candela
- Department of Pharmacy and Biotechnology, Bologna University, via Belmeloro 6, 40126 Bologna, Italy
| | - Maria Abbondanza Pantaleo
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, Bologna University, 40138 Bologna, Italy
- "G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), Bologna University, via Massarenti 9, 40138 Bologna, Italy
| | - Stefano Bellentani
- Department of Gastroenterology and Hepatology, Centre Point Clinic, 24e Little Russell Street, Holborn, London WC1A 2HS, UK
| | - Francesco Tovoli
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
| | | | - Guido Biasco
- Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, Bologna University, 40138 Bologna, Italy
- "G. Prodi" Interdepartmental Center for Cancer Research (C.I.R.C.), Bologna University, via Massarenti 9, 40138 Bologna, Italy
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de Jonge J, Olthoff KM. Liver regeneration. BLUMGART'S SURGERY OF THE LIVER, BILIARY TRACT AND PANCREAS, 2-VOLUME SET 2017:93-109.e7. [DOI: 10.1016/b978-0-323-34062-5.00006-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Rogler CE, Bebawee R, Matarlo J, Locker J, Pattamanuch N, Gupta S, Rogler LE. Triple Staining Including FOXA2 Identifies Stem Cell Lineages Undergoing Hepatic and Biliary Differentiation in Cirrhotic Human Liver. J Histochem Cytochem 2016; 65:33-46. [PMID: 27879410 DOI: 10.1369/0022155416675153] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Recent investigations have reported many markers associated with human liver stem/progenitor cells, "oval cells," and identified "niches" in diseased livers where stem cells occur. However, there has remained a need to identify entire lineages of stem cells as they differentiate into bile ducts or hepatocytes. We have used combined immunohistochemical staining for a marker of hepatic commitment and specification (FOXA2 [Forkhead box A2]), hepatocyte maturation (Albumin and HepPar1), and features of bile ducts (CK19 [cytokeratin 19]) to identify lineages of stem cells differentiating toward the hepatocytic or bile ductular compartments of end-stage cirrhotic human liver. We identified large clusters of disorganized, FOXA2 expressing, oval cells in localized liver regions surrounded by fibrotic matrix, designated as "micro-niches." Specific FOXA2-positive cells within the micro-niches organize into primitive duct structures that support both hepatocytic and bile ductular differentiation enabling identification of entire lineages of cells forming the two types of structures. We also detected expression of hsa-miR-122 in primitive ductular reactions expected for hepatocytic differentiation and hsa-miR-23b cluster expression that drives liver cell fate decisions in cells undergoing lineage commitment. Our data establish the foundation for a mechanistic hypothesis on how stem cell lineages progress in specialized micro-niches in cirrhotic end-stage liver disease.
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Affiliation(s)
- Charles E Rogler
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.,Departments of Genetics (CER), Albert Einstein College of Medicine, Bronx, New York.,Departments of Microbiology and Immunology (CER), Albert Einstein College of Medicine, Bronx, New York
| | - Remon Bebawee
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York
| | - Joe Matarlo
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York
| | - Joseph Locker
- Division of Molecular Anatomic Pathology, Department of Pathology, University of Pittsburg, Pittsburg, Pennsylvania (JL)
| | - Nicole Pattamanuch
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.,Montefiore Medical Center, Bronx, New York (NP)
| | - Sanjeev Gupta
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York.,Departments of Pathology (SG), Albert Einstein College of Medicine, Bronx, New York
| | - Leslie E Rogler
- Marion Bessin Liver Research Center, Division of Gastroenterology and Liver Disease, Departments of Medicine (CER, RB, JM, NP, SG, LER), Albert Einstein College of Medicine, Bronx, New York
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Xu W, Wang NR, Wang HF, Feng Q, Deng J, Gong ZQ, Sun J, Lou XL, Yu XF, Zhou L, Hu JP, Huang XF, Qi XQ, Deng YJ, Gong R, Guo Y, Wang MM, Xiao JC, Deng H. Analysis of epithelial-mesenchymal transition markers in the histogenesis of hepatic progenitor cell in HBV-related liver diseases. Diagn Pathol 2016; 11:136. [PMID: 27881141 PMCID: PMC5121942 DOI: 10.1186/s13000-016-0587-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 11/16/2016] [Indexed: 12/27/2022] Open
Abstract
Background The origin and heterogeneity of hepatic progenitor cells (HPCs) remain unclear. This study aimed to investigate the involvement of epithelial-mesenchymal transition (EMT) in the histogenesis of HPCs. Methods Surgical liver specimens from patients with HBV-related hepatitis and cirrhosis were investigated with double immunofluorescence labeling to detect antigens associated with HPCs and EMT. Ductular reactions were subjected to quantitative reverse transcription PCR following isolation by laser capture microdissection. Electron microscopic examination was performed to find an ultrastructural evidence of EMT. Results The number of EpCAM-positive HPCs was proportional to the disease severity. The S100A4 expression of HPCs was firstly observed in mild hepatitis and increased significantly in moderate hepatitis, but decreased in severe hepatitis and cirrhosis. The levels of MMP-2, Twist, and Snail increased in direct proportion to the number of HPCs. Some hepatocytes adjacent to portal tracts in cirrhosis showed positivity for MMP-2. Although CK7 and E-cadherin levels decreased in mild and moderate hepatitis, HPCs re-expressed both of them in severe hepatitis and cirrhosis. However, HPCs expressed neither vimentin nor αSMA. The relative mRNA expression levels of EpCAM and EMT-associated markers supported immunohistochemical results. Electron microscopic examination demonstrated the existence of intercellular junctions among HPCs, cholangiocytes, and intermediate hepatocyte-like cells. Conclusion We provided preliminary evidence for the involvement of EMT in the histogenesis of HPCs from cholangiocytes in HBV-related liver diseases. HPCs may re-transdifferentiate into hepatocytes, and the differentiation direction depends, at least in part, on interactions between HPCs and the surrounding microenvironment, especially the non-resolving inflammation caused by HBV infection.
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Affiliation(s)
- Wei Xu
- Department of General Surgery, Jiangxi Children's Hospital, Nanchang, China
| | - Nong-Rong Wang
- Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China.,Department of Gastroenterology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hua-Feng Wang
- Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Qiong Feng
- Department of Pathology, The Second Affiliated Hospital of Nanchang University, Nanchang, China.,Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, China
| | - Jun Deng
- Emergency Department, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhi-Qiang Gong
- Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, China
| | - Jian Sun
- Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiao-Liang Lou
- Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xue-Feng Yu
- Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Lv Zhou
- Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jin-Ping Hu
- Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiao-Feng Huang
- Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiao-Qing Qi
- Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yan-Juan Deng
- Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Rui Gong
- Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Yan Guo
- Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China
| | - Meng-Meng Wang
- Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jia-Cheng Xiao
- Department of Pathology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.,Department of Pathology, Tenth People's Hospital of Tongji University, Shanghai, China
| | - Huan Deng
- Molecular Medicine and Genetics Center, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China. .,Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, China. .,Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang, China. .,Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, 133 South Guangchang Road, Nanchang, 330006, Jiangxi, China.
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Gajalakshmi P, Majumder S, Viebahn CS, Swaminathan A, Yeoh GC, Chatterjee S. Interleukin-6 secreted by bipotential murine oval liver stem cells induces apoptosis of activated hepatic stellate cells by activating NF-κB-inducible nitric oxide synthase signaling. Biochem Cell Biol 2016; 95:263-272. [PMID: 28177770 DOI: 10.1139/bcb-2016-0011] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Liver fibrosis is now well recognized as the causative factor for increased mortality from complications associated with liver pathologies. Activated hepatic stellate cells (HSCs) play a critical role in the progression of liver fibrosis. Therefore, targeting these activated HSCs to prevent and (or) treat liver disease is a worthwhile approach to explore. In the present in vitro study, we investigated the use of bipotential murine oval liver cells (BMOL) in regulating the functions of activated HSCs to prevent progression of liver fibrosis. We used a conditioned medium-based approach to study the effect of BMOL cells on activated HSC survival and function. Our data showed that BMOL cells block the contraction of activated HSCs by inducing apoptosis of these cells. We demonstrated that BMOL cells secrete soluble factors, such as interleukin-6 (IL-6), which induced apoptosis of activated HSCs. Using both pharmacological and molecular inhibitor approaches, we further identified that IL-6-mediated activation of NF-κB-iNOS-NO-ROS signaling in activated HSCs plays a critical role in BMOL-cell-mediated apoptosis of activated HSCs. Thus, the present study provides an alternative cell-based therapeutic approach to treat liver fibrosis.
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Affiliation(s)
| | - Syamantak Majumder
- b Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada
| | - Cornelia S Viebahn
- c Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Australia
| | - Akila Swaminathan
- a Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, India
| | - George C Yeoh
- c Centre for Medical Research, Harry Perkins Institute of Medical Research, University of Western Australia, Nedlands, Australia
| | - Suvro Chatterjee
- a Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, India.,d Department of Biotechnology, Anna University, Chennai, India
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The Progress and Prospects of Putative Biomarkers for Liver Cancer Stem Cells in Hepatocellular Carcinoma. Stem Cells Int 2016; 2016:7614971. [PMID: 27610139 PMCID: PMC5005617 DOI: 10.1155/2016/7614971] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 06/06/2016] [Accepted: 07/04/2016] [Indexed: 01/30/2023] Open
Abstract
Accumulating evidence suggests that hepatocellular carcinoma (HCC) is organized by liver cancer stem cells (LCSCs), which are a subset of cells with “stem-like” characteristics. Identification of the LCSCs is a fundamental and important problem in HCC research. LCSCs have been investigated by various stem cell biomarkers. There is still lack of consensus regarding the existence of a “global” marker for LCSCs in HCC. In this review article, we summarize the progress and prospects of putative biomarkers for LCSCs in the past decades, which is essential to develop future therapies targeting CSCs and to predict prognosis and curative effect of these therapies.
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40
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Chaudhari P, Tian L, Deshmukh A, Jang YY. Expression kinetics of hepatic progenitor markers in cellular models of human liver development recapitulating hepatocyte and biliary cell fate commitment. Exp Biol Med (Maywood) 2016; 241:1653-62. [PMID: 27390263 DOI: 10.1177/1535370216657901] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Due to the limitations of research using human embryos and the lack of a biological model of human liver development, the roles of the various markers associated with liver stem or progenitor cell potential in humans are largely speculative, and based on studies utilizing animal models and certain patient tissues. Human pluripotent stem cell-based in vitro multistage hepatic differentiation systems may serve as good surrogate models for mimicking normal human liver development, pathogenesis and injury/regeneration studies. Here, we describe the implications of various liver stem or progenitor cell markers and their bipotency (i.e. hepatocytic- and biliary-epithelial cell differentiation), based on the pluripotent stem cell-derived model of human liver development. Future studies using the human cellular model(s) of liver and biliary development will provide more human relevant biological and/or pathological roles of distinct markers expressed in heterogeneous liver stem/progenitor cell populations.
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Affiliation(s)
- Pooja Chaudhari
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21205, USA Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore 21205, USA Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore 21205, USA
| | - Lipeng Tian
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21205, USA
| | - Abhijeet Deshmukh
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21205, USA
| | - Yoon-Young Jang
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore 21205, USA Cellular and Molecular Medicine Graduate Program, Johns Hopkins University School of Medicine, Baltimore 21205, USA Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore 21205, USA
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Mekonnen GA, Ijzer J, Nederbragt H. Tenascin-C in Chronic Canine Hepatitis: Immunohistochemical Localization and Correlation with Necro-Inflammatory Activity, Fibrotic Stage, and Expression of Alpha-Smooth Muscle Actin, Cytokeratin 7, and CD3+ Cells. Vet Pathol 2016; 44:803-13. [DOI: 10.1354/vp.44-6-803] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
During fibrosis, the extracellular matrix (ECM) is continuously remodeled and increases in volume due to the production of various proteins. We studied the distribution of tenascin-C (TN-C) and the correlation of TN-C with the necro-inflammatory activity and expression of alpha–smooth muscle actin (α-SMA), cytokeratin 7 (CK7), and CD3+ T-lymphocytes in canine chronic hepatitis. This was analyzed using immunohistochemistry and semiquantitative scoring. We used 3 groups ( n = 19) of dogs: group 1 ( n = 5) with neonatal hepatitis/lobular dissecting hepatitis (NH/LDH), group 2 ( n = 8) with chronic hepatitis/cirrhosis (CH/CIRR), and group 3 ( n = 6) consisting of healthy animals. In normal livers, TN-C was localized in Disse's space and around bile ducts and blood vessels. In CH/CIRR livers, TN-C was localized at the periphery of the regenerating nodules and was conspicuous in the bridging fibrous bands. In NH/LDH, TN-C was diffusely distributed along the reticular fibers that dissected between single cells or groups of hepatocytes. α-SMA in the normal hepatic parenchyma showed an irregular distribution along the perisinusoidal linings. In other groups, α-SMA was increased in fibrotic septa and perisinusoidal linings. In normal livers, CK7 was positive in bile ducts. In other groups, CK7-expressing cells were conspicuous in the portal-parenchymal interface, the periphery of the regenerative nodules, and the degenerated parenchyma. The pattern of CD3+ lymphocytes was inversely proportional to that of TN-C. These results also showed that TN-C is strongly correlated with increased fibrotic stage, inflammatory activity, and expression of CK7 and α-SMA. TN-C, CK7, and CD3 expression did not differ between diagnostic groups.
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Affiliation(s)
- G. A. Mekonnen
- National Animal Health Research Center, Sebeta, Ethiopia
- Utrecht University, Faculty of Veterinary Medicine, Department of Pathobiology, Division of Pathology, Utrecht, the Netherlands
| | - J. Ijzer
- Utrecht University, Faculty of Veterinary Medicine, Department of Pathobiology, Division of Pathology, Utrecht, the Netherlands
| | - H. Nederbragt
- Utrecht University, Faculty of Veterinary Medicine, Department of Pathobiology, Division of Pathology, Utrecht, the Netherlands
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Hammam OA, Elkhafif N, Attia YM, Mansour MT, Elmazar MM, Abdelsalam RM, Kenawy SA, El-Khatib AS. Wharton's jelly-derived mesenchymal stem cells combined with praziquantel as a potential therapy for Schistosoma mansoni-induced liver fibrosis. Sci Rep 2016; 6:21005. [PMID: 26876222 PMCID: PMC4753476 DOI: 10.1038/srep21005] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 01/12/2016] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is one of the most serious consequences of S. mansoni infection. The aim of the present study was to investigate the potential anti-fibrotic effect of human Wharton’s jelly-derived mesenchymal stem cells (WJMSCs) combined with praziquantel (PZQ) in S. mansoni-infected mice. S. mansoni-infected mice received early (8th week post infection) and late (16th week post infection) treatment with WJMSCs, alone and combined with oral PZQ. At the 10th month post infection, livers were collected for subsequent flow cytometric, histopathological, morphometric, immunohistochemical, gene expression, and gelatin zymographic studies. After transplantation, WJMSCs differentiated into functioning liver-like cells as evidenced by their ability to express human hepatocyte-specific markers. Regression of S. mansoni-induced liver fibrosis was also observed in transplanted groups, as evidenced by histopathological, morphometric, and gelatin zymographic results besides decreased expression of three essential contributors to liver fibrosis in this particular model; alpha smooth muscle actin, collagen-I, and interleukin-13. PZQ additionally enhanced the beneficial effects observed in WJMSCs-treated groups. Our results suggest that combining WJMSCs to PZQ caused better enhancement in S. mansoni-induced liver fibrosis, compared to using each alone.
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Affiliation(s)
- Olfat A Hammam
- Department of Pathology, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza 12411, Egypt
| | - Nagwa Elkhafif
- Department of Electron Microscopy, Theodor Bilharz Research Institute, Warrak El-Hadar, Imbaba, P.O. Box 30, Giza 12411, Egypt
| | - Yasmeen M Attia
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, P.O. Box 43, Cairo 11837, Egypt
| | - Mohamed T Mansour
- Department of Virology and Immunology, Cancer Biology Department, National Cancer Institute, Cairo University, Kasr El-Aini, Cairo 11712, Egypt
| | - Mohamed M Elmazar
- Department of Pharmacology, Faculty of Pharmacy, The British University in Egypt (BUE), El-Sherouk City, P.O. Box 43, Cairo 11837, Egypt
| | - Rania M Abdelsalam
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt
| | - Sanaa A Kenawy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt
| | - Aiman S El-Khatib
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini, Cairo 11562, Egypt
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Zhang P, Zhu X, Wu Y, Hu R, Li D, Du J, Jiao X, He X. Histone deacetylase inhibitors reduce WB-F344 oval cell viability and migration capability by suppressing AKT/mTOR signaling in vitro. Arch Biochem Biophys 2015; 590:1-9. [PMID: 26558695 DOI: 10.1016/j.abb.2015.11.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Revised: 11/03/2015] [Accepted: 11/04/2015] [Indexed: 12/12/2022]
Abstract
Histone deacetylase (HDAC) can blockDNA replication and transcription and altered HDAC expression was associated with tumorigenesis. This study investigated the effects of HDAC inhibitors on hepatic oval cells and aimed to delineate the underlying molecular events. Hepatic oval cells were treated with two different HDAC inhibitors, suberoylanilidehydroxamic acid (SAHA) and trichostatin-A (TSA). Cells were subjected to cell morphology, cell viability, cell cycle, and wound healing assays. The expression of proteins related to both apoptosis and the cell cycle, and proteins of the AKT/mammalian target of rapamycin (mTOR) signaling pathway were analyzed by Western blot. The data showed that HDAC inhibitors reduced oval cell viability and migration capability, and arrested oval cells at the G0/G1 and S phases of the cell cycle, in a dose- and time-dependent manner. HDAC inhibitors altered cell morphology and reduced oval cell viability, and downregulated the expression of PCNA, cyclinD1, c-Myc and Bmi1 proteins, while also suppressing AKT/mTOR and its downstream target activity. In conclusion, this study demonstrates that HDAC inhibitors affect oval cells by suppressing AKT/mTOR signaling.
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Affiliation(s)
- Peng Zhang
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xiaofeng Zhu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ying Wu
- Department of Biostatistics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ronglin Hu
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Dongming Li
- Department of Hepatobiliary Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Jun Du
- Department of Microbial and Biochemical Pharmacy, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Xingyuan Jiao
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
| | - Xiaoshun He
- Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
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Kuo FY, Huang CC, Chen CL, Chuang JH, Riehle K, Swanson PE, Yeh MM. Immunohistochemical characterization of the regenerative compartment in biliary atresia: a comparison between Kasai procedure and transplant cases. Hum Pathol 2015; 46:1633-9. [PMID: 26297252 DOI: 10.1016/j.humpath.2015.07.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2015] [Revised: 06/22/2015] [Accepted: 07/01/2015] [Indexed: 01/24/2023]
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Bremmer F, Ströbel P, Jarry H, Strecker J, Gaisa N, Strauß A, Schweyer S, Radzun HJ, Behnes CL. CK19 is a sensitive marker for yolk sac tumours of the testis. Diagn Pathol 2015; 10:7. [PMID: 25889715 PMCID: PMC4384355 DOI: 10.1186/s13000-015-0243-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 03/04/2015] [Indexed: 01/07/2023] Open
Abstract
Background Malignant germ cell tumours are the most common malignant tumours in young men. They are histologically divided into seminomas and non-seminomas. Non-seminomas are further subdivided into embryonic carcinomas, yolk sac tumours, chorionic carcinomas, and teratomas. For the therapeutic management it is essential to differentiate between these histological subtypes. Methods Investigated cases included normal testis (n = 50), intratubular germ cell neoplasia (n = 25), seminomas (n = 67), embryonic carcinomas (n = 56), yolk sac tumours (n = 29), chorionic carcinomas (n = 2), teratomas (n = 7) and four metastases of YST’s for their CK19 expression. In addition Leydig cell- (n = 10) and Sertoli cell- tumours (n = 4) were included in this study. Results All investigated seminomas, embryonic carcinomas as well as normal testis and intratubular germ cell neoplasias did not express CK19. In contrast, all investigated yolk sac tumours strongly expressed CK19 protein. These findings became also evident in mixed germ cell tumours consisting of embryonic carcinomas and yolk sac tumours, although CK19-expression could also be observed in analysed chorionic carcinomas and epithelial components of teratomas. Conclusion CK19 proved to be a sensitive marker to identify yolk sac tumours of the testis and to distinguish them from other germ cell tumours, especially seminomas and embryonic carcinomas. Virtual slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4075546891400979.
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Affiliation(s)
- Felix Bremmer
- Institute of Pathology, University Medical Center, University of Göttingen, Göttingen, Germany.
| | - Philipp Ströbel
- Institute of Pathology, University Medical Center, University of Göttingen, Göttingen, Germany.
| | - Hubertus Jarry
- University Medical Center, University of Göttingen, Göttingen, Germany.
| | - Jasmin Strecker
- Institute of Pathology, University Medical Center, University of Göttingen, Göttingen, Germany.
| | - Nadine Gaisa
- Institute of Pathology, RWTH Aachen University, Aachen, Germany.
| | - Arne Strauß
- Department of Urology, University Medical Center, University of Göttingen, Göttingen, Germany.
| | | | - Heinz-Joachim Radzun
- Institute of Pathology, University Medical Center, University of Göttingen, Göttingen, Germany.
| | - Carl-Ludwig Behnes
- Institute of Pathology, University Medical Center, University of Göttingen, Göttingen, Germany.
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Best J, Manka P, Syn WK, Dollé L, van Grunsven LA, Canbay A. Role of liver progenitors in liver regeneration. Hepatobiliary Surg Nutr 2015; 4:48-58. [PMID: 25713804 DOI: 10.3978/j.issn.2304-3881.2015.01.16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 01/20/2015] [Indexed: 12/16/2022]
Abstract
During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.
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Affiliation(s)
- Jan Best
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Paul Manka
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Wing-Kin Syn
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Laurent Dollé
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Leo A van Grunsven
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Ali Canbay
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
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Gonzalez-Sanchez E, Vaquero J, Fouassier L, Chignard N. E-cadherin, guardian of liver physiology. Clin Res Hepatol Gastroenterol 2015; 39:3-6. [PMID: 25459993 DOI: 10.1016/j.clinre.2014.09.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 09/26/2014] [Accepted: 09/30/2014] [Indexed: 02/04/2023]
Abstract
E-cadherin is a cell-to-cell adhesion molecule involved in epithelial cell behavior, tissue formation and cancer suppression. In the liver, E-cadherin is expressed by hepatocytes and biliary epithelial cells. However, the exact role of E-cadherin in hepatic pathophysiology remains largely unknown. Recently, specific loss of E-cadherin in liver epithelial cells has been shown to favor periportal fibrosis, periportal inflammation and liver cancer progression, suggesting that E-cadherin is a central liver protector.
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Affiliation(s)
- Ester Gonzalez-Sanchez
- Inserm UMR_S 938, centre de recherche Saint-Antoine, 75012 Paris, France; Sorbonne universités, UPMC, université Paris 06, 75012 Paris, France
| | - Javier Vaquero
- Inserm UMR_S 938, centre de recherche Saint-Antoine, 75012 Paris, France; Sorbonne universités, UPMC, université Paris 06, 75012 Paris, France
| | - Laura Fouassier
- Inserm UMR_S 938, centre de recherche Saint-Antoine, 75012 Paris, France; Sorbonne universités, UPMC, université Paris 06, 75012 Paris, France
| | - Nicolas Chignard
- Inserm UMR_S 938, centre de recherche Saint-Antoine, 75012 Paris, France; Sorbonne universités, UPMC, université Paris 06, 75012 Paris, France.
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Abstract
Cholangiolocellular carcinoma (CoCC) is categorized as a different entity from ordinary intrahepatic cholangiocarcinoma (ICC) due to its unique clinical, radiological and histological features. The lesion is supposed to originate from cholangioles, where hepatic stem/progenitor cells exist. However, the interlobular duct is also speculated to be the origin of CoCC. According to the findings of morphometric and immunohistochemical studies, CoCC closely resembles the interlobular duct. The unique clinical and pathological features of this disease can also be explained by the interlobular duct origin theory. The malignant counterparts of cholangioles and interlobular ducts have been categorized as CoCC to date. In order to differentiate between true CoCC (cholangiole origin) and pseudo-CoCC (interlobular duct origin), assessing the size of the cancer duct, positivity for c-Kit and coexistence of an ordinary ICC component is useful.
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Affiliation(s)
- Fukuo Kondo
- Department of Pathology, Teikyo University Hospital, Japan
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Katoonizadeh A, Poustchi H, Malekzadeh R. Hepatic progenitor cells in liver regeneration: current advances and clinical perspectives. Liver Int 2014; 34:1464-72. [PMID: 24750779 DOI: 10.1111/liv.12573] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Accepted: 04/17/2014] [Indexed: 12/12/2022]
Abstract
When there is a massive loss of hepatocytes and/or an inhibition in the proliferative capacity of the mature hepatocytes, activation of a dormant cell population of resident hepatic progenitor cells (HPCs) occurs. Depending on the type of liver damage HPCs generate new hepatocytes and biliary cells to repopulate the liver placing them as potential candidates for cell therapy in human liver failure. Liver injury specific mechanisms through which HPCs differentiate towards mature epithelial cell types are recently become understood. Such new insights will enable us not only to direct HPCs behaviour for therapeutic purposes, but also to develop clinically feasible methods for in vivo differentiation of other stem cell types towards functional hepatocytes. This review aimed to provide the current improved knowledge of the role of HPCs niche and its signals in directing the behaviour and fate of HPCs and to translate this basic knowledge of HPCs activation/differentiation into its clinical applications.
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Affiliation(s)
- Aezam Katoonizadeh
- Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
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Franchitto A, Onori P, Renzi A, Carpino G, Mancinelli R, Alvaro D, Gaudio E. Recent advances on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. ANNALS OF TRANSLATIONAL MEDICINE 2014; 1:27. [PMID: 25332971 DOI: 10.3978/j.issn.2305-5839.2012.10.03] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 09/10/2012] [Accepted: 10/15/2012] [Indexed: 12/14/2022]
Abstract
Cholangiocytes are epithelial cells lining the biliary epithelium. Cholangiocytes play several key roles in the modification of ductal bile and are also the target cells in chronic cholestatic liver diseases (i.e., cholangiopathies) such as PSC, PBC, polycystic liver disease (PCLD) and cholangiocarcinoma (CCA). During these pathologies, cholangiocytes (which in normal condition are in a quiescent state) begin to proliferate acquiring phenotypes of neuroendocrine cells, and start secreting different cytokines, growth factors, neuropeptides, and hormones to modulate cholangiocytes proliferation and interaction with the surrounding environment, trying to reestablish the balance between proliferation/loss of cholangiocytes for the maintenance of biliary homeostasis. The purpose of this review is to summarize the recent findings on the mechanisms regulating cholangiocyte proliferation and the significance of the neuroendocrine regulation of cholangiocyte pathophysiology. To clarify the mechanisms of action of these factors we will provide new potential strategies for the management of chronic liver diseases.
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Affiliation(s)
- Antonio Franchitto
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Paolo Onori
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Anastasia Renzi
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Guido Carpino
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Romina Mancinelli
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Domenico Alvaro
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
| | - Eugenio Gaudio
- 1 Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, University of Rome "Sapienza", Rome, Italy ; 2 Eleonora Lorillard Spencer-Cenci Foundation, Rome, Italy ; 3 Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy ; 4 Department of Health Science, University of Rome "Foro Italico", Italy ; 5 Department of Medico-Surgical Sciences and Biotechnologies, Polo Pontino, Sapienza, University of Rome "Sapienza", Rome, Italy
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