|
1
|
Tang S, Wu S, Zhang W, Ma L, Zuo L, Wang H. Immunology and treatments of fatty liver disease. Arch Toxicol 2025; 99:127-152. [PMID: 39692857 DOI: 10.1007/s00204-024-03920-1] [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: 09/05/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024]
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are two major chronic liver diseases worldwide. The triggers for fatty liver can be derived from external sources such as adipose tissue, the gut, personal diet, and genetics, or internal sources, including immune cell responses, lipotoxicity, hepatocyte death, mitochondrial dysfunction, and extracellular vesicles. However, their pathogenesis varies to some extent. This review summarizes various immune mechanisms and therapeutic targets associated with these two types of fatty liver disease. It describes the gut-liver axis and adipose tissue-liver crosstalk, as well as the roles of different immune cells (both innate and adaptive immune cells) in fatty liver disease. Additionally, mitochondrial dysfunction, extracellular vesicles, microRNAs (miRNAs), and gastrointestinal hormones are also related to the pathogenesis of fatty liver. Understanding the pathogenesis of fatty liver and corresponding therapeutic strategies provides a new perspective for developing novel treatments for fatty liver disease.
Collapse
Affiliation(s)
- Sainan Tang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China
| | - Shanshan Wu
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Lili Ma
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, Anhui, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China.
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China.
| |
Collapse
|
|
2
|
Boubaddi M, Marichez A, Adam JP, Lapuyade B, Debordeaux F, Tlili G, Chiche L, Laurent C. Comprehensive Review of Future Liver Remnant (FLR) Assessment and Hypertrophy Techniques Before Major Hepatectomy: How to Assess and Manage the FLR. Ann Surg Oncol 2024; 31:9205-9220. [PMID: 39230854 DOI: 10.1245/s10434-024-16108-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Accepted: 08/16/2024] [Indexed: 09/05/2024]
Abstract
BACKGROUND The regenerative capacities of the liver and improvements in surgical techniques have expanded the possibilities of resectability. Liver resection is often the only curative treatment for primary and secondary malignancies, despite the risk of post-hepatectomy liver failure (PHLF). This serious complication (with a 50% mortality rate) can be avoided by better assessment of liver volume and function of the future liver remnant (FLR). OBJECTIVE The aim of this review was to understand and assess clinical, biological, and imaging predictors of PHLF risk, as well as the various hypertrophy techniques, to achieve an adequate FLR before hepatectomy. METHOD We reviewed the state of the art in liver regeneration and FLR hypertrophy techniques. RESULTS The use of new biological scores (such as the aspartate aminotransferase/platelet ratio index + albumin-bilirubin [APRI+ALBI] score), concurrent utilization of 99mTc-mebrofenin scintigraphy (HBS), or dynamic hepatocyte contrast-enhanced MRI (DHCE-MRI) for liver volumetry helps predict the risk of PHLF. Besides portal vein embolization, there are other FLR optimization techniques that have their indications in case of risk of failure (e.g., associating liver partition and portal vein ligation for staged hepatectomy, liver venous deprivation) or in specific situations (transarterial radioembolization). CONCLUSION There is a need to standardize volumetry and function measurement techniques, as well as FLR hypertrophy techniques, to limit the risk of PHLF.
Collapse
Affiliation(s)
- Mehdi Boubaddi
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France.
- Bordeaux Institute of Oncology, BRIC U1312, INSERM, Bordeaux University, Bordeaux, France.
| | - Arthur Marichez
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France
- Bordeaux Institute of Oncology, BRIC U1312, INSERM, Bordeaux University, Bordeaux, France
| | - Jean-Philippe Adam
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Bruno Lapuyade
- Radiology Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Frederic Debordeaux
- Nuclear Medicine Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Ghoufrane Tlili
- Nuclear Medicine Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Laurence Chiche
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France
| | - Christophe Laurent
- Hepatobiliary and Pancreatic Surgery Department, Bordeaux University Hospital Center, Bordeaux, France
- Bordeaux Institute of Oncology, BRIC U1312, INSERM, Bordeaux University, Bordeaux, France
| |
Collapse
|
|
3
|
Song G, Feng G, Li Q, Peng J, Ge W, Long Y, Cui Z. Transcriptomic Characterization of Key Factors and Signaling Pathways for the Regeneration of Partially Hepatectomized Liver in Zebrafish. Int J Mol Sci 2024; 25:7212. [PMID: 39000319 PMCID: PMC11241411 DOI: 10.3390/ijms25137212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
Liver regeneration induced by partial hepatectomy (PHx) has attracted intensive research interests due to the great significance for liver resection and transplantation. The zebrafish (Danio rerio) is an excellent model to study liver regeneration. In the fish subjected to PHx (the tip of the ventral lobe was resected), the lost liver mass could be fully regenerated in seven days. However, the regulatory mechanisms underlying the liver regeneration remain largely unknown. In this study, gene expression profiles during the regeneration of PHx-treated liver were explored by RNA sequencing (RNA-seq). The genes responsive to the injury of PHx treatment were identified and classified into different clusters based on the expression profiles. Representative gene ontology (GO) enrichments for the early responsive genes included hormone activity, ribosome biogenesis and rRNA processing, etc., while the late responsive genes were enriched in biological processes such as glutathione metabolic process, antioxidant activity and cellular detoxification. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments were also identified for the differentially expressed genes (DEGs) between the time-series samples and the sham controls. The proteasome was overrepresented by the up-regulated genes at all of the sampling time points. Inhibiting proteasome activity by the application of MG132 to the fish enhanced the expression of Pcna (proliferating cell nuclear antigen), an indicator of hepatocyte proliferation after PHx. Our data provide novel insights into the molecular mechanisms underlying the regeneration of PHx-treated liver.
Collapse
Affiliation(s)
- Guili Song
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Guohui Feng
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Qing Li
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Jinrong Peng
- College of Animal Sciences, Zhejiang University, Hangzhou 310058, China
| | - Wei Ge
- Department of Biomedical Sciences and Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of Macau, Taipa, Macau SAR 999078, China
| | - Yong Long
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
| | - Zongbin Cui
- Key Laboratory of Breeding Biotechnology and Sustainable Aquaculture, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China
- Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou 510070, China
| |
Collapse
|
|
4
|
Grayck MR, McCarthy WC, Solar M, Golden E, Balasubramaniyan N, Zheng L, Sherlock LG, Wright CJ. GSK3β/NF-κB -dependent transcriptional regulation of homeostatic hepatocyte Tnf production. Am J Physiol Gastrointest Liver Physiol 2024; 326:G374-G384. [PMID: 38193163 PMCID: PMC11211040 DOI: 10.1152/ajpgi.00229.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 12/18/2023] [Accepted: 12/23/2023] [Indexed: 01/10/2024]
Abstract
Maintenance of hepatocyte homeostasis plays an important role in mediating the pathogenesis of many diseases. A growing body of literature has established a critical role played by tumor necrosis factor-α (TNFα) in maintaining hepatocyte homeostasis; however, the transcriptional mechanisms underlying constitutive Tnf expression are unknown. Whole liver fractions and primary hepatocytes from adult control C57BL/6 mice and the murine hepatocyte cell line AML12 were assessed for constitutive Tnf expression. Impacts of glycogen synthase kinase-3 β (GSK3β) and nuclear factor κB (NF-κB) inhibition on constitutive Tnf expression were assessed in AML12 cells. Finally, AML12 cell proliferation following GSK3β and NF-κB inhibition was evaluated. Constitutive Tnf gene expression is present in whole liver, primary hepatocytes, and cultured AML12 hepatocytes. Cytokine-induced Tnf gene expression is regulated by NF-κB activation. Pharmacological inhibition of GSK3β resulted in a time- and dose-dependent inhibition of Tnf gene expression. GSK3β inhibition decreased nuclear levels of the NF-κB subunits p65 and p50. We determined that NF-κB transcription factor subunit p65 binds to consensus sequence elements present in the murine TNFα promoter and inhibition of GSK3β decreases binding and subsequent Tnf expression. Finally, AML12 cell growth was significantly reduced following GSK3β and NF-κB inhibition. These results demonstrate that GSK3β and NF-κB are essential for mediating Tnf expression and constitutive hepatocyte cell growth. These findings add to a growing body of literature on TNFα mediated hepatocyte homeostasis and identify novel molecular mechanisms involved in mediating response to various disease states in the liver.NEW & NOTEWORTHY Maintenance of hepatocyte homeostasis plays an important role in controlling the pathogenesis of many diseases. Our findings add to a growing body of literature on tumor necrosis factor-α (TNFα)-mediated hepatocyte homeostasis and identify novel molecular mechanisms involved in regulating this response.
Collapse
Affiliation(s)
- Maya R Grayck
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - William C McCarthy
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Mack Solar
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Emma Golden
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Natarajan Balasubramaniyan
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Lijun Zheng
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Laura G Sherlock
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| | - Clyde J Wright
- Section of Neonatology, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States
| |
Collapse
|
|
5
|
Zhang C, Sun C, Zhao Y, Ye B, Yu G. Signaling pathways of liver regeneration: Biological mechanisms and implications. iScience 2024; 27:108683. [PMID: 38155779 PMCID: PMC10753089 DOI: 10.1016/j.isci.2023.108683] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2023] Open
Abstract
The liver possesses a unique regenerative ability to restore its original mass, in this regard, partial hepatectomy (PHx) and partial liver transplantation (PLTx) can be executed smoothly and safely, which has important implications for the treatment of liver disease. Liver regeneration (LR) can be the very complicated procedure that involves multiple cytokines and transcription factors that interact with each other to activate different signaling pathways. Activation of these pathways can drive the LR process, which can be divided into three stages, namely, the initiation, progression, and termination stages. Therefore, it is important to investigate the pathways involved in LR to elucidate the mechanism of LR. This study reviews the latest research on the key signaling pathways in the different stages of LR.
Collapse
Affiliation(s)
- Chunyan Zhang
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Caifang Sun
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Yabin Zhao
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - Bingyu Ye
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| | - GuoYing Yu
- State Key Laboratory Cell Differentiation and Regulation, Henan International Joint Laboratory of Pulmonary Fibrosis, Henan Center for Outstanding Overseas Scientists of Pulmonary Fibrosis, College of Life Science, Institute of Biomedical Science, Henan Normal University, Xinxiang, Henan, China
| |
Collapse
|
|
6
|
Kern AE, Ortmayr G, Assinger A, Starlinger P. The role of microRNAs in the different phases of liver regeneration. Expert Rev Gastroenterol Hepatol 2023; 17:959-973. [PMID: 37811642 DOI: 10.1080/17474124.2023.2267422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
INTRODUCTION Since the first discovery of microRNAs (miRs) extensive evidence reveals their indispensable role in different patho-physiological processes. They are recognized as critical regulators of hepatic regeneration, as they modulate multiple complex signaling pathways affecting liver regeneration. MiR-related translational suppression and degradation of target mRNAs and proteins are not limited to one specific gene, but act on multiple targets. AREAS COVERED In this review, we are going to explore the role of miRs in the context of liver regeneration and discuss the regulatory effects attributed to specific miRs. Moreover, specific pathways crucial for liver regeneration will be discussed, with a particular emphasis on the involvement of miRs within the respective signaling cascades. EXPERT OPINION The considerable amount of studies exploring miR functions in a variety of diseases paved the way for the development of miR-directed therapeutics. Clinical implementation has already shown promising results, but additional research is warranted to assure safe and efficient delivery. Nevertheless, given the broad functional properties of miRs and their critical involvement during hepatic regeneration, they represent an attractive treatment target to promote liver recovery after hepatic resection.
Collapse
Affiliation(s)
- Anna Emilia Kern
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
| | - Gregor Ortmayr
- Center for Cancer Research, Medical University of Vienna, Vienna, Austria
| | - Alice Assinger
- Department of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| | - Patrick Starlinger
- Department of General Surgery, Division of Visceral Surgery, Medical University of Vienna, Vienna, Austria
- Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA
- Center of Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
| |
Collapse
|
|
7
|
Deng W, Hu T, Xiong W, Jiang X, Cao Y, Li Z, Jiang H, Wang X. Soluble epoxide hydrolase deficiency promotes liver regeneration and ameliorates liver injury in mice by regulating angiocrine factors and angiogenesis. Biochim Biophys Acta Gen Subj 2023:130394. [PMID: 37315719 DOI: 10.1016/j.bbagen.2023.130394] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 05/21/2023] [Accepted: 05/24/2023] [Indexed: 06/16/2023]
Abstract
BACKGROUND Soluble epoxide hydrolase (sEH) is a key enzyme for the hydrolysis of epoxyeicosatrienoic acids (EETs) and has been implicated in the pathogenesis of hepatic inflammation, fibrosis, cancer, and nonalcoholic fatty liver disease. However, the role of sEH in liver regeneration and injury remains unclear. METHODS This study used sEH-deficient (sEH-/-) mice and wild-type (WT) mice. Hepatocyte proliferation was assessed by immunohistochemical (IHC) staining for Ki67. Liver injury was evaluated by histological staining with hematoxylin and eosin (H&E), Masson's trichrome, and Sirius red, as well as IHC staining for α-SMA. Hepatic macrophage infiltration and angiogenesis were reflected by IHC staining for CD68 and CD31. Liver angiocrine levels were detected by ELISA. The mRNA levels of angiocrine or cell cycle-related genes were measured by quantitative real-time RT-PCR (qPCR). The protein levels of cell proliferation-related protein and phosphorylated signal transducer and activator of transcription 3 (STAT3) were detected by western blotting. RESULTS sEH mRNA and protein levels were significantly upregulated in mice after 2/3 partial hepatectomy (PHx). Compared with WT mice, sEH-/- mice exhibited a higher liver/body weight ratio and more Ki67-positive cells on days 2 and 3 after PHx. The accelerated liver regeneration in sEH-/- mice was attributed to angiogenesis and endothelial-derived angiocrine (HGF) production. Subsequently, hepatic protein expression of cyclinD1 (CYCD1) and the downstream direct targets of the STAT3 pathway, such as c-fos, c-jun, and c-myc, were also suppressed post-PHx in sEH-/- compared to WT mice. Furthermore, sEH deficiency attenuated CCl4-induced acute liver injury and reduced fibrosis in both CCl4 and bile duct ligation (BDL)-induced liver fibrosis rodent models. Compared with WT mice, sEH-/- mice had slightly decreased hepatic macrophage infiltration and angiogenesis. Meanwhile, sEH-/- BDL mice had more Ki67-positive cells in the liver than WT BDL mice. CONCLUSIONS sEH deficiency alters the angiocrine profile of liver endothelial to accelerate hepatocyte proliferation and liver regeneration, and blunts acute liver injury and fibrosis by inhibiting inflammation and angiogenesis. sEH inhibition is a promising target for liver diseases to improve liver regeneration and damage.
Collapse
Affiliation(s)
- Wensheng Deng
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Tengcheng Hu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Weixin Xiong
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang 33006, China
| | - Xiaohua Jiang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Yi Cao
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Zhengrong Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China
| | - Hai Jiang
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang 33006, China; Laboratory of Digestive Surgery, Nanchang University, Nanchang 33006, China.
| | - Xinxin Wang
- Department of Radiotherapy, The Third Hospital of Nanchang, Nanchang 330002, China.
| |
Collapse
|
|
8
|
Di-Iacovo N, Pieroni S, Piobbico D, Castelli M, Scopetti D, Ferracchiato S, Della-Fazia MA, Servillo G. Liver Regeneration and Immunity: A Tale to Tell. Int J Mol Sci 2023; 24:1176. [PMID: 36674692 PMCID: PMC9864482 DOI: 10.3390/ijms24021176] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 12/28/2022] [Accepted: 12/30/2022] [Indexed: 01/11/2023] Open
Abstract
The physiological importance of the liver is demonstrated by its unique and essential ability to regenerate following extensive injuries affecting its function. By regenerating, the liver reacts to hepatic damage and thus enables homeostasis to be restored. The aim of this review is to add new findings that integrate the regenerative pathway to the current knowledge. An optimal regeneration is achieved through the integration of two main pathways: IL-6/JAK/STAT3, which promotes hepatocyte proliferation, and PI3K/PDK1/Akt, which in turn enhances cell growth. Proliferation and cell growth are events that must be balanced during the three phases of the regenerative process: initiation, proliferation and termination. Achieving the correct liver/body weight ratio is ensured by several pathways as extracellular matrix signalling, apoptosis through caspase-3 activation, and molecules including transforming growth factor-beta, and cyclic adenosine monophosphate. The actors involved in the regenerative process are numerous and many of them are also pivotal players in both the immune and non-immune inflammatory process, that is observed in the early stages of hepatic regeneration. Balance of Th17/Treg is important in liver inflammatory process outcomes. Knowledge of liver regeneration will allow a more detailed characterisation of the molecular mechanisms that are crucial in the interplay between proliferation and inflammation.
Collapse
Affiliation(s)
- Nicola Di-Iacovo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Stefania Pieroni
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Danilo Piobbico
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Marilena Castelli
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Damiano Scopetti
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Simona Ferracchiato
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Maria Agnese Della-Fazia
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
| | - Giuseppe Servillo
- Department of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy
- Centro Universitario di Ricerca sulla Genomica Funzionale (C.U.R.Ge.F.), University of Perugia, 06123 Perugia, Italy
| |
Collapse
|
|
9
|
Vlach M, Coppens-Exandier H, Jamin A, Berchel M, Scaviner J, Chesné C, Montier T, Jaffrès PA, Corlu A, Loyer P. Liposome-Mediated Gene Transfer in Differentiated HepaRG™ Cells: Expression of Liver Specific Functions and Application to the Cytochrome P450 2D6 Expression. Cells 2022; 11:cells11233904. [PMID: 36497165 PMCID: PMC9737581 DOI: 10.3390/cells11233904] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/19/2022] [Accepted: 11/29/2022] [Indexed: 12/12/2022] Open
Abstract
The goal of this study was to establish a procedure for gene delivery mediated by cationic liposomes in quiescent differentiated HepaRG™ human hepatoma cells. We first identified several cationic lipids promoting efficient gene transfer with low toxicity in actively dividing HepG2, HuH7, BC2 and progenitor HepaRG™ human hepatoma cells. The lipophosphoramidate Syn1-based nanovector, which allowed the highest transfection efficiencies of progenitor HepaRG™ cells, was next used to transfect differentiated HepaRG™ cells. Lipofection of these cells using Syn1-based liposome was poorly efficient most likely because the differentiated HepaRG™ cells are highly quiescent. Thus, we engineered the differentiated HepaRG™ Mitogenic medium supplement (ADD1001) that triggered robust proliferation of differentiated cells. Importantly, we characterized the phenotypical changes occurring during proliferation of differentiated HepaRG™ cells and demonstrated that mitogenic stimulation induced a partial and transient decrease in the expression levels of some liver specific functions followed by a fast recovery of the full differentiation status upon removal of the mitogens. Taking advantage of the proliferation of HepaRG™ cells, we defined lipofection conditions using Syn1-based liposomes allowing transient expression of the cytochrome P450 2D6, a phase I enzyme poorly expressed in HepaRG cells, which opens new means for drug metabolism studies in HepaRG™ cells.
Collapse
Affiliation(s)
- Manuel Vlach
- Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35000 Rennes, France
- Institut AGRO Rennes-Angers, F-35042 Rennes, France
| | - Hugo Coppens-Exandier
- Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35000 Rennes, France
- Biopredic International, F-35760 Saint Grégoire, France
| | - Agnès Jamin
- Biopredic International, F-35760 Saint Grégoire, France
| | - Mathieu Berchel
- Univ. Brest, CNRS, CEMCA, UMR 6521, F-29238 Brest, France
- Plateforme BiogenOuest SynNanoVect, F-44035 Nantes, France
| | - Julien Scaviner
- Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35000 Rennes, France
- Biopredic International, F-35760 Saint Grégoire, France
| | | | - Tristan Montier
- Plateforme BiogenOuest SynNanoVect, F-44035 Nantes, France
- Univ. Brest, INSERM, EFS, UMR 1078, GGB-GTCA, F-29200 Brest, France
| | - Paul-Alain Jaffrès
- Univ. Brest, CNRS, CEMCA, UMR 6521, F-29238 Brest, France
- Plateforme BiogenOuest SynNanoVect, F-44035 Nantes, France
| | - Anne Corlu
- Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35000 Rennes, France
- Correspondence: (A.C.); (P.L.); Tel.: +33-(02)-23233873 (P.L.)
| | - Pascal Loyer
- Institut NUMECAN (Nutrition Metabolisms and Cancer), F-35000 Rennes, France
- Plateforme BiogenOuest SynNanoVect, F-44035 Nantes, France
- Correspondence: (A.C.); (P.L.); Tel.: +33-(02)-23233873 (P.L.)
| |
Collapse
|
|
10
|
Liu C, Wang L, Xu M, Sun Y, Xing Z, Zhang J, Wang C, Dong L. Reprogramming the spleen into a functioning 'liver' in vivo. Gut 2022; 71:2325-2336. [PMID: 34996824 DOI: 10.1136/gutjnl-2021-325018] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 12/22/2021] [Indexed: 12/20/2022]
Abstract
OBJECTIVE Liver regeneration remains one of the biggest clinical challenges. Here, we aim to transform the spleen into a liver-like organ via directly reprogramming the splenic fibroblasts into hepatocytes in vivo. DESIGN In the mouse spleen, the number of fibroblasts was through silica particles (SiO2) stimulation, the expanded fibroblasts were converted to hepatocytes (iHeps) by lentiviral transfection of three key transcriptional factors (Foxa3, Gata4 and Hnf1a), and the iHeps were further expanded with tumour necrosis factor-α (TNF-α) and lentivirus-mediated expression of epidermal growth factor (EGF) and hepatocyte growth factor (HGF). RESULTS SiO2 stimulation tripled the number of activated fibroblasts. Foxa3, Gata4 and Hnf1a converted SiO2-remodelled spleen fibroblasts into 2×106 functional iHeps in one spleen. TNF-α protein and lentivirus-mediated expression of EGF and HGF further enabled the total hepatocytes to expand to 8×106 per spleen. iHeps possessed hepatic functions-such as glycogen storage, lipid accumulation and drug metabolism-and performed fundamental liver functions to improve the survival rate of mice with 90% hepatectomy. CONCLUSION Direct conversion of the spleen into a liver-like organ, without cell or tissue transplantation, establishes fundamental hepatic functions in mice, suggesting its potential value for the treatment of end-stage liver diseases.
Collapse
Affiliation(s)
- Chunyan Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Lintao Wang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China.,Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Mengzhen Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Yajie Sun
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Zhen Xing
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Junfeng Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China
| | - Chunming Wang
- Institute of Chinese Medical Sciences, University of Macau, Taipa, Macau, China
| | - Lei Dong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu, China .,Chemistry and Biomedicine Innovative Center, Nanjing University, Nanjing, Jiangsu, China
| |
Collapse
|
|
11
|
Yang I, Son Y, Shin JH, Kim IY, Seong JK. Ahnak depletion accelerates liver regeneration by modulating the TGF-β/Smad signaling pathway. BMB Rep 2022. [PMID: 35880432 PMCID: PMC9442348 DOI: 10.5483/bmbrep.2022.55.8.071] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Insook Yang
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Yeri Son
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Jae Hoon Shin
- Department of Surgery, University of Michigan, Ann Arbor 48109, MI, USA
| | - Il Yong Kim
- Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Korea
| | - Je Kyung Seong
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
- Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, Korea
- Interdisciplinary Program for Bioinformatics, Program for Cancer Biology and BIO-MAX Institute, Seoul National University, Seoul 08826, Korea
| |
Collapse
|
|
12
|
Yang I, Son Y, Shin JH, Kim IY, Seong JK. Ahnak depletion accelerates liver regeneration by modulating the TGF-β/Smad signaling pathway. BMB Rep 2022; 55:401-406. [PMID: 35880432 PMCID: PMC9442348] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 05/08/2022] [Accepted: 06/30/2022] [Indexed: 03/08/2024] Open
Abstract
Ahnak, a large protein first identified as an inhibitor of TGF-β signaling in human neuroblastoma, was recently shown to promote TGF-β in some cancers. The TGF-β signaling pathway regulates cell growth, various biological functions, and cancer growth and metastasis. In this study, we used Ahnak knockout (KO) mice that underwent a 70% partial hepatectomy (PH) to investigate the function of Ahnak in TGF-β signaling during liver regeneration. At the indicated time points after PH, we analyzed the mRNA and protein expression of the TGF -β/Smad signaling pathway and cell cycle-related factors, evaluated the cell cycle through proliferating cell nuclear antigen (PCNA) immunostaining, analyzed the mitotic index by hematoxylin and eosin staining. We also measured the ratio of liver tissue weight to body weight. Activation of TGF-β signaling was confirmed by analyzing the levels of phospho-Smad 2 and 3 in the liver at the indicated time points after PH and was lower in Ahnak KO mice than in WT mice. The expression levels of cyclin B1, D1, and E1; proteins in the Rb/E2F transcriptional pathway, which regulates the cell cycle; and the numbers of PCNA-positive cells were increased in Ahnak KO mice and showed tendencies opposite that of TGF-β expression. During postoperative regeneration, the liver weight to body weight ratio tended to increase faster in Ahnak KO mice. However, 7 days after PH, both groups of mice showed similar rates of regeneration, following which their active regeneration stopped. Analysis of hepatocytes undergoing mitosis showed that there were more mitotic cells in Ahnak KO mice, consistent with the weight ratio. Our findings suggest that Ahnak enhances TGF-β signaling during postoperative liver regeneration, resulting in cell cycle disruption; this highlights a novel role of Ahnak in liver regeneration. These results provide new insight into liver regeneration and potential treatment targets for liver diseases that require surgical treatment. [BMB Reports 2022; 55(8): 401-406].
Collapse
Affiliation(s)
- Insook Yang
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul 08826, USA
| | - Yeri Son
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul 08826, USA
| | - Jae Hoon Shin
- Department of Surgery, University of Michigan, Ann Arbor 48109, MI, USA
| | - Il Yong Kim
- Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, USA
| | - Je Kyung Seong
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University, Seoul 08826, USA
- Korea Mouse Phenotyping Center, Seoul National University, Seoul 08826, USA
- Interdisciplinary Program for Bioinformatics, Program for Cancer Biology and BIO-MAX Institute, Seoul National University, Seoul 08826, Korea, MI, USA
| |
Collapse
|
|
13
|
Cassese G, Han HS, Al Farai A, Guiu B, Troisi RI, Panaro F. Future remnant Liver optimization: preoperative assessment, volume augmentation procedures and management of PVE failure. Minerva Surg 2022; 77:368-379. [PMID: 35332767 DOI: 10.23736/s2724-5691.22.09541-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Surgery is the cornerstone treatment for patients with primary or metastatic hepatic tumors. Thanks to surgical and anesthetic technological advances, current indications for liver resections have been significantly expanded to include any patient in whom all disease can be resected with a negative margin (R0) while preserving an adequate future residual liver (FRL). Post-hepatectomy liver failure (PHLF) is still a feared complication following major liver surgery, associated with high morbidity, mortality and cost implications. PHLF is mainly linked to both the size and quality of the FRL. Significant advances have been made in detailed preoperative assessment, to predict and mitigate this complication, even if an ideal methodology has yet to be defined. Several procedures have been described to induce hypertrophy of the FRL when needed. Each technique has its advantages and limitations, and among them portal vein embolization (PVE) is still considered the standard of care. About 20% of patients after PVE fail to undergo the scheduled hepatectomy, and newer secondary procedures, such as segment 4 embolization, ALPPS and HVE, have been proposed as salvage strategies. The aim of this review is to discuss the current modalities available and new perspectives in the optimization of FRL in patients undergoing major liver resection.
Collapse
Affiliation(s)
- Gianluca Cassese
- Minimally Invasive and Robotic HPB Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.,Seoul National University College of Medicine, Department of Surgery, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Ho-Seong Han
- Seoul National University College of Medicine, Department of Surgery, Seoul National University Bundang Hospital, Seoul, South Korea
| | - Abdallah Al Farai
- Department of Surgical Oncology, Sultan Qaboos Comprehensive Cancer Care and Research Center, Muscat, Oman
| | - Boris Guiu
- Department of Radiology, Montpellier University Hospital, Montpellier, France
| | - Roberto I Troisi
- Minimally Invasive and Robotic HPB Unit, Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Fabrizio Panaro
- Montpellier University Hospital School of Medicine, Unit of Digestive Surgery and Liver Transplantation, Montpellier University Hospital, Montpellier-Nimes University, Montpellier, France -
| |
Collapse
|
|
14
|
Robarts DR, McGreal SR, Umbaugh DS, Parkes WS, Kotulkar M, Abernathy S, Lee N, Jaeschke H, Gunewardena S, Whelan SA, Hanover JA, Zachara NE, Slawson C, Apte U. Regulation of Liver Regeneration by Hepatocyte O-GlcNAcylation in Mice. Cell Mol Gastroenterol Hepatol 2022; 13:1510-1529. [PMID: 35093590 PMCID: PMC9043307 DOI: 10.1016/j.jcmgh.2022.01.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 01/18/2022] [Accepted: 01/19/2022] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS The liver has a unique capacity to regenerate after injury in a highly orchestrated and regulated manner. Here, we report that O-GlcNAcylation, an intracellular post-translational modification regulated by 2 enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), is a critical termination signal for liver regeneration following partial hepatectomy (PHX). METHODS We studied liver regeneration after PHX on hepatocyte specific OGT and OGA knockout mice (OGT-KO and OGA-KO), which caused a significant decrease (OGT-KO) and increase (OGA-KO) in hepatic O-GlcNAcylation, respectively. RESULTS OGA-KO mice had normal regeneration, but the OGT-KO mice exhibited substantial defects in termination of liver regeneration with increased liver injury, sustained cell proliferation resulting in significant hepatomegaly, hepatic dysplasia, and appearance of small nodules at 28 days after PHX. This was accompanied by a sustained increase in expression of cyclins along with significant induction in pro-inflammatory and pro-fibrotic gene expression in the OGT-KO livers. RNA-sequencing studies revealed inactivation of hepatocyte nuclear 4 alpha (HNF4α), the master regulator of hepatic differentiation and a known termination signal, in OGT-KO mice at 28 days after PHX, which was confirmed by both Western blot and immunohistochemistry analysis. Furthermore, a significant decrease in HNFα target genes was observed in OGT-KO mice, indicating a lack of hepatocyte differentiation following decreased hepatic O-GlcNAcylation. Immunoprecipitation experiments revealed HNF4α is O-GlcNAcylated in normal differentiated hepatocytes. CONCLUSIONS These studies show that O-GlcNAcylation plays a critical role in the termination of liver regeneration via regulation of HNF4α in hepatocytes.
Collapse
Affiliation(s)
- Dakota R Robarts
- Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas
| | - Steven R McGreal
- Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas
| | - David S Umbaugh
- Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas
| | - Wendena S Parkes
- Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas
| | - Manasi Kotulkar
- Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas
| | - Sarah Abernathy
- Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas
| | - Norman Lee
- Department of Chemistry, Boston University, Boston, Massachusetts
| | - Hartmut Jaeschke
- Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas
| | | | - Stephen A Whelan
- Department of Chemistry, Boston University, Boston, Massachusetts
| | - John A Hanover
- Laboratory of Cell Biochemistry and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Natasha E Zachara
- Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Chad Slawson
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center, Kansas City, Kansas
| | - Udayan Apte
- Department of Pharmacology, Toxicology and Therapeutics, Kansas City, Kansas.
| |
Collapse
|
|
15
|
Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
Collapse
Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| |
Collapse
|
|
16
|
Memeo R, Conticchio M, Deshayes E, Nadalin S, Herrero A, Guiu B, Panaro F. Optimization of the future remnant liver: review of the current strategies in Europe. Hepatobiliary Surg Nutr 2021; 10:350-363. [PMID: 34159162 DOI: 10.21037/hbsn-20-394] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Liver resection still represent the treatment of choice for liver malignancies, but in some cases inadequate future remnant liver (FRL) can lead to post hepatectomy liver failure (PHLF) that still represents the most common cause of death after hepatectomy. Several strategies in recent era have been developed in order to generate a compensatory hypertrophy of the FRL, reducing the risk of post hepatectomy liver failure. Portal vein embolization, portal vein ligation, and ALLPS are the most popular techniques historically adopted up to now. The liver venous deprivation and the radio-embolization are the most recent promising techniques. Despite even more precise tools to calculate the relationship among volume and function, such as scintigraphy with 99mTc-mebrofenin (HBS), no consensus is still available to define which of the above mentioned augmentation strategy is more adequate in terms of kind of surgery, complexity of the pathology and quality of liver parenchyma. The aim of this article is to analyse these different strategies to achieve sufficient FRL.
Collapse
Affiliation(s)
- Riccardo Memeo
- Division of Hepato-Pancreato-Biliary Surgery, Department of Surgery, "F. Miulli" General Hospital, Acquaviva delle Fonti, Bari, Italy
| | | | - Emmanuel Deshayes
- Department of Nuclear Medicine, Institute du Cancer de Montpellier (ICM), Montpellier, France.,INSERM U1194, Montpellier Cancer Research Institute, Montpellier University, Montpellier, France
| | - Silvio Nadalin
- Department of General, Visceral and Transplant Surgery, University Hospital Tübingen, Germany
| | - Astrid Herrero
- Department of Surgery, Division of HBP Surgery and Liver Transplantation, St-Eloi University Hospital, Montpellier, France
| | - Boris Guiu
- INSERM U1194, Montpellier Cancer Research Institute, Montpellier University, Montpellier, France.,Department of Radiology, St-Eloi University Hospital, Montpellier, France
| | - Fabrizio Panaro
- Department of Surgery, Division of HBP Surgery and Liver Transplantation, St-Eloi University Hospital, Montpellier, France
| |
Collapse
|
|
17
|
Hoffmann K, Nagel AJ, Tanabe K, Fuchs J, Dehlke K, Ghamarnejad O, Lemekhova A, Mehrabi A. Markers of liver regeneration-the role of growth factors and cytokines: a systematic review. BMC Surg 2020; 20:31. [PMID: 32050952 PMCID: PMC7017496 DOI: 10.1186/s12893-019-0664-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 12/12/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Post-hepatectomy liver failure contributes significantly to postoperative mortality after liver resection. The prediction of the individual risk for liver failure is challenging. This review aimed to provide an overview of cytokine and growth factor triggered signaling pathways involved in liver regeneration after resection. METHODS MEDLINE and Cochrane databases were searched without language restrictions for articles from the time of inception of the databases till March 2019. All studies with comparative data on the effect of cytokines and growth factors on liver regeneration in animals and humans were included. RESULTS Overall 3.353 articles comprising 40 studies involving 1.498 patients and 101 animal studies were identified and met the inclusion criteria. All included trials on humans were retrospective cohort/observational studies. There was substantial heterogeneity across all included studies with respect to the analyzed cytokines and growth factors and the described endpoints. CONCLUSION High-level evidence on serial measurements of growth factors and cytokines in blood samples used to predict liver regeneration after resection is still lacking. To address the heterogeneity of patients and potential markers, high throughput serial analyses may offer a method to predict an individual's regenerative potential in the future.
Collapse
Affiliation(s)
- Katrin Hoffmann
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany.
| | - Alexander Johannes Nagel
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Kazukata Tanabe
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | | | - Karolin Dehlke
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Omid Ghamarnejad
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Anastasia Lemekhova
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| | - Arianeb Mehrabi
- Department of General, Visceral and Transplant Surgery, Ruprecht Karls University, Im Neuenheimer Feld, 110 69120, Heidelberg, Germany
| |
Collapse
|
|
18
|
Shwartz A, Goessling W, Yin C. Macrophages in Zebrafish Models of Liver Diseases. Front Immunol 2019; 10:2840. [PMID: 31867007 PMCID: PMC6904306 DOI: 10.3389/fimmu.2019.02840] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2019] [Accepted: 11/19/2019] [Indexed: 12/16/2022] Open
Abstract
Hepatic macrophages are key components of the liver immunity and consist of two main populations. Liver resident macrophages, known as Kupffer cells in mammals, are crucial for maintaining normal liver homeostasis. Upon injury, they become activated to release proinflammatory cytokines and chemokines and recruit a large population of inflammatory monocyte-derived macrophages to the liver. During the progression of liver diseases, macrophages are highly plastic and have opposing functions depending on the signaling cues that they receive from the microenvironment. A comprehensive understanding of liver macrophages is essential for developing therapeutic interventions that target these cells in acute and chronic liver diseases. Mouse studies have provided the bulk of our current knowledge of liver macrophages. The emergence of various liver disease models and availability of transgenic tools to visualize and manipulate macrophages have made the teleost zebrafish (Danio rerio) an attractive new vertebrate model to study liver macrophages. In this review, we summarize the origin and behaviors of macrophages in healthy and injured livers in zebrafish. We highlight the roles of macrophages in zebrafish models of alcoholic and non-alcoholic liver diseases, hepatocellular carcinoma, and liver regeneration, and how they compare with the roles that have been described in mammals. We also discuss the advantages and challenges of using zebrafish to study liver macrophages.
Collapse
Affiliation(s)
- Arkadi Shwartz
- Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
| | - Wolfram Goessling
- Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
- Harvard Stem Cell Institute, Cambridge, MA, United States
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
- Broad Institute, Massachusetts Institute of Technology and Harvard, Cambridge, MA, United States
- Division of Health Sciences and Technology, Harvard and Massachusetts Institute of Technology, Boston, MA, United States
- Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | - Chunyue Yin
- Division of Gastroenterology, Hepatology and Nutrition and Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| |
Collapse
|
|
19
|
Ozaki M. Cellular and molecular mechanisms of liver regeneration: Proliferation, growth, death and protection of hepatocytes. Semin Cell Dev Biol 2019; 100:62-73. [PMID: 31669133 DOI: 10.1016/j.semcdb.2019.10.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 10/09/2019] [Accepted: 10/14/2019] [Indexed: 01/08/2023]
Abstract
Liver regeneration is an important and necessary process that the liver depends on for recovery from injury. The regeneration process consists of a complex network of cells and organs, including liver cells (parenchymal and non-parenchymal cells) and extrahepatic organs (thyroid, adrenal glands, pancreas, duodenum, spleen, and autonomic nervous system). The regeneration process of a normal, healthy liver depends mainly on hepatocyte proliferation, growth, and programmed cell death. Cell proliferation and growth are regulated in a cooperative manner by interleukin (IL)-6/janus kinase (Jak)/signal transducers and activators of transcription-3 (STAT3), and phosphoinositide 3-kinase (PI3-K)/phosphoinositide-dependent protein kinase 1 (PDK1)/Akt pathways. The IL-6/Jak/STAT3 pathway regulates hepatocyte proliferation and protects against cell death and oxidative stress. The PI3-K/PDK1/Akt pathway is primarily responsible for the regulation of cell size, sending mitotic signals in addition to pro-survival, antiapoptotic and antioxidative signals. Though programmed cell death may interfere with liver regeneration in a pathological situation, it seems to play an important role during the termination phase, even in a normal, healthy liver regeneration. However, further study is needed to fully elucidate the mechanisms regulating the processes of liver regeneration with regard to cell-to-cell and organ-to-organ networks at the molecular and cellular levels.
Collapse
Affiliation(s)
- Michitaka Ozaki
- Department of Biological Response and Regulation, Faculty of Health Sciences, Hokkaido University, N12, W5, Kita-ku, Sapporo, Hokkaido, 060-0812, Japan.
| |
Collapse
|
|
20
|
Elchaninov AV, Fatkhudinov TK, Vishnyakova PA, Lokhonina AV, Sukhikh GT. Phenotypical and Functional Polymorphism of Liver Resident Macrophages. Cells 2019; 8:E1032. [PMID: 31491903 PMCID: PMC6769646 DOI: 10.3390/cells8091032] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 02/07/2023] Open
Abstract
Liver diseases are one of the main causes of mortality. In this regard, the development of new ways of reparative processes stimulation is relevant. Macrophages play a leading role in the regulation of liver homeostasis in physiological conditions and in pathology. In this regard, the development of new liver treatment methods is impossible without taking into account this cell population. Resident macrophages of the liver, Kupffer cells, represent a unique cell population, first of all, due to their development. Most of the liver macrophages belong to the self-sustaining macrophage cell population, whose origin is not bone marrow. In addition, Kupffer cells are involved in such processes as regulation of hepatocyte proliferation and apoptosis, remodeling of the intercellular matrix, lipid metabolism, protective function, etc. Such a broad spectrum of liver macrophage functions indicates their high functional plasticity. The review summarizes recent data on the development, phenotypic and functional plasticity, and participation in the reparative processes of liver macrophages: resident macrophages (Kupffer cells) and bone marrow-derived macrophages.
Collapse
Affiliation(s)
- Andrey V Elchaninov
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
- Histology, Embryology and Cytology Department, Ministry of Healthcare of The Russian Federation, Pirogov Russian National Research Medical University, 1 Ostrovitianov Street, Moscow 117997, Russia.
| | - Timur Kh Fatkhudinov
- Histology, Embryology and Cytology Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya Street, Moscow 117198, Russia.
- Scientific Research Institute of Human Morphology, 3 Tsurupa Street, Moscow 117418, Russia.
| | - Polina A Vishnyakova
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
| | - Anastasia V Lokhonina
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
- Histology, Embryology and Cytology Department, Peoples' Friendship University of Russia, 6 Miklukho-Maklaya Street, Moscow 117198, Russia.
| | - Gennady T Sukhikh
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, Moscow 117997, Russia.
| |
Collapse
|
|
21
|
Peng WC, Logan CY, Fish M, Anbarchian T, Aguisanda F, Álvarez-Varela A, Wu P, Jin Y, Zhu J, Li B, Grompe M, Wang B, Nusse R. Inflammatory Cytokine TNFα Promotes the Long-Term Expansion of Primary Hepatocytes in 3D Culture. Cell 2019; 175:1607-1619.e15. [PMID: 30500539 DOI: 10.1016/j.cell.2018.11.012] [Citation(s) in RCA: 215] [Impact Index Per Article: 35.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 08/15/2018] [Accepted: 11/12/2018] [Indexed: 12/17/2022]
Abstract
In the healthy adult liver, most hepatocytes proliferate minimally. However, upon physical or chemical injury to the liver, hepatocytes proliferate extensively in vivo under the direction of multiple extracellular cues, including Wnt and pro-inflammatory signals. Currently, liver organoids can be generated readily in vitro from bile-duct epithelial cells, but not hepatocytes. Here, we show that TNFα, an injury-induced inflammatory cytokine, promotes the expansion of hepatocytes in 3D culture and enables serial passaging and long-term culture for more than 6 months. Single-cell RNA sequencing reveals broad expression of hepatocyte markers. Strikingly, in vitro-expanded hepatocytes engrafted, and significantly repopulated, the injured livers of Fah-/- mice. We anticipate that tissue repair signals can be harnessed to promote the expansion of otherwise hard-to-culture cell-types, with broad implications.
Collapse
Affiliation(s)
- Weng Chuan Peng
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
| | - Catriona Y Logan
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Matt Fish
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Teni Anbarchian
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Francis Aguisanda
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Adrián Álvarez-Varela
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Peng Wu
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Yinhua Jin
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Junjie Zhu
- Department of Electrical Engineering, Stanford University, Stanford, CA 94305, USA
| | - Bin Li
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR 97239, USA
| | - Markus Grompe
- Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR 97239, USA
| | - Bruce Wang
- Department of Medicine and Liver Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Roel Nusse
- Howard Hughes Medical Institute, Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
| |
Collapse
|
|
22
|
Günther C, Brevini T, Sampaziotis F, Neurath MF. What gastroenterologists and hepatologists should know about organoids in 2019. Dig Liver Dis 2019; 51:753-760. [PMID: 30948332 DOI: 10.1016/j.dld.2019.02.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 02/27/2019] [Indexed: 12/11/2022]
Abstract
Most of the research behind new medical advances is carried out using either animal models or cancer cells, which both have their disadvantage in particular with regard to medical applications such as personalized medicine and novel therapeutic approaches. However, recent advances in stem cell biology have enabled long-term culturing of organotypic intestinal or hepatic tissues derived from tissue resident or pluripotent stem cells. These 3D structures, denoted as organoids, represent a substantial advance in structural and functional complexity over traditional in vitro cell culture models that are often non-physiological and transformed. They can recapitulate the in vivo architecture, functionality and genetic signature of the corresponding tissue. The opportunity to model epithelial cell biology, epithelial turnover, barrier dynamics, immune-epithelial communication and host-microbe interaction more efficiently than previous culture systems, greatly enhance the translational potential of organotypic hepato-gastrointestinal culture systems. Thus there is increasing interest in using such cultured cells as a source for tissue engineering, regenerative medicine and personalized medicine. This review will highlight some of the established and also some exciting novel perspectives on organoids in the fields of gastroenterology and hepatology.
Collapse
Affiliation(s)
- Claudia Günther
- Department of Medicine 1, University Hospital, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany
| | - Teresa Brevini
- Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge, UK
| | - Fotios Sampaziotis
- Wellcome Trust-Medical Research Council Stem Cell Institute, Cambridge Stem Cell Institute, Anne McLaren Laboratory, Department of Surgery, University of Cambridge, Cambridge, UK; Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK; Department of Hepatology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK.
| | - Markus F Neurath
- Department of Medicine 1, University Hospital, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany.
| |
Collapse
|
|
23
|
Le Roy B, Dupré A, Gallon A, Chabrot P, Gagnière J, Buc E. Liver hypertrophy: Underlying mechanisms and promoting procedures before major hepatectomy. J Visc Surg 2018; 155:393-401. [PMID: 30126801 DOI: 10.1016/j.jviscsurg.2018.03.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Various procedures can promote hypertrophy of the future liver remnant (FLR) before major hepatectomy to prevent postoperative liver failure. The pathophysiological situation following portal vein embolization (PVE), hepatic artery ligation/embolization or hepatectomy remains unclear. On one hand, the main mechanisms of hepatic regeneration appear to be driven by hepatic hypoxia (involving the hepatic arterial buffer response), an increased portal blood flow inducing shear stress and the involvement of several mediators (inflammatory cytokines, vasoregulators, growth factors, eicosanoids and several hormones). On the other hand, several factors are associated with impaired liver regeneration, such as biliary obstruction, malnutrition, diabetes mellitus, male gender, age, ethanol and viral infection. All these mechanisms may explain the varying degrees of hypertrophy observed following a surgical or radiological procedure promoting hypertrophy the FLR. Radiological procedures include left and right portal vein embolization (extended or not to segment 4), sequential PVE and hepatic vein embolization (HVE), and more recently combined PVE and HVE. Surgical procedures include associated liver partition and portal vein ligation for staged hepatectomy, and more recently the combined portal embolization and arterial ligation procedure. This review aimed to clarify the pathophysiology of liver regeneration; it also describes radiological or surgical procedures employed to improve liver regeneration in terms of volumetric changes, the feasibility of the second step and the benefits and drawbacks of each procedure.
Collapse
Affiliation(s)
- B Le Roy
- Department of Digestive and Hepatobiliary Surgery, Hôpital Estaing, CHU Clermont-Ferrand, 1, place Lucie-et-Raymond-Aubrac, 63003 Clermont-Ferrand, France; UMR Auvergne UMR 6602 UCA/CNRS/SIGMA, Clermont-Ferrand Faculty of Medicine, 28, place Henri-Dunant, 63000 Clermont-Ferrand, France.
| | - A Dupré
- Inserm, LabTAU UMR1032, Centre Léon-Bérard, Université Claude-Bernard Lyon 1, 69003 Lyon, France
| | - A Gallon
- Department of Vascular Radiology, Hôpital Gabriel Montpied, CHU Clermont-Ferrand, place Henri-Dunant, 63000 Clermont-Ferrand, France; UMR Auvergne UMR 6602 UCA/CNRS/SIGMA, Clermont-Ferrand Faculty of Medicine, 28, place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - P Chabrot
- Department of Vascular Radiology, Hôpital Gabriel Montpied, CHU Clermont-Ferrand, place Henri-Dunant, 63000 Clermont-Ferrand, France; UMR Auvergne UMR 6602 UCA/CNRS/SIGMA, Clermont-Ferrand Faculty of Medicine, 28, place Henri-Dunant, 63000 Clermont-Ferrand, France
| | - J Gagnière
- Department of Digestive and Hepatobiliary Surgery, Hôpital Estaing, CHU Clermont-Ferrand, 1, place Lucie-et-Raymond-Aubrac, 63003 Clermont-Ferrand, France
| | - E Buc
- Department of Digestive and Hepatobiliary Surgery, Hôpital Estaing, CHU Clermont-Ferrand, 1, place Lucie-et-Raymond-Aubrac, 63003 Clermont-Ferrand, France; UMR Auvergne UMR 6602 UCA/CNRS/SIGMA, Clermont-Ferrand Faculty of Medicine, 28, place Henri-Dunant, 63000 Clermont-Ferrand, France
| |
Collapse
|
|
24
|
Han R, Zhang F, Wan C, Liu L, Zhong Q, Ding W. Effect of perfluorooctane sulphonate-induced Kupffer cell activation on hepatocyte proliferation through the NF-κB/TNF-α/IL-6-dependent pathway. CHEMOSPHERE 2018; 200:283-294. [PMID: 29494909 DOI: 10.1016/j.chemosphere.2018.02.137] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 02/21/2018] [Accepted: 02/22/2018] [Indexed: 05/18/2023]
Abstract
Perfluorooctane sulfonate (PFOS), one member of polyfluoroalkyl chemicals (PFASs), persist in the environment and are found in relatively high concentrations in animal livers. PFOS has been shown to induce tumour of the liver in rats following chronic dietary administration. However, the molecular mechanisms involved in PFOS-induced hepatocellular hypertrophy are still not well characterized. In this study, male Sprague-Dawley rats were daily gavaged with PFOS (1 or 10 mg/kg body weight) for 28 days. Rat primary cultured Kupffer cells or hepatocytes were exposed to 100 μM PFOS for 0-48 h. Our results showed that PFOS exposure caused serious hepatocellular damage and obvious inflammatory cell infiltration and increased serum tumour necrosis factor-ɑ (TNF-α) and interleukin-6 (IL-6) levels. Particularly, PFOS exposure triggered Kupffer cell activation and significantly upregulated the expression of proliferating cell nuclear antigen (PCNA), c-Jun, c-MYC and Cyclin D1 (CyD1) in liver. In vitro, PFOS significantly induced production of TNF-α and IL-6 in Kupffer cells and increased PCNA, c-Jun, c-MYC and CyD1 expression in the primary hepatocytes co-cultured with Kupffer cells. However, Kupffer cell activation was mostly abolished by anti-TNF-α or anti-IL6 treatment. Furthermore, blockage of TNF-α and IL-6 significantly inhibited hepatocyte proliferation by gadolinium chloride (GdCl3) pre-treatment in PFOS-treated mice and primary cultured Kupffer cells. On the other hand, NF-κB inhibitor (PDTC) and c-Jun amino-terminal kinase (JNK) inhibitor (SP600125) significantly inhibited production of PFOS-induced TNF-α and IL-6. Taken together, these data suggest that PFOS induces Kupffer cell activation, leading to hepatocyte proliferation by through the NF-κB/TNF-ɑ/IL-6-dependent pathway.
Collapse
Affiliation(s)
- Rui Han
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Fang Zhang
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Chong Wan
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Limin Liu
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Qiang Zhong
- Department of Emergency Medicine, Tongji Hospital Affiliated to Tongji Medical College Huazhong, University of Science & Technology, Wuhan, China.
| | - Wenjun Ding
- Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China.
| |
Collapse
|
|
25
|
Abstract
Liver regeneration after simple resection represents a unique process in which the organ returns to its original size and histologic structure. Over the past 30 years, there has been significant progress in elucidating the mechanisms associated with regeneration after loss of hepatic mass. Liver regeneration after acute liver failure shares several of these classical pathways. It differs, however, in key processes, including the role of both differentiated and stemlike cells. This article outlines these differences in addition to new molecular mechanisms, including immunomodulation, microRNAs, and the gut-liver axis. In addition, applications to the patient population, including prognostication and stem cell therapies, are explored.
Collapse
Affiliation(s)
- Keith M Wirth
- Department of Surgery, University of Minnesota Medical School, 420 Delaware Street SouthEast, MMC 195, Minneapolis, MN 55455, USA.
| | - Scott Kizy
- Department of Surgery, University of Minnesota Medical School, 420 Delaware Street SouthEast, MMC 195, Minneapolis, MN 55455, USA
| | - Clifford J Steer
- Departments of Medicine, and Genetics, Cell Biology and Development, University of Minnesota Medical School, 420 Delaware Street SouthEast, MMC 36, Minneapolis, MN 55455, USA
| |
Collapse
|
|
26
|
Dosimetric parameters predicting contralateral liver hypertrophy after unilobar radioembolization of hepatocellular carcinoma. Eur J Nucl Med Mol Imaging 2017; 45:392-401. [PMID: 29177870 PMCID: PMC5787216 DOI: 10.1007/s00259-017-3845-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 09/28/2017] [Indexed: 02/07/2023]
Abstract
Purpose This study aimed at identifying prior therapy dosimetric parameters using 99mTc-labeled macro-aggregates of albumin (MAA) that are associated with contralateral hepatic hypertrophy occurring after unilobar radioembolization of hepatocellular carcinoma (HCC) performed with 90Y–loaded glass microspheres. Methods The dosimetry data of 73 HCC patients were collected prior to the treatment with 90Y–loaded microspheres for unilateral disease. The injected liver dose (ILD), the tumor dose (TD) and healthy injected liver dose (HILD) were calculated based on MAA quantification. Following treatment, the maximal hypertrophy (MHT) of an untreated lobe was calculated. Results Mean MHT was 35.4 ± 40.4%. When using continuous variables, the MHT was not correlated with any tested variable, i.e., injected activity, ILD, HILD or TD except with a percentage of future remnant liver (FRL) following the 90Y–microspheres injection (r = −0.56). MHT ≥ 10% was significantly more frequent for patients with HILD ≥ 88 Gy, (52% of the cases), i.e., in 92.2% versus 65.7% for HILD < 88 Gy (p = 0.032). MHT ≥ 10% was also significantly more frequent for patients with a TD ≥ 205 Gy and a tumor volume (VT) ≥ 100 cm3 in patients with initial FRL < 50%. MHT ≥10% was seen in 83.9% for patients with either an HILD ≥ 88 Gy or a TD ≥ 205 Gy for tumors larger than 100cm3 (85% of the cases), versus only 54.5% (p = 0.0265) for patients with none of those parameters. MHT ≥10% was also associated with FRL and the Child-Pugh score. Using multivariate analysis, the Child-Pugh score (p < 0.0001), FRL (p = 0.0023) and HILD (p = 0.0029) were still significantly associated with MHT ≥10%. Conclusion This study demonstrates for the first time that HILD is significantly associated with liver hypertrophy. There is also an impact of high tumor doses in large lesions in one subgroup of patients. Larger prospective studies evaluating the MAA dosimetric parameters have to be conducted to confirm these promising results.
Collapse
|
|
27
|
McCracken JM, Chalise P, Briley SM, Dennis KL, Jiang L, Duncan FE, Pritchard MT. C57BL/6 Substrains Exhibit Different Responses to Acute Carbon Tetrachloride Exposure: Implications for Work Involving Transgenic Mice. Gene Expr 2017; 17:187-205. [PMID: 28234577 PMCID: PMC5500426 DOI: 10.3727/105221617x695050] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Biological differences exist between strains of laboratory mice, and it is becoming increasingly evident that there are differences between substrains. In the C57BL/6 mouse, the primary substrains are called 6J and 6N. Previous studies have demonstrated that 6J and 6N mice differ in response to many experimental models of human disease. The aim of our study was to determine if differences exist between 6J and 6N mice in terms of their response to acute carbon tetrachloride (CCl4) exposure. Mice were given CCl4 once and were euthanized 12 to 96 h later. Relative to 6J mice, we found that 6N mice had increased liver injury but more rapid repair. This was because of the increased speed with which necrotic hepatocytes were removed in 6N mice and was directly related to increased recruitment of macrophages to the liver. In parallel, enhanced liver regeneration was observed in 6N relative to 6J mice. Hepatic stellate cell activation occurred earlier in 6N mice, but there was no difference in matrix metabolism between substrains. Taken together, these data demonstrate specific and significant differences in how the C57BL/6 substrains respond to acute CCl4, which has important implications for all mouse studies utilizing this model.
Collapse
Affiliation(s)
- Jennifer M. McCracken
- *Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Prabhakar Chalise
- †Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Shawn M. Briley
- ‡Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Katie L. Dennis
- §Department of Pathology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Lu Jiang
- *Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Francesca E. Duncan
- ‡Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Michele T. Pritchard
- *Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| |
Collapse
|
|
28
|
Kinoshita M, Miyazaki H, Nakashima H, Nakashima M, Nishikawa M, Ishikiriyama T, Kato S, Iwaya K, Hiroi S, Shinomiya N, Seki S. In vivo Lipopolysaccharide Tolerance Recruits CD11b+ Macrophages to the Liver with Enhanced Bactericidal Activity and Low Tumor Necrosis Factor-Releasing Capability, Resulting in Drastic Resistance to Lethal Septicemia. J Innate Immun 2017; 9:493-510. [PMID: 28675904 DOI: 10.1159/000475931] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 04/21/2017] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVES In vivo lipopolysaccharide (LPS) tolerance on bacterial infection was investigated, focusing on liver macrophages. METHODS LPS tolerance was induced by intraperitoneal injections with 5 μg/kg of LPS for 3 consecutive days, and then mice were intravenously infected with Escherichia coli. RESULTS All LPS-primed mice survived lethal bacterial infection. Drastic enhancement of bactericidal activity of liver macrophages strongly contributed to bacterial clearance. Although LPS-primed mice produced substantial amounts of tumor necrosis factor (TNF) inside the liver, TNF efflux into the systemic circulation was markedly suppressed. These mice showed a dramatic increase in CD11b+ monocyte- derived macrophages in the liver. The CD11b+ macrophages that increased in LPS-primed mice were those with strong phagocytic/bactericidal activity and an upregulated expression of Fcγ receptor I, but the subfraction with a potent TNF-producing capacity and poor phagocytic activity diminished. The adoptive transfer of CD11b+ macrophages from LPS-primed mice to control mice increased survival after bacterial infection and reduced the elevation of plasma TNF. LPS priming did not affect the CD68+ resident Kupffer cells, and CD68+ Kupffer cell-depleted mice still exhibited LPS tolerance with strong resistance to bacteremia. CONCLUSIONS LPS tolerance recruits CD11b+ macrophages to the liver with enhanced bactericidal activity, which plays a central role in resistance to lethal bacteremia.
Collapse
Affiliation(s)
- Manabu Kinoshita
- Department of Immunology and Microbiology, National Defense Medical College, Tokorozawa, Japan
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
29
|
Shoda LK, Battista C, Siler SQ, Pisetsky DS, Watkins PB, Howell BA. Mechanistic Modelling of Drug-Induced Liver Injury: Investigating the Role of Innate Immune Responses. GENE REGULATION AND SYSTEMS BIOLOGY 2017; 11:1177625017696074. [PMID: 28615926 PMCID: PMC5459514 DOI: 10.1177/1177625017696074] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 02/04/2017] [Indexed: 12/19/2022]
Abstract
Drug-induced liver injury (DILI) remains an adverse event of significant concern for drug development and marketed drugs, and the field would benefit from better tools to identify liver liabilities early in development and/or to mitigate potential DILI risk in otherwise promising drugs. DILIsym software takes a quantitative systems toxicology approach to represent DILI in pre-clinical species and in humans for the mechanistic investigation of liver toxicity. In addition to multiple intrinsic mechanisms of hepatocyte toxicity (ie, oxidative stress, bile acid accumulation, mitochondrial dysfunction), DILIsym includes the interaction between hepatocytes and cells of the innate immune response in the amplification of liver injury and in liver regeneration. The representation of innate immune responses, detailed here, consolidates much of the available data on the innate immune response in DILI within a single framework and affords the opportunity to systematically investigate the contribution of the innate response to DILI.
Collapse
Affiliation(s)
- Lisl Km Shoda
- DILIsym Services, Inc., Research Triangle Park, NC, USA
| | - Christina Battista
- DILIsym Services, Inc., Research Triangle Park, NC, USA.,UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC, USA
| | - Scott Q Siler
- DILIsym Services, Inc., Research Triangle Park, NC, USA
| | - David S Pisetsky
- Medical Research Service, Durham VA Medical Center and Duke University Medical Center, Durham, NC, USA
| | - Paul B Watkins
- UNC Institute for Drug Safety Sciences, University of North Carolina at Chapel Hill, Research Triangle Park, NC, USA
| | | |
Collapse
|
|
30
|
Cytokines in Hepatic Injury. LIVER PATHOPHYSIOLOGY 2017. [DOI: 10.1016/b978-0-12-804274-8.00027-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
31
|
Paranjpe S, Bowen WC, Mars WM, Orr A, Haynes MM, DeFrances MC, Liu S, Tseng GC, Tsagianni A, Michalopoulos GK. Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology 2016; 64:1711-1724. [PMID: 27397846 PMCID: PMC5074871 DOI: 10.1002/hep.28721] [Citation(s) in RCA: 79] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023]
Abstract
UNLABELLED Receptor tyrosine kinases MET and epidermal growth factor receptor (EGFR) are critically involved in initiation of liver regeneration. Other cytokines and signaling molecules also participate in the early part of the process. Regeneration employs effective redundancy schemes to compensate for the missing signals. Elimination of any single extracellular signaling pathway only delays but does not abolish the process. Our present study, however, shows that combined systemic elimination of MET and EGFR signaling (MET knockout + EGFR-inhibited mice) abolishes liver regeneration, prevents restoration of liver mass, and leads to liver decompensation. MET knockout or simply EGFR-inhibited mice had distinct and signaling-specific alterations in Ser/Thr phosphorylation of mammalian target of rapamycin, AKT, extracellular signal-regulated kinases 1/2, phosphatase and tensin homolog, adenosine monophosphate-activated protein kinase α, etc. In the combined MET and EGFR signaling elimination of MET knockout + EGFR-inhibited mice, however, alterations dependent on either MET or EGFR combined to create shutdown of many programs vital to hepatocytes. These included decrease in expression of enzymes related to fatty acid metabolism, urea cycle, cell replication, and mitochondrial functions and increase in expression of glycolysis enzymes. There was, however, increased expression of genes of plasma proteins. Hepatocyte average volume decreased to 35% of control, with a proportional decrease in the dimensions of the hepatic lobules. Mice died at 15-18 days after hepatectomy with ascites, increased plasma ammonia, and very small livers. CONCLUSION MET and EGFR separately control many nonoverlapping signaling endpoints, allowing for compensation when only one of the signals is blocked, though the combined elimination of the signals is not tolerated; the results provide critical new information on interactive MET and EGFR signaling and the contribution of their combined absence to regeneration arrest and liver decompensation. (Hepatology 2016;64:1711-1724).
Collapse
Affiliation(s)
- Shirish Paranjpe
- Department of Pathology, School of Medicine, University of Pittsburgh
| | - William C. Bowen
- Department of Pathology, School of Medicine, University of Pittsburgh
| | - Wendy M. Mars
- Department of Pathology, School of Medicine, University of Pittsburgh
| | - Anne Orr
- Department of Pathology, School of Medicine, University of Pittsburgh
| | - Meagan M. Haynes
- Department of Pathology, School of Medicine, University of Pittsburgh
| | | | - Silvia Liu
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh
| | - George C. Tseng
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh
| | | | | |
Collapse
|
|
32
|
Perioperative hepatocyte growth factor (HGF) infusions improve hepatic regeneration following portal branch ligation (PBL) in rodents. Surg Endosc 2016; 31:2789-2797. [PMID: 27752816 DOI: 10.1007/s00464-016-5288-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Accepted: 10/05/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND As hepatic surgery has become safer and more commonly performed, the extent of hepatic resections has increased. When there is not enough expected hepatic reserve to facilitate primary resection of hepatic tumors, a clinical adjunct to facilitating primary resection is portal vein embolization (PVE). PVE allows the hepatic remnant to increase to an appropriate size prior to resection via hepatocyte regeneration; however, PVE is not always successful in facilitating adequate regeneration. One of the strongest trophic factors for hepatocyte regeneration is hepatocyte growth factor (HGF). The purpose of this study was to improve hepatic regeneration with perioperative HGF infusions in an animal model that mimics PVE. METHODS Portal branch ligation (PBL) in rodents is equivalent to PVE in humans. We performed left-sided PBL in Sprague-Dawley rodents with the experimental group receiving perioperative HGF infusions. Baseline and postoperative liver volumetrics were obtained with CT scanning methods as performed in clinical practice. Baseline and postoperative liver functions were assessed via indocyanine green (ICG) elimination testing. RESULTS HGF infused rodents had statistically significant increase in all postoperative liver volumetrics. Most clinically relevant were increased right liver volumes (RLV), 14.10 versus 7.85 cm3 (p value 0.0001), and increased degree of hypertrophy (DH %), 159.23 versus 47.11 % (p value 0.0079). HGF infused rodents also had a quick return to baseline liver function, 2.38 days compared to 6.13 days (p value 0.0001). CONCLUSION Perioperative HGF infusions significantly increase hepatic regeneration following PBL in rodents. Perioperative HGF infusions following PVE are a possible adjunct to increase the amount of patients able to successfully undergo primary resection for hepatic tumors. Further basic science is warranted in examining the use of HGF infusions to increase hepatic regeneration and translating that basic science work to clinical practice.
Collapse
|
|
33
|
Abstract
Liver regeneration after partial hepatectomy is an extremely complicated pathophysiologic process, which involves the up-regulation of many proliferation associated proteins and genes. The molecular mechanisms responsible for initiating, maintaining, and terminating this process are still under active investigation and remain one of the research focuses in the field of regenerative medicine. Studies of the mechanism of liver regeneration can provide a theoretical foundation for regeneration promotion and hepatic failure prevention, which is extremely important in clinical practice. This review aims to elucidate the molecular mechanism responsible for the initiation, proliferation and termination of liver regeneration.
Collapse
|
|
34
|
Okay E, Simsek T, Subasi C, Gunes A, Duruksu G, Gurbuz Y, Gacar G, Karaoz E. Cross effects of resveratrol and mesenchymal stem cells on liver regeneration and homing in partially hepatectomized rats. Stem Cell Rev Rep 2016; 11:322-31. [PMID: 25416627 DOI: 10.1007/s12015-014-9572-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In this study, we examined the effect of preoperatively administered resveratrol (RV) and mesenchymal stem cells (MSCs) on regeneration of partially hepatectomized rat liver. We also evaluated the effect of RV on homing of MSCs. MSCs were isolated from bone marrow and cultured in vitro. Wistar albino rats were randomly divided into four groups. In groups, rats received (1) no treatment, (2) single dose RV, (3) MSCs and (4) RV plus MSCs before partial hepatectomy (PH). Injected MSCs were traced by labeling them with green fluorescent protein, and liver regeneration was determined by comparison of liver weight gain, histological examination and immunohistochemical staining with proliferating cell nuclear antigen (PCNA) for mitotic cells. The expression levels of tumor necrosis factor -alpha (TNF-α), interleukin-6 (IL-6) and hepatocyte growth factor (HGF) were also determined in the parafin sections of liver specimens with immunohistochemical staining. Administration of RV and MSCs separately or together enhanced liver regeneration despite decreasing the TNF-α and IL-6 expression. This positive contribution was probably due to direct raising effect on HGF for RV and HGF expression for MSCs that we demonstrated with immunohistochemical staining. Additionally, RV increased the homing of MSCs in liver probably related to life prolonging effect on MSCs. These results indicate that preoperative RV as well as MSCs application enhances liver regeneration after partial hepatectomy in rats. Paying attention to RV about the effect on liver regeneration and homing of MSCs might be the goal of further investigations.
Collapse
Affiliation(s)
- Erdem Okay
- Department of General Surgery, Kocaeli University School of Medicine, Umuttepe, Kocaeli, Turkey,
| | | | | | | | | | | | | | | |
Collapse
|
|
35
|
Deshpande KT, Liu S, McCracken JM, Jiang L, Gaw TE, Kaydo LN, Richard ZC, O'Neil MF, Pritchard MT. Moderate (2%, v/v) Ethanol Feeding Alters Hepatic Wound Healing after Acute Carbon Tetrachloride Exposure in Mice. Biomolecules 2016; 6:5. [PMID: 26751492 PMCID: PMC4808799 DOI: 10.3390/biom6010005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Revised: 11/26/2015] [Accepted: 12/09/2015] [Indexed: 12/12/2022] Open
Abstract
Wound healing consists of three overlapping phases: inflammation, proliferation, and matrix synthesis and remodeling. Prolonged alcohol abuse can cause liver fibrosis due to deregulated matrix remodeling. Previous studies demonstrated that moderate ethanol feeding enhances liver fibrogenic markers and frank fibrosis independent of differences in CCl4-induced liver injury. Our objective was to determine whether or not other phases of the hepatic wound healing response were affected by moderate ethanol after CCl4 exposure. Mice were fed moderate ethanol (2% v/v) for two days and then were exposed to CCl4 and euthanized 24–96 h later. Liver injury was not different between pair- and ethanol-fed mice; however, removal of necrotic tissue was delayed after CCl4-induced liver injury in ethanol-fed mice. Inflammation, measured by TNFα mRNA and protein and hepatic Ly6c transcript accumulation, was reduced and associated with enhanced hepatocyte apoptosis after ethanol feeding. Hepatocytes entered the cell cycle equivalently in pair- and ethanol-fed mice after CCl4 exposure, but hepatocyte proliferation was prolonged in livers from ethanol-fed mice. CCl4-induced hepatic stellate cell activation was increased and matrix remodeling was prolonged in ethanol-fed mice compared to controls. Taken together, moderate ethanol affected each phase of the wound healing response to CCl4. These data highlight previously unknown effects of moderate ethanol exposure on hepatic wound healing after acute hepatotoxicant exposure.
Collapse
Affiliation(s)
- Krutika T Deshpande
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
- Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
| | - Shinlan Liu
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
- Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
| | - Jennifer M McCracken
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
- Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
| | - Lu Jiang
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
- Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
| | - Ta Ehpaw Gaw
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
- Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
| | - Lindsey N Kaydo
- Department of Gastroenterology and Hepatology, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA.
| | - Zachary C Richard
- Department of Gastroenterology and Hepatology, Case Western Reserve University, 10900 Euclid Ave., Cleveland, OH 44106, USA.
| | - Maura F O'Neil
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
- Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
| | - Michele T Pritchard
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
- Department of Pathology, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, USA.
| |
Collapse
|
|
36
|
Feng G, Long Y, Peng J, Li Q, Cui Z. Transcriptomic characterization of the dorsal lobes after hepatectomy of the ventral lobe in zebrafish. BMC Genomics 2015; 16:979. [PMID: 26584608 PMCID: PMC4653908 DOI: 10.1186/s12864-015-2145-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2015] [Accepted: 10/26/2015] [Indexed: 02/08/2023] Open
Abstract
Background The liver possesses an ability of compensatory growth after removing three of five lobes in mammals or one of three lobes in zebrafish. The reenter of hepatocytes into the cell cycle is one of the hallmarks for the initiation of liver compensatory growth, but cellular and molecular mechanisms underlying the activation of hepatocytes remain largely unknown. Results To better understand the process, transcriptional profiles of the remaining liver dorsal lobes in female zebrafish were generated with RNA-seq. About 44 million raw reads were obtained from three sequencing libraries and 71 % of raw reads were mapped to the reference genome of zebrafish. A total number of 5652 genes were differentially expressed in at least one of two time points during the compensatory growth of liver dorsal lobes and classified into different functional categories. A number of genes encoding angiogenesis-related growth factors/ligands and apoptosis-associated cytokines were strongly expressed at 6-h time point after the removal of the ventral lobe. Gene ontology enrichment analysis of genes up-regulated during early stages of liver compensatory growth revealed that small GTPase-mediated signal transduction, RNA processing and intracellular protein transport were the most highly overrepresented biological processes and SNARE interactions in vesicular transport, proteasome and basal transcription factors were the most highly enriched pathways. Moreover, 477 genes differently expressed during liver compensatory growth of both female zebrafish and mice were involved in the response to stimulus, DNA replication, metabolic processes of fatty acid, lipid and steroid, multicellular organismal homeostasis and extracellular matrix constituent secretion. Conclusions Multiple biological processes and signaling pathways are immediately activated in remaining dorsal lobes of female zebrafish right after removal of the ventral lobe and these findings provide crucial clues for further identification of cis-elements and trans-factors that are extensively involved in the initiation of liver compensatory growth. Electronic supplementary material The online version of this article (doi:10.1186/s12864-015-2145-5) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Guohui Feng
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China. .,University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Yong Long
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
| | - Jinrong Peng
- Zhejiang University, Hangzhou, 310058, Zhejiang, China.
| | - Qing Li
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
| | - Zongbin Cui
- The Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, 430072, Hubei, China.
| |
Collapse
|
|
37
|
Abstract
The mammalian liver is one of the most regenerative tissues in the body, capable of fully recovering mass and function after a variety of injuries. This factor alone makes the liver unusual among mammalian tissues, but even more atypical is the widely held notion that the method of repair depends on the manner of injury. Specifically, the liver is believed to regenerate via replication of existing cells under certain conditions and via differentiation from specialized cells--so-called facultative stem cells--under others. Nevertheless, despite the liver's dramatic and unique regenerative response, the cellular and molecular features of liver homeostasis and regeneration are only now starting to come into relief. This review provides an overview of normal liver function and development and focuses on the evidence for and against various models of liver homeostasis and regeneration.
Collapse
Affiliation(s)
- Ben Z Stanger
- Division of Gastroenterology, Department of Medicine, Abramson Family Cancer Research Institute, and Department of Cell and Developmental Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104;
| |
Collapse
|
|
38
|
Mouse CD11b+Kupffer Cells Recruited from Bone Marrow Accelerate Liver Regeneration after Partial Hepatectomy. PLoS One 2015; 10:e0136774. [PMID: 26333171 PMCID: PMC4557907 DOI: 10.1371/journal.pone.0136774] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Accepted: 08/08/2015] [Indexed: 01/11/2023] Open
Abstract
TNF and Fas/FasL are vital components, not only in hepatocyte injury, but are also required for hepatocyte regeneration. Liver F4/80+Kupffer cells are classified into two subsets; resident radio-resistant CD68+cells with phagocytic and bactericidal activity, and recruited radio-sensitive CD11b+cells with cytokine-producing capacity. The aim of this study was to investigate the role of these Kupffer cells in the liver regeneration after partial hepatectomy (PHx) in mice. The proportion of Kupffer cell subsets in the remnant liver was examined in C57BL/6 mice by flow cytometry after PHx. To examine the role of CD11b+Kupffer cells/Mφ, mice were depleted of these cells before PHx by non-lethal 5 Gy irradiation with or without bone marrow transplantation (BMT) or the injection of a CCR2 (MCP-1 receptor) antagonist, and liver regeneration was evaluated. Although the proportion of CD68+Kupffer cells did not significantly change after PHx, the proportion of CD11b+Kupffer cells/Mφ and their FasL expression was greatly increased at three days after PHx, when the hepatocytes vigorously proliferate. Serum TNF and MCP-1 levels peaked one day after PHx. Irradiation eliminated the CD11b+Kupffer cells/Mφ for approximately two weeks in the liver, while CD68+Kupffer cells, NK cells and NKT cells remained, and hepatocyte regeneration was retarded. However, BMT partially restored CD11b+Kupffer cells/Mφ and recovered the liver regeneration. Furthermore, CCR2 antagonist treatment decreased the CD11b+Kupffer cells/Mφ and significantly inhibited liver regeneration. The CD11b+Kupffer cells/Mφ recruited from bone marrow by the MCP-1 produced by CD68+Kupffer cells play a pivotal role in liver regeneration via the TNF/FasL/Fas pathway after PHx.
Collapse
|
|
39
|
Wen Y, Feng D, Wu H, Liu W, Li H, Wang F, Xia Q, Gao WQ, Kong X. Defective Initiation of Liver Regeneration in Osteopontin-Deficient Mice after Partial Hepatectomy due to Insufficient Activation of IL-6/Stat3 Pathway. Int J Biol Sci 2015; 11:1236-47. [PMID: 26327817 PMCID: PMC4551759 DOI: 10.7150/ijbs.12118] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 07/29/2015] [Indexed: 01/31/2023] Open
Abstract
The initial process in liver regeneration after partial hepatectomy involves the recruitment of immune cells and the release of cytokines. Osteopontin (OPN), a pro-inflammatory protein, plays critical roles in immune cell activation and migration. Although OPN has been implicated in the pathogenesis of many liver diseases, the role of OPN in liver regeneration remains obscure. In the present study, we found that serum and hepatic OPN protein levels were significantly elevated in wild-type (WT) mice after partial hepatectomy (PHx) and that bile ductal epithelia were the major cell source of hepatic OPN. Compared to WT mice, OPN knockout (KO) mice exhibited delayed liver regeneration after PHx. This delay in OPN-/- mice was attributed to impaired hepatic infiltration of macrophages and neutrophils, decreased serum and hepatic IL-6 levels, and blunted activation of macrophages after PHx. Furthermore, we demonstrate that the attenuated activation of macrophages is at least partially due to decreased hepatic and portal vein LPS levels in OPN-/- mice. In response to decreased IL-6 levels, the activation of signal transducer and transcription (Stat) 3 was reduced in hepatocytes of OPN-/- mice compared to WT mice after PHx. Consequently, hepatic activation of the downstream direct targets of IL6/Stat3, such as c-fos, c-jun, and c-myc, was also suppressed post-PHx in OPN-/- mice compared to WT mice. Collectively, these results support a unique role for OPN during the priming phase of liver regeneration, in which OPN enhances the recruitment of macrophages and neutrophils, and triggers hepatocyte proliferation through Kupffer cell-derived IL-6 release and the downstream activation of Stat3.
Collapse
Affiliation(s)
- Yankai Wen
- 1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Liver Surgery, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Dechun Feng
- 2. Laboratory of liver diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Hailong Wu
- 1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Liver Surgery, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Wenjun Liu
- 1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Liver Surgery, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Hongjie Li
- 1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Liver Surgery, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Fang Wang
- 1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Liver Surgery, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Qiang Xia
- 1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Liver Surgery, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Wei-Qiang Gao
- 1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Liver Surgery, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoni Kong
- 1. State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Department of Liver Surgery, Ren Ji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China
| |
Collapse
|
|
40
|
Nojima H, Freeman CM, Gulbins E, Lentsch AB. Sphingolipids in liver injury, repair and regeneration. Biol Chem 2015; 396:633-43. [PMID: 25781682 DOI: 10.1515/hsz-2014-0296] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 03/09/2015] [Indexed: 02/05/2023]
Abstract
Abstract
Sphingolipids are not only essential components of cellular membranes but also function as intracellular and extracellular mediators that regulate important physiological cellular processes including cell survival, proliferation, apoptosis, differentiation, migration and immune responses. The liver possesses the unique ability to regenerate after injury in a complex manner that involves numerous mediators, including sphingolipids such as ceramide and sphingosine 1-phosphate. Here we present the current understanding of the involvement of the sphingolipid pathway and the role this pathway plays in regulating liver injury, repair and regeneration. The regulation of sphingolipids and their enzymes may have a great impact in the development of novel therapeutic modalities for a variety of liver injuries and diseases.
Collapse
|
|
41
|
Yoshiya S, Shirabe K, Imai D, Toshima T, Yamashita YI, Ikegami T, Okano S, Yoshizumi T, Kawanaka H, Maehara Y. Blockade of the apelin-APJ system promotes mouse liver regeneration by activating Kupffer cells after partial hepatectomy. J Gastroenterol 2015; 50:573-82. [PMID: 25148722 DOI: 10.1007/s00535-014-0992-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Accepted: 08/04/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND Liver regeneration after massive hepatectomy or living donor liver transplantation is critical. The apelin-APJ system is involved in the regulation of cardiovascular function, inflammation, fluid homeostasis, the adipo-insular axis, and angiogenesis, but its function in liver regeneration remains unclear. METHODS We investigated the impact of pharmacologic blockade of the apelin-APJ system, using the specific APJ antagonist F13A on liver regeneration after hepatectomy in mice. RESULTS F13A-treated mice had significantly higher serum concentrations of tumor necrosis factor (TNF)-α and interleukin (IL)-6 than control mice, due to F13A-promoted activation of Kupffer cells. Compared with untreated mice, F13A enhanced the signal transducer and activator of transcription 3 and mitogen-activated protein kinase pathways, stimulated cell-cycle progression, and promoted hepatocyte proliferation and liver regeneration without inducing apoptosis or inflammation in regenerating livers. In vitro, Kupffer cells expressed APJ and were activated directly by F13A treatment, releasing TNF-α and IL-6. Moreover, F13A-treated mice had a higher survival rate than untreated mice in the extended hepatectomy model. CONCLUSIONS F13A treatment promotes early phase liver regeneration after hepatectomy by promoting the activation of Kupffer cells and increasing serum levels of TNF-α and IL-6. F13A treatment may become a therapeutic option to facilitate efficient liver regeneration after liver surgery.
Collapse
Affiliation(s)
- Shohei Yoshiya
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan,
| | | | | | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Abstract
Alcoholic liver disease (ALD) is a complex process that includes a wide spectrum of hepatic lesions, from steatosis to cirrhosis. Cell injury, inflammation, oxidative stress, regeneration and bacterial translocation are key drivers of alcohol-induced liver injury. Alcoholic hepatitis is the most severe form of all the alcohol-induced liver lesions. Animal models of ALD mainly involve mild liver damage (that is, steatosis and moderate inflammation), whereas severe alcoholic hepatitis in humans occurs in the setting of cirrhosis and is associated with severe liver failure. For this reason, translational studies using humans and human samples are crucial for the development of new therapeutic strategies. Although multiple attempts have been made to improve patient outcome, the treatment of alcoholic hepatitis is still based on abstinence from alcohol and brief exposure to corticosteroids. However, nearly 40% of patients with the most severe forms of alcoholic hepatitis will not benefit from treatment. We suggest that future clinical trials need to focus on end points other than mortality. This Review discusses the main pathways associated with the progression of liver disease, as well as potential therapeutic strategies targeting these pathways.
Collapse
|
|
43
|
Corlu A, Loyer P. Culture Conditions Promoting Hepatocyte Proliferation and Cell Cycle Synchronization. Methods Mol Biol 2015; 1250:27-51. [PMID: 26272133 DOI: 10.1007/978-1-4939-2074-7_3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
The liver overcomes damages induced by harmful substances or viral infections and allows the use of extended resection in human therapy through its remarkable ability to regenerate. The regeneration process relies on the massive proliferation of differentiated hepatocytes that exit quiescence and undergo a limited number of cell cycles to restore the hepatic mass. Many discoveries on the regulation of hepatocyte proliferation have benefited from the use of in vitro models of cultures of primary hepatocytes as well as hepatoma cells as opposed to data obtained from in vivo models of liver regeneration, such as following partial hepatectomy in rodents. In this chapter, the most pertinent in vitro models used to promote the proliferation of hepatocytes and technical procedures to synchronize their progression throughout the cell cycle are presented with the goal to investigate the regulation of the hepatocyte cell cycle and the molecular pathways regulating liver regeneration.
Collapse
Affiliation(s)
- Anne Corlu
- Inserm, UMR 991, Liver, Metabolisms and Cancer, Hôpital Pontchaillou, University of Rennes 1, Rennes Cedex, 35033, France
| | | |
Collapse
|
|
44
|
Cetta F, Fusai G, Malagò M. Liver Pathophysiology: Liver Regeneration, Vascular Alterations, and Ischemia/Reperfusion. BENIGN TUMORS OF THE LIVER 2015:35-45. [DOI: 10.1007/978-3-319-12985-3_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
|
|
45
|
Tackett BC, Sun H, Mei Y, Maynard JP, Cheruvu S, Mani A, Hernandez-Garcia A, Vigneswaran N, Karpen SJ, Thevananther S. P2Y2 purinergic receptor activation is essential for efficient hepatocyte proliferation in response to partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 2014; 307:G1073-87. [PMID: 25301185 PMCID: PMC4254960 DOI: 10.1152/ajpgi.00092.2014] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 09/30/2014] [Indexed: 01/31/2023]
Abstract
Extracellular nucleotides via activation of P2 purinergic receptors influence hepatocyte proliferation and liver regeneration in response to 70% partial hepatectomy (PH). Adult hepatocytes express multiple P2Y (G protein-coupled) and P2X (ligand-gated ion channels) purinergic receptor subtypes. However, the identity of key receptor subtype(s) important for efficient hepatocyte proliferation in regenerating livers remains unknown. To evaluate the impact of P2Y2 purinergic receptor-mediated signaling on hepatocyte proliferation in regenerating livers, wild-type (WT) and P2Y2 purinergic receptor knockout (P2Y2-/-) mice were subjected to 70% PH. Liver tissues were analyzed for activation of early events critical for hepatocyte priming and subsequent cell cycle progression. Our findings suggest that early activation of p42/44 ERK MAPK (5 min), early growth response-1 (Egr-1) and activator protein-1 (AP-1) DNA-binding activity (30 min), and subsequent hepatocyte proliferation (24-72 h) in response to 70% PH were impaired in P2Y2-/- mice. Interestingly, early induction of cytokines (TNF-α, IL-6) and cytokine-mediated signaling (NF-κB, STAT-3) were intact in P2Y2-/- remnant livers, uncovering the importance of cytokine-independent and nucleotide-dependent early priming events critical for subsequent hepatocyte proliferation in regenerating livers. Hepatocytes isolated from the WT and P2Y2-/- mice were treated with ATP or ATPγS for 5-120 min and 12-24 h. Extracellular ATP alone, via activation of P2Y2 purinergic receptors, was sufficient to induce ERK phosphorylation, Egr-1 protein expression, and key cyclins and cell cycle progression of hepatocytes in vitro. Collectively, these findings highlight the functional significance of P2Y2 purinergic receptor activation for efficient hepatocyte priming and proliferation in response to PH.
Collapse
Affiliation(s)
- Bryan C Tackett
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, Texas; Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas
| | - Hongdan Sun
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, Texas
| | - Yu Mei
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, Texas
| | - Janielle P Maynard
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, Texas; Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas
| | - Sayuri Cheruvu
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, Texas
| | - Arunmani Mani
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, Texas
| | | | - Nadarajah Vigneswaran
- Department of Diagnostic Sciences, University of Texas Dental Branch in Houston, Houston, Texas
| | - Saul J Karpen
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, Texas; Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas
| | - Sundararajah Thevananther
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Liver Center, Houston, Texas; Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas;
| |
Collapse
|
|
46
|
Abstract
Liver regeneration after partial hepatectomy is the only example of a regenerative process in mammals in which the organ/body weight ratio returns to 100% of the original when the process is complete. The adjustment of liver weight to the needs of the body suggests a complicated set of control points, a 'hepatostat'. There has been much progress in elucidation of mechanisms involved in initiation of liver regeneration. More recent studies have focused on termination pathways, because these may be the underlying controls of the hepatostat and their elimination may be relevant to hepatic neoplasia. When the standard regenerative process is thwarted due to failure of either hepatocytes or biliary epithelial cells to proliferate, each of the two epithelial compartments can function as a source of facultative stem cells for the other.
Collapse
Affiliation(s)
- George K Michalopoulos
- Department of Pathology, University of Pittsburgh School of Medicine, Bioscience Tower South, Pittsburgh, PA 15261, USA
| |
Collapse
|
|
47
|
Su Z, Li P, Wu B, Ma H, Wang Y, Liu G, Zeng H, Li Z, Wei X. PHBVHHx scaffolds loaded with umbilical cord-derived mesenchymal stem cells or hepatocyte-like cells differentiated from these cells for liver tissue engineering. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2014; 45:374-82. [PMID: 25491842 DOI: 10.1016/j.msec.2014.09.022] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/02/2014] [Revised: 08/02/2014] [Accepted: 09/11/2014] [Indexed: 12/20/2022]
Abstract
More attention has recently been focused on the treatment of various kinds of hepatic diseases based on cell-based therapies. In this study, mesenchymal stem cells were isolated from umbilical cord (UC-MSCs). Results confirmed that UC-MSCs could differentiate into adipocytes, osteoblasts and hepatocytes. Poly(3-hydroxybutyrate-co-3-hydroxyvalerate-co-3-hydroxyhexanoate) (PHBVHHx), a new member of polyhydroxyalkanoate (PHA) family, was produced by bacteria. Liver-injured mouse model was established by CCl4 injection. PHBVHHx scaffolds were transplanted into the liver-injured mice. Liver morphology on day 28 post-transplantation of scaffolds loaded with UC-MSCs or hepatocyte-like cells differentiated from UC-MSCs significantly improved and looked similar to the normal liver. Concentrations of albumin (ALB) significantly increased, and total bilirubin (TB) and alanine axminotransferase (ALT) significantly decreased on days 14 and 28 post-transplantation of scaffolds loaded with UC-MSCs or differentiated UC-MSCs. HE staining showed that on day 28 post-transplantation of scaffolds loaded with UC-MSCs or differentiated UC-MSCs, livers had similar tissue structure of normal livers. Masson staining showed that on day 28 post-transplantation of scaffolds loaded with UC-MSCs or differentiated UC-MSCs, livers had less blue staining for collagen deposition compared with the others. These results demonstrated that PHBVHHx scaffolds loaded with UC-MSCs or differentiated UC-MSCs had the similar effect on injured livers and significantly promoted the recovery of injured livers.
Collapse
Affiliation(s)
- Zhongchun Su
- Institute of Biomedicine, College of Life Science and Technology, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China
| | - Pengshan Li
- Institute of Biomedicine, College of Life Science and Technology, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China
| | - Bogang Wu
- Institute of Biomedicine, College of Life Science and Technology, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China
| | - Huan Ma
- Institute of Biomedicine, College of Life Science and Technology, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China
| | - Yuechun Wang
- Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Gexiu Liu
- Department of Physiology, School of Medicine, Jinan University, Guangzhou 510632, China
| | - Huilan Zeng
- Department of Hematology, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Zhizhong Li
- Department of Bone, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China
| | - Xing Wei
- Institute of Biomedicine, College of Life Science and Technology, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China.
| |
Collapse
|
|
48
|
Remote ischemic preconditioning prevents lipopolysaccharide-induced liver injury through inhibition of NF-κB activation in mice. J Anesth 2014; 28:898-905. [DOI: 10.1007/s00540-014-1850-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 05/07/2014] [Indexed: 01/13/2023]
|
|
49
|
Bellet MM, Piobbico D, Bartoli D, Castelli M, Pieroni S, Brunacci C, Chiacchiaretta M, Del Sordo R, Fallarino F, Sidoni A, Puccetti P, Romani L, Servillo G, Della Fazia MA. NEDD4 controls the expression of GUCD1, a protein upregulated in proliferating liver cells. Cell Cycle 2014; 13:1902-11. [PMID: 24743017 DOI: 10.4161/cc.28760] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Liver regeneration is a unique means of studying cell proliferation in vivo. Screening of a large cDNA library from regenerating liver has previously allowed us to identify and characterize a cluster of genes encoding proteins with important roles in proliferative processes. Here, by examining different rat and human tissues as well as cell lines, we characterized a highly conserved gene, guanylyl cyclase domain containing 1 (GUCD1), whose modulation occurs in liver regeneration and cell cycle progression in vitro. High-level expression of GUCD1 transcripts was observed in livers from patients with hepatocellular carcinoma. A yeast two-hybrid interaction assay, aimed at identifying any relevant interaction partners of GUCD1, revealed direct interactions with NEDD4-1 (E3 ubiquitin protein ligase neural precursor cell expressed, developmentally downregulated gene 4), resulting in control of GUCD1 stability. Thus, we have characterized expression and function of a ubiquitous protein, GUCD1, which might have a role in regulating normal and abnormal cell growth in the liver.
Collapse
Affiliation(s)
| | - Danilo Piobbico
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | - Daniela Bartoli
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | - Marilena Castelli
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | - Stefania Pieroni
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | - Cinzia Brunacci
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | | | - Rachele Del Sordo
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | | | - Angelo Sidoni
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | - Paolo Puccetti
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | - Luigina Romani
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | - Giuseppe Servillo
- Department of Experimental Medicine; University of Perugia; Perugia, Italy
| | | |
Collapse
|
|
50
|
Periwal V, Gaillard JR, Needleman L, Doria C. Mathematical model of liver regeneration in human live donors. J Cell Physiol 2014; 229:599-606. [PMID: 24446196 DOI: 10.1002/jcp.24482] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2013] [Accepted: 09/30/2013] [Indexed: 01/31/2023]
Abstract
Liver regeneration after injury occurs in many mammals. Rat liver regenerates after partial hepatectomy over a period of 2 weeks while human liver regeneration takes several months. Notwithstanding this enormous difference in time-scales, with new data from five human live liver transplant donors, we show that a mathematical model of rat liver regeneration can be transferred to human, with all biochemical interactions and signaling unchanged. Only six phenomenological parameters need change, and three of these parameter changes are rescalings of rate constants by the ratio of human lifespan to rat lifespan. Data from three donor subjects with approximately equal resections were used to fit the three parameters and the data from the other two donor subjects was used to independently verify the fit.
Collapse
Affiliation(s)
- V Periwal
- Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | | | | | | |
Collapse
|