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Rieder F, Nagy LE, Maher TM, Distler JHW, Kramann R, Hinz B, Prunotto M. Fibrosis: cross-organ biology and pathways to development of innovative drugs. Nat Rev Drug Discov 2025:10.1038/s41573-025-01158-9. [PMID: 40102636 DOI: 10.1038/s41573-025-01158-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/10/2025] [Indexed: 03/20/2025]
Abstract
Fibrosis is a pathophysiological mechanism involved in chronic and progressive diseases that results in excessive tissue scarring. Diseases associated with fibrosis include metabolic dysfunction-associated steatohepatitis (MASH), inflammatory bowel diseases (IBDs), chronic kidney disease (CKD), idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc), which are collectively responsible for substantial morbidity and mortality. Although a few drugs with direct antifibrotic activity are approved for pulmonary fibrosis and considerable progress has been made in the understanding of mechanisms of fibrosis, translation of this knowledge into effective therapies continues to be limited and challenging. With the aim of assisting developers of novel antifibrotic drugs, this Review integrates viewpoints of biologists and physician-scientists on core pathways involved in fibrosis across organs, as well as on specific characteristics and approaches to assess therapeutic interventions for fibrotic diseases of the lung, gut, kidney, skin and liver. This discussion is used as a basis to propose strategies to improve the translation of potential antifibrotic therapies.
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Affiliation(s)
- Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA.
- Program for Global Translational Inflammatory Bowel Diseases (GRID), Chicago, IL, USA.
| | - Laura E Nagy
- Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
- Northern Ohio Alcohol Center, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Toby M Maher
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
- National Heart and Lung Institute, Imperial College, London, UK
| | - Jörg H W Distler
- Department of Rheumatology, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
- Hiller Research Center, University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Rafael Kramann
- Department of Nephrology and Clinical Immunology, RWTH Aachen; Medical Faculty, Aachen, Germany
- Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, Netherlands
| | - Boris Hinz
- Keenan Research Institute for Biomedical Science of the St Michael's Hospital, Toronto, Ontario, Canada
- Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada
| | - Marco Prunotto
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland.
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Chen L, Yang H, Wang J, Zhang H, Fu K, Yan Y, Liu Z. MEOX1-mediated transcriptional regulation of circABHD3 exacerbates hepatic fibrosis through promoting m6A/YTHDF2-dependent YPEL3 mRNA decay to activate β-catenin signaling. PLoS Genet 2025; 21:e1011622. [PMID: 40100806 PMCID: PMC11918346 DOI: 10.1371/journal.pgen.1011622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Accepted: 02/13/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Hepatic fibrosis may progress to liver cirrhosis and eventually cause death. Epithelial-mesenchymal transition (EMT) of hepatocytes plays critical roles in hepatic fibrosis. Exploring the mechanisms underlying EMT is crucial for a better understanding of hepatic fibrosis pathogenesis. METHODS Hepatocyte EMT wad induced with TGF-β1 and evaluated by Western blotting and immunofluorescence staining. Methylated RNA immunoprecipitation (MeRIP) was applied to assess N6-methyladenosine (m6A) modification. RIP and RNA pull-down assays were performed to analyze the interaction between circABHD3, YTHDF2 and YPEL3 mRNA. MEOX1-mediated transcription of ABHD3 was examined by luciferase and chromatin immunoprecipitation (ChIP). Mice were intraperitoneally injected with CCl4 or treated with bile duct ligation (BDL) surgery for hepatic fibrosis induction. Liver injury and collagen deposition were examined with hematoxylin and eosin (HE), Masson, and Sirius Red staining. Alanine transaminase (ALT), aspartate transaminase (AST) and hydroxyproline (HYP) were examined using ELISA. RESULTS CircABHD3 was upregulated in in vitro and in vivo models of hepatic fibrosis and patients. Knockdown of circABHD3 inhibited TGF-β1-induced expression of fibrosis markers, EMT and mitochondrial impairment in hepatocytes. MEOX1 could directly bind to the promoter of ABHD3 to facilitate its transcription and subsequent circABHD3 generation. Knockdown of MEOX1 suppressed TGF-β1-induced EMT and mitochondrial impairment through suppression of circABHD3. CircABHD3 destabilized YPEL3 mRNA via promoting YTHDF2-dependent recognition of m6A-modified YPEL3 mRNA to trigger β-catenin signaling activation. Furthermore, circABHD3 silencing-mediated inhibition of EMT and mitochondrial impairment was counteracted by YPEL3 knockdown and activation of β-catenin signaling. Depletion of circABHD3 significantly reduced EMT, mitochondrial impairment and hepatic fibrosis via promoting YPEL3 expression and suppressing β-catenin signaling in vivo. CONCLUSION MEOX1-mediated generation of circABHD3 promotes EMT and mitochondrial impairment by enhancing YTHDF2-mediated degradation of YPEL3 mRNA and activating downstream β-catenin signaling, thus exacerbating hepatic fibrosis.
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Affiliation(s)
- Limin Chen
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
| | - Hui Yang
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
| | - Juan Wang
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
| | - Haoye Zhang
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
| | - Kangkang Fu
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
| | - Yu Yan
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
| | - Zhenguo Liu
- Department of Infectious Disease, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
- Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, Hunan Province, P.R. China
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Lin CH, Cheng CF, Chiou YS, Wang I, Kuo CY. Molecular Biological Mechanisms of Action of Chrysophanol in Hepatic Stellate Cells Activated by Hepatic B Virus X Based on Network Pharmacology. Intervirology 2024; 67:119-135. [PMID: 39647471 PMCID: PMC11623962 DOI: 10.1159/000542355] [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: 05/05/2024] [Accepted: 10/28/2024] [Indexed: 12/10/2024] Open
Abstract
INTRODUCTION Chrysophanol (Cho) is a natural anthraquinone with biological effects such as inducing ferroptosis and anticancer activity. The hepatitis B virus X protein (HBx) is essential for HBV replication. We aimed to identify the key pathways in HBx-induced hepatic stellate cell (HSC) activation and to characterize the potential mechanisms of action of Cho against liver fibrosis. METHODS HSC-T6 cells were transfected with FLAG (control group) or FLAG-HBx (HBx group), and RNA sequencing and Western blotting analysis were conducted to assess the effects of HBx and Cho on specific molecular targets and signaling pathways. RESULTS Gene ontology and pathway analyses indicated that the genes targeted by HBx participate in immunological responses, chemokine and cytokine activity, cell-substrate adhesion, extracellular matrix organization, growth factor binding, defense responses, and antigen processing and presentation. RNA-seq and Western blotting data revealed that HBx-activated HSC-T6 cells exhibited upregulated expression of mammalian target of rapamycin (mTOR), phosphorylated mTOR (p-mTOR), S6, phosphorylated S6 (p-S6), peroxisome proliferator-activated receptor (PPAR-α), phosphorylated-PPAR-α (p-PPAR-α), CYP27, α-smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), and Integrin-β1, which was reversed after treatment with Cho. These results were also verified in a HBx-activated HSC-T6 and LX-2 cell model and thioacetamide-induced liver fibrosis mouse model. CONCLUSIONS Thus, our findings indicate that Cho ameliorates HBx-induced HSC activation and liver fibrosis via inhibition of the mTOR and PPARs signaling pathways, suggesting that Cho is a potential therapeutic for chronic liver inflammation-mediated diseases.
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Affiliation(s)
- Chih-Hung Lin
- Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei, Taiwan
- Ph.D. Program in Nutrition and Food Science, Fu Jen Catholic University, New Taipei, Taiwan
| | - Ching-Feng Cheng
- Department of Paediatrics, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- Department of Paediatrics, School of Medicine, Tzu Chi University, Hualien, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
| | - Yi-Shiou Chiou
- Master’s Degree Programme in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Inga Wang
- Department of Rehabilitation Sciences and Technology, University of Wisconsin- Milwaukee, Milwaukee, WI, USA
| | - Chan-Yen Kuo
- Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, New Taipei, Taiwan
- Department of Medical Technology, Jenteh Junior College of Medicine, Nursing and Management, Miaoli, Taiwan
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Hu Y, Peng L, Zhuo X, Yang C, Zhang Y. Hedgehog Signaling Pathway in Fibrosis and Targeted Therapies. Biomolecules 2024; 14:1485. [PMID: 39766192 PMCID: PMC11727624 DOI: 10.3390/biom14121485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/17/2024] [Accepted: 11/20/2024] [Indexed: 01/12/2025] Open
Abstract
Hedgehog (Hh) signaling is a well-established developmental pathway; it is crucial for early embryogenesis, cell differentiation, and damage-driven regeneration. It is being increasingly recognized that dysregulated Hh signaling is also involved in fibrotic diseases, which are characterized by excessive extracellular matrix deposition that compromises tissue architecture and function. As in-depth insights into the mechanisms of Hh signaling are obtained, its complex involvement in fibrosis is gradually being illuminated. Notably, some Hh-targeted inhibitors are currently under exploration in preclinical and clinical trials as a means to prevent fibrosis progression. In this review, we provide a concise overview of the biological mechanisms involved in Hh signaling. We summarize the latest advances in our understanding of the roles of Hh signaling in fibrogenesis across the liver, kidneys, airways, and lungs, as well as other tissues and organs, with an emphasis on both the shared features and, more critically, the distinct functional variations observed across these tissues and organs. We thus highlight the context dependence of Hh signaling, as well as discuss the current status and the challenges of Hh-targeted therapies for fibrosis.
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Affiliation(s)
- Yuchen Hu
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.H.); (L.P.); (X.Z.)
- Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Linrui Peng
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.H.); (L.P.); (X.Z.)
- Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xinyu Zhuo
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.H.); (L.P.); (X.Z.)
- Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Chan Yang
- Division of Endocrinology and Metabolism, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China;
| | - Yuwei Zhang
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu 610041, China; (Y.H.); (L.P.); (X.Z.)
- Center for Diabetes and Metabolism Research, West China Hospital, Sichuan University, Chengdu 610041, China
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Lu X, Yu L, Zheng J, Li A, Li J, Lou H, Zhang W, Guo H, Wang Y, Li X, Gao Y, Fan X, Borlak J. miR-106b-5p protects against drug-induced liver injury by targeting vimentin to stimulate liver regeneration. MedComm (Beijing) 2024; 5:e692. [PMID: 39170945 PMCID: PMC11337467 DOI: 10.1002/mco2.692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 07/02/2024] [Accepted: 07/17/2024] [Indexed: 08/23/2024] Open
Abstract
Understanding the endogenous mechanism of adaptive response to drug-induced liver injury (arDILI) may discover innovative strategies to manage DILI. To gain mechanistic insight into arDILI, we investigated exosomal miRNAs in the adaptive response to toosendanin-induced liver injury (TILI) of mice. Exosomal miR-106b-5p was identified as a specific regulator of arDILI by comprehensive miRNA profiling. Outstandingly, miR-106b-5p agomir treatment alleviated TILI and other DILI by inhibiting apoptosis and promoting hepatocyte proliferation. Conversely, antagomir treatments had opposite effects, indicating that miR-106b-5p protects mice from liver injury. Injured hepatocytes released miR-106b-5p-enriched exosomes taken up by surrounding hepatocytes. Vim (encodes vimentin) was identified as an important target of miR-106b-5p by dual luciferase reporter and siRNA assays. Furthermore, single-cell RNA-sequencing analysis of toosendanin-injured mouse liver revealed a cluster of Vim + hepatocytes; nonetheless declined following miR-106b-5p cotreatment. More importantly, Vim knockout protected mice from acetaminophen poisoning and TILI. In the clinic, serum miR-106b-5p expression levels correlated with the severity of DILI. Indeed, liver biopsies of clinical cases exposed to different DILI causing drugs revealed marked vimentin expression among harmed hepatocytes, confirming clinical relevance. Together, we report mechanisms of arDILI whereby miR-106b-5p safeguards restorative tissue repair by targeting vimentin.
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Affiliation(s)
- Xiaoyan Lu
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
- State Key Laboratory of Chinese Medicine ModernizationInnovation Center of Yangtze River DeltaZhejiang UniversityJiaxingChina
- State Key Laboratory of Component‐Based Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Lingqi Yu
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
- State Key Laboratory of Chinese Medicine ModernizationInnovation Center of Yangtze River DeltaZhejiang UniversityJiaxingChina
| | - Jie Zheng
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - Anyao Li
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - Junying Li
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - He Lou
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
| | - Wentao Zhang
- Department of Hepatobiliarythe First Affiliated Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
| | - Hui Guo
- Department of Hepatobiliarythe First Affiliated Hospital of Tianjin University of Traditional Chinese MedicineTianjinChina
| | - Yuzhen Wang
- Department of PharmacySir Run Run Shaw HospitalZhejiang University School of MedicineHangzhouChina
| | - Xuemei Li
- State Key Laboratory of Component‐Based Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
| | - Yue Gao
- State Key Laboratory of Component‐Based Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
- Department of Pharmaceutical SciencesBeijing Institute of Radiation MedicineBeijingChina
| | - Xiaohui Fan
- Pharmaceutical Informatics InstituteCollege of Pharmaceutical SciencesZhejiang UniversityHangzhouChina
- State Key Laboratory of Chinese Medicine ModernizationInnovation Center of Yangtze River DeltaZhejiang UniversityJiaxingChina
- State Key Laboratory of Component‐Based Chinese MedicineTianjin University of Traditional Chinese MedicineTianjinChina
- The Joint‐Laboratory of Clinical Multi‐Omics Research Between Zhejiang University and Ningbo Municipal Hospital of TCMNingbo Municipal Hospital of TCMNingboChina
| | - Jürgen Borlak
- Centre for Pharmacology and ToxicologyHannover Medical SchoolHannoverGermany
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Cao Y. Lack of basic rationale in epithelial-mesenchymal transition and its related concepts. Cell Biosci 2024; 14:104. [PMID: 39164745 PMCID: PMC11334496 DOI: 10.1186/s13578-024-01282-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 08/05/2024] [Indexed: 08/22/2024] Open
Abstract
Epithelial-mesenchymal transition (EMT) is defined as a cellular process during which epithelial cells acquire mesenchymal phenotypes and behavior following the downregulation of epithelial features. EMT and its reversed process, the mesenchymal-epithelial transition (MET), and the special form of EMT, the endothelial-mesenchymal transition (EndMT), have been considered as mainstream concepts and general rules driving developmental and pathological processes, particularly cancer. However, discrepancies and disputes over EMT and EMT research have also grown over time. EMT is defined as transition between two cellular states, but it is unanimously agreed by EMT researchers that (1) neither the epithelial and mesenchymal states nor their regulatory networks have been clearly defined, (2) no EMT markers or factors can represent universally epithelial and mesenchymal states, and thus (3) EMT cannot be assessed on the basis of one or a few EMT markers. In contrast to definition and proposed roles of EMT, loss of epithelial feature does not cause mesenchymal phenotype, and EMT does not contribute to embryonic mesenchyme and neural crest formation, the key developmental events from which the EMT concept was derived. EMT and MET, represented by change in cell shapes or adhesiveness, or symbolized by EMT factors, are biased interpretation of the overall change in cellular property and regulatory networks during development and cancer progression. Moreover, EMT and MET are consequences rather than driving factors of developmental and pathological processes. The true meaning of EMT in some developmental and pathological processes, such as fibrosis, needs re-evaluation. EMT is believed to endow malignant features, such as migration, stemness, etc., to cancer cells. However, the core property of cancer (tumorigenic) cells is neural stemness, and the core EMT factors are components of the regulatory networks of neural stemness. Thus, EMT in cancer progression is misattribution of the roles of neural stemness to the unknown mesenchymal state. Similarly, neural crest EMT is misattribution of intrinsic property of neural crest cells to the unknown mesenchymal state. Lack of basic rationale in EMT and related concepts urges re-evaluation of their significance as general rules for understanding developmental and pathological processes, and re-evaluation of their significance in scientific research.
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Affiliation(s)
- Ying Cao
- The MOE Key Laboratory of Model Animals for Disease Study, Model Animal Research Center, Medical School of Nanjing University, 12 Xuefu Road, Pukou High-Tech Zone, Nanjing, 210061, China.
- Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China.
- Shenzhen Research Institute of Nanjing University, Shenzhen, China.
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Akkız H, Gieseler RK, Canbay A. Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells. Int J Mol Sci 2024; 25:7873. [PMID: 39063116 PMCID: PMC11277292 DOI: 10.3390/ijms25147873] [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: 05/23/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
The burden of chronic liver disease is globally increasing at an alarming rate. Chronic liver injury leads to liver inflammation and fibrosis (LF) as critical determinants of long-term outcomes such as cirrhosis, liver cancer, and mortality. LF is a wound-healing process characterized by excessive deposition of extracellular matrix (ECM) proteins due to the activation of hepatic stellate cells (HSCs). In the healthy liver, quiescent HSCs metabolize and store retinoids. Upon fibrogenic activation, quiescent HSCs transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; and produce proinflammatory soluble mediators, collagens, and inhibitors of ECM degradation. Activated HSCs are the main effector cells during hepatic fibrogenesis. In addition, the accumulation and activation of profibrogenic macrophages in response to hepatocyte death play a critical role in the initiation of HSC activation and survival. The main source of myofibroblasts is resident HSCs. Activated HSCs migrate to the site of active fibrogenesis to initiate the formation of a fibrous scar. Single-cell technologies revealed that quiescent HSCs are highly homogenous, while activated HSCs/myofibroblasts are much more heterogeneous. The complex process of inflammation results from the response of various hepatic cells to hepatocellular death and inflammatory signals related to intrahepatic injury pathways or extrahepatic mediators. Inflammatory processes modulate fibrogenesis by activating HSCs and, in turn, drive immune mechanisms via cytokines and chemokines. Increasing evidence also suggests that cellular stress responses contribute to fibrogenesis. Recent data demonstrated that LF can revert even at advanced stages of cirrhosis if the underlying cause is eliminated, which inhibits the inflammatory and profibrogenic cells. However, despite numerous clinical studies on plausible drug candidates, an approved antifibrotic therapy still remains elusive. This state-of-the-art review presents cellular and molecular mechanisms involved in hepatic fibrogenesis and its resolution, as well as comprehensively discusses the drivers linking liver injury to chronic liver inflammation and LF.
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Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, University of Bahçeşehir, Beşiktaş, Istanbul 34353, Turkey
| | - Robert K. Gieseler
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus, Ruhr University Bochum, In der Schornau 23–25, 44892 Bochum, Germany; (R.K.G.); (A.C.)
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Chen S, Zhuang D, Jia Q, Guo B, Hu G. Advances in Noninvasive Molecular Imaging Probes for Liver Fibrosis Diagnosis. Biomater Res 2024; 28:0042. [PMID: 38952717 PMCID: PMC11214848 DOI: 10.34133/bmr.0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 05/08/2024] [Indexed: 07/03/2024] Open
Abstract
Liver fibrosis is a wound-healing response to chronic liver injury, which may lead to cirrhosis and cancer. Early-stage fibrosis is reversible, and it is difficult to precisely diagnose with conventional imaging modalities such as magnetic resonance imaging, positron emission tomography, single-photon emission computed tomography, and ultrasound imaging. In contrast, probe-assisted molecular imaging offers a promising noninvasive approach to visualize early fibrosis changes in vivo, thus facilitating early diagnosis and staging liver fibrosis, and even monitoring of the treatment response. Here, the most recent progress in molecular imaging technologies for liver fibrosis is updated. We start by illustrating pathogenesis for liver fibrosis, which includes capillarization of liver sinusoidal endothelial cells, cellular and molecular processes involved in inflammation and fibrogenesis, as well as processes of collagen synthesis, oxidation, and cross-linking. Furthermore, the biological targets used in molecular imaging of liver fibrosis are summarized, which are composed of receptors on hepatic stellate cells, macrophages, and even liver collagen. Notably, the focus is on insights into the advances in imaging modalities developed for liver fibrosis diagnosis and the update in the corresponding contrast agents. In addition, challenges and opportunities for future research and clinical translation of the molecular imaging modalities and the contrast agents are pointed out. We hope that this review would serve as a guide for scientists and students who are interested in liver fibrosis imaging and treatment, and as well expedite the translation of molecular imaging technologies from bench to bedside.
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Affiliation(s)
- Shaofang Chen
- Department of Radiology, Shenzhen People’s Hospital (The Second Clinical Medical College,
Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Danping Zhuang
- Department of Radiology, Shenzhen People’s Hospital (The Second Clinical Medical College,
Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Qingyun Jia
- Department of Radiology, Shenzhen People’s Hospital (The Second Clinical Medical College,
Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
| | - Bing Guo
- School of Science, Shenzhen Key Laboratory of Flexible Printed Electronics Technology, Shenzhen Key Laboratory of Advanced Functional Carbon Materials Research and Comprehensive Application,
Harbin Institute of Technology, Shenzhen 518055, China
| | - Genwen Hu
- Department of Radiology, Shenzhen People’s Hospital (The Second Clinical Medical College,
Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China
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Thiery JP, Sheng G, Shu X, Runyan R. How studies in developmental epithelial-mesenchymal transition and mesenchymal-epithelial transition inspired new research paradigms in biomedicine. Development 2024; 151:dev200128. [PMID: 38300897 DOI: 10.1242/dev.200128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Epithelial-mesenchymal transition (EMT) and its reverse mechanism, mesenchymal-epithelial transition (MET), are evolutionarily conserved mechanisms initially identified in studies of early metazoan development. EMT may even have been established in choanoflagellates, the closest unicellular relative of Metazoa. These crucial morphological transitions operate during body plan formation and subsequently in organogenesis. These findings have prompted an increasing number of investigators in biomedicine to assess the importance of such mechanisms that drive epithelial cell plasticity in multiple diseases associated with congenital disabilities and fibrosis, and, most importantly, in the progression of carcinoma. EMT and MET also play crucial roles in regenerative medicine, notably by contributing epigenetic changes in somatic cells to initiate reprogramming into stem cells and their subsequent differentiation into distinct lineages.
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Affiliation(s)
| | - Guojun Sheng
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto 860-0811, Japan
| | - Xiaodong Shu
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Raymond Runyan
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ 85721, USA
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Ceci L, Gaudio E, Kennedy L. Cellular Interactions and Crosstalk Facilitating Biliary Fibrosis in Cholestasis. Cell Mol Gastroenterol Hepatol 2024; 17:553-565. [PMID: 38216052 PMCID: PMC10883986 DOI: 10.1016/j.jcmgh.2024.01.005] [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: 11/01/2023] [Revised: 01/05/2024] [Accepted: 01/08/2024] [Indexed: 01/14/2024]
Abstract
Biliary fibrosis is seen in cholangiopathies, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In PBC and PSC, biliary fibrosis is associated with worse outcomes and histologic scores. Within the liver, both hepatic stellate cells (HSCs) and portal fibroblasts (PFs) contribute to biliary fibrosis, but their roles can differ. PFs reside near the bile ducts and may be the first responders to biliary damage, whereas HSCs may be recruited later and initiate bridging fibrosis. Indeed, different models of biliary fibrosis can activate PFs and HSCs to varying degrees. The portal niche can be composed of cholangiocytes, HSCs, PFs, endothelial cells, and various immune cells, and interactions between these cell types drive biliary fibrosis. In this review, we discuss the mechanisms of biliary fibrosis and the roles of PFs and HSCs in this process. We will also evaluate cellular interactions and mechanisms that contribute to biliary fibrosis in different models and highlight future perspectives and potential therapeutics.
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Affiliation(s)
- Ludovica Ceci
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, University of Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza, University of Rome, Italy
| | - Lindsey Kennedy
- Department of Research, Richard L. Roudebush VA Medical Center, Indianapolis, Indiana; Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
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Bogomolova A, Balakrishnan A, Ott M, Sharma AD. "The Good, the Bad, and the Ugly" - About Diverse Phenotypes of Hepatic Stellate Cells in the Liver. Cell Mol Gastroenterol Hepatol 2024; 17:607-622. [PMID: 38216053 PMCID: PMC10900761 DOI: 10.1016/j.jcmgh.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 01/04/2024] [Accepted: 01/04/2024] [Indexed: 01/14/2024]
Abstract
Hepatic stellate cells (HSCs) and their activated derivatives, often referred to as myofibroblasts (MFs), play a key role in progression of chronic liver injuries leading to fibrosis, cirrhosis, and hepatocellular carcinoma. Until recently, MFs were considered a homogenous cell type majorly due to lack of techniques that allow complex molecular studies at a single-cell resolution. Recent technical advancements in genetic lineage-tracing models as well as the exponential growth of studies with single-cell transcriptome and proteome analyses have uncovered hidden heterogeneities among the HSC and MF populations in healthy states as well as chronic liver injuries at the various stages of tissue deformation. The identification of different phenotypes along the HSC/MF axis, which either maintain essential liver functions ("good" HSCs), emerge during fibrosis ("bad" HSCs), or even promote hepatocellular carcinoma ("ugly" HSCs), may lay the foundation for targeting a particular MF phenotype as potential treatment for chronic liver injuries.
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Affiliation(s)
- Alexandra Bogomolova
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Research Group RNA Therapeutics & Liver Regeneration, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany
| | - Asha Balakrishnan
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Michael Ott
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
| | - Amar Deep Sharma
- Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany; Research Group RNA Therapeutics & Liver Regeneration, REBIRTH-Research Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.
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12
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Caon E, Forlano R, Mullish BH, Manousou P, Rombouts K. Liver sinusoidal cells in the diagnosis and treatment of liver diseases: Role of hepatic stellate cells. SINUSOIDAL CELLS IN LIVER DISEASES 2024:513-532. [DOI: 10.1016/b978-0-323-95262-0.00025-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Wells RG. Liver fibrosis: Our evolving understanding. Clin Liver Dis (Hoboken) 2024; 23:e0243. [PMID: 38961878 PMCID: PMC11221862 DOI: 10.1097/cld.0000000000000243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 03/29/2024] [Indexed: 07/05/2024] Open
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14
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Crawford JM, Bioulac-Sage P, Hytiroglou P. Structure, Function and Responses to Injury. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:1-95. [DOI: 10.1016/b978-0-7020-8228-3.00001-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Ohm B, Moneke I, Jungraithmayr W. Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis. Br J Pharmacol 2023; 180:2846-2861. [PMID: 36196001 DOI: 10.1111/bph.15967] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/07/2022] [Accepted: 09/29/2022] [Indexed: 11/28/2022] Open
Abstract
Cluster of differentiation 26 (CD26)/dipeptidyl peptidase 4 (DPP4) is an exopeptidase that is expressed as a transmembrane protein in many organs but also present in a circulating soluble form. Beyond its enzymatic and costimulatory activity, CD26/DPP4 is involved in the pathogenesis of chronic fibrotic diseases across many organ types, such as liver cirrhosis, kidney fibrosis and lung fibrosis. Organ fibrosis is associated with a high morbidity and mortality, and there are no causative therapies that can effectively attenuate the progress of the disease. Growing evidence suggests that inhibiting CD26/DPP4 can modulate the profibrotic tissue microenvironment and thus reduce fibrotic changes within affected organs. This review summarizes the role of CD26/DPP4 in fibroproliferative disorders and highlights new opportunities for an antifibrotic treatment by CD26/DPP4 inhibition. As a major advantage, CD26/DPP4 inhibitors have been in safe and routine clinical use in type 2 diabetes for many years and thus qualify for repurposing to repurpose as a promising therapeutic against fibrosis. LINKED ARTICLES: This article is part of a themed issue on Translational Advances in Fibrosis as a Therapeutic Target. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.22/issuetoc.
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Affiliation(s)
- Birte Ohm
- Department of Thoracic Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Isabelle Moneke
- Department of Thoracic Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Wolfgang Jungraithmayr
- Department of Thoracic Surgery, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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16
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Zheng W, Bian S, Qiu S, Bishop CE, Wan M, Xu N, Sun X, Sequeira RC, Atala A, Gu Z, Zhao W. Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis. Inflamm Regen 2023; 43:47. [PMID: 37798761 PMCID: PMC10557276 DOI: 10.1186/s41232-023-00297-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 09/13/2023] [Indexed: 10/07/2023] Open
Abstract
BACKGROUND Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms. METHODS The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-β1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations. RESULTS TGF-β1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-β1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2). CONCLUSION Pd-MSCs-EVs ameliorated TGF-β1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis.
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Affiliation(s)
- Wenjie Zheng
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
| | - Saiyan Bian
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Shi Qiu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Colin E Bishop
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC, 27157, USA
| | - Meimei Wan
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Nuo Xu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Xieyin Sun
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China
| | - Russel Clive Sequeira
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC, 27157, USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC, 27157, USA
| | - Zhifeng Gu
- Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
| | - Weixin Zhao
- Wake Forest Institute for Regenerative Medicine, Wake Forest University Health Sciences, Medical Center Blvd, Winston-Salem, NC, 27157, USA.
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17
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Kim HY, Sakane S, Eguileor A, Carvalho Gontijo Weber R, Lee W, Liu X, Lam K, Ishizuka K, Rosenthal SB, Diggle K, Brenner DA, Kisseleva T. The Origin and Fate of Liver Myofibroblasts. Cell Mol Gastroenterol Hepatol 2023; 17:93-106. [PMID: 37743012 PMCID: PMC10665929 DOI: 10.1016/j.jcmgh.2023.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 09/26/2023]
Abstract
Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts.
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Affiliation(s)
- Hyun Young Kim
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sadatsugu Sakane
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Raquel Carvalho Gontijo Weber
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Wonseok Lee
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Xiao Liu
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Kevin Lam
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sara Brin Rosenthal
- Center for Computational Biology and Bioinformatics, University of California San Diego, La Jolla, California
| | - Karin Diggle
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - David A Brenner
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego School of Medicine, La Jolla, California.
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18
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Liu X, Lam K, Zhao H, Sakane S, Kim HY, Eguileor A, Diggle K, Wu S, Gontijo Weber RC, Soroosh P, Hosseini M, Mekeel K, Brenner DA, Kisseleva T. Isolation of primary human liver cells from normal and nonalcoholic steatohepatitis livers. STAR Protoc 2023; 4:102391. [PMID: 37405925 PMCID: PMC10345194 DOI: 10.1016/j.xpro.2023.102391] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/14/2023] [Accepted: 05/26/2023] [Indexed: 07/07/2023] Open
Abstract
Here, we present a protocol for isolating human hepatocytes and neural progenitor cells from normal and nonalcoholic steatohepatitis livers. We describe steps for perfusion for scaled-up liver cell isolation and optimization of chemical digestion to achieve maximal yield and cell viability. We then detail a liver cell cryopreservation and potential applications, such as the use of human liver cells as a tool to link experimental and translational research.
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Affiliation(s)
- Xiao Liu
- Department of Medicine, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA; Department of Surgery, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA.
| | - Kevin Lam
- Department of Medicine, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - Huayi Zhao
- Department of Medicine, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - Sadatsugu Sakane
- Department of Medicine, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - Hyun Young Kim
- Department of Medicine, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - Alvaro Eguileor
- Department of Medicine, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - Karin Diggle
- Department of Medicine, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA; Department of Surgery, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - Shuai Wu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Raquel Carvalho Gontijo Weber
- Department of Medicine, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA; Department of Surgery, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - Pejman Soroosh
- Janssen Pharmaceutical R&D, Immunometabolism Obesity and Metabolic Disorders, San Diego, CA, USA
| | - Mojgan Hosseini
- Department of Pathology, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - Kristin Mekeel
- Department of Surgery, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - David A Brenner
- Department of Medicine, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, La Jolla, San Diego School of Medicine, La Jolla, CA, USA.
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19
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Aguilar-Bravo B, Ariño S, Blaya D, Pose E, Martinez García de la Torre RA, Latasa MU, Martínez-Sánchez C, Zanatto L, Sererols-Viñas L, Cantallops-Vilà P, Affo S, Coll M, Thillen X, Dubuquoy L, Avila MA, Argemi J, Paz AL, Nevzorova YA, Cubero FJ, Bataller R, Lozano JJ, Ginès P, Mathurin P, Sancho-Bru P. Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 as a driver of cell reprogramming. J Hepatol 2023; 79:728-740. [PMID: 37088308 PMCID: PMC10540088 DOI: 10.1016/j.jhep.2023.04.013] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 03/17/2023] [Accepted: 04/08/2023] [Indexed: 04/25/2023]
Abstract
BACKGROUND & AIMS Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood. METHODS HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. RESULTS Here, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. CONCLUSIONS This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. IMPACT AND IMPLICATIONS Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair.
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Affiliation(s)
- Beatriz Aguilar-Bravo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Silvia Ariño
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Delia Blaya
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Elisa Pose
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Liver Unit, Hospital Clínic, Barcelona, Spain
| | | | - María U Latasa
- Hepatology Program, Liver Unit, Instituto de Investigación de Navarra (IdisNA), Clínica Universidad de Navarra and Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain
| | - Celia Martínez-Sánchez
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Laura Zanatto
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laura Sererols-Viñas
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Paula Cantallops-Vilà
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Silvia Affo
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Mar Coll
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Xavier Thillen
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Laurent Dubuquoy
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Matías A Avila
- Hepatology Program, Liver Unit, Instituto de Investigación de Navarra (IdisNA), Clínica Universidad de Navarra and Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Josepmaria Argemi
- Hepatology Program, Liver Unit, Instituto de Investigación de Navarra (IdisNA), Clínica Universidad de Navarra and Centro de Investigación Médica Aplicada (CIMA), Universidad de Navarra, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Arantza Lamas Paz
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Yulia A Nevzorova
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Francisco Javier Cubero
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Department of Immunology, Ophthalmology and ENT, School of Medicine, Complutense University, Madrid, Spain
| | - Ramon Bataller
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Liver Unit, Hospital Clínic, Barcelona, Spain; Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Juan José Lozano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
| | - Pere Ginès
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Liver Unit, Hospital Clínic, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Philippe Mathurin
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Pau Sancho-Bru
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Faculty of Medicine, University of Barcelona, Barcelona, Spain.
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20
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Lotto J, Stephan TL, Hoodless PA. Fetal liver development and implications for liver disease pathogenesis. Nat Rev Gastroenterol Hepatol 2023; 20:561-581. [PMID: 37208503 DOI: 10.1038/s41575-023-00775-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/30/2023] [Indexed: 05/21/2023]
Abstract
The metabolic, digestive and homeostatic roles of the liver are dependent on proper crosstalk and organization of hepatic cell lineages. These hepatic cell lineages are derived from their respective progenitors early in organogenesis in a spatiotemporally controlled manner, contributing to the liver's specialized and diverse microarchitecture. Advances in genomics, lineage tracing and microscopy have led to seminal discoveries in the past decade that have elucidated liver cell lineage hierarchies. In particular, single-cell genomics has enabled researchers to explore diversity within the liver, especially early in development when the application of bulk genomics was previously constrained due to the organ's small scale, resulting in low cell numbers. These discoveries have substantially advanced our understanding of cell differentiation trajectories, cell fate decisions, cell lineage plasticity and the signalling microenvironment underlying the formation of the liver. In addition, they have provided insights into the pathogenesis of liver disease and cancer, in which developmental processes participate in disease emergence and regeneration. Future work will focus on the translation of this knowledge to optimize in vitro models of liver development and fine-tune regenerative medicine strategies to treat liver disease. In this Review, we discuss the emergence of hepatic parenchymal and non-parenchymal cells, advances that have been made in in vitro modelling of liver development and draw parallels between developmental and pathological processes.
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Affiliation(s)
- Jeremy Lotto
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada
| | - Tabea L Stephan
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada
| | - Pamela A Hoodless
- Terry Fox Laboratory, BC Cancer, Vancouver, BC, Canada.
- Cell and Developmental Biology Program, University of British Columbia, Vancouver, BC, Canada.
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21
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Gong Y, Liu Z, Zhang Y, Zhang J, Zheng Y, Wu Z. AGER1 deficiency-triggered ferroptosis drives fibrosis progression in nonalcoholic steatohepatitis with type 2 diabetes mellitus. Cell Death Discov 2023; 9:178. [PMID: 37280194 DOI: 10.1038/s41420-023-01477-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 05/12/2023] [Accepted: 05/30/2023] [Indexed: 06/08/2023] Open
Abstract
Hyperglycemia is an independent risk factor for the rapid progression of nonalcoholic steatohepatitis (NASH) to liver fibrosis with an incompletely defined mechanism. Ferroptosis is a novel form of programmed cell death that has been identified as a pathogenic mechanism in various diseases. However, the role of ferroptosis in the development of liver fibrosis in NASH with type 2 diabetes mellitus (T2DM) is unclear. Here, we observed the histopathological features of the progression of NASH to liver fibrosis as well as hepatocyte epithelial-mesenchymal transition (EMT) in a mouse model of NASH with T2DM and high-glucose-cultured steatotic human normal liver (LO2) cells. The distinctive features of ferroptosis, including iron overload, decreased antioxidant capacity, the accumulation of reactive oxygen species, and elevated lipid peroxidation products, were confirmed in vivo and in vitro. Liver fibrosis and hepatocyte EMT were markedly alleviated after treatment with the ferroptosis inhibitor ferrostatin-1. Furthermore, a decrease in the gene and protein levels of AGE receptor 1 (AGER1) was detected in the transition from NASH to liver fibrosis. Overexpression of AGER1 dramatically reversed hepatocyte EMT in high-glucose-cultured steatotic LO2 cells, whereas the knockdown of AGER1 had the opposite effect. The mechanisms underlying the phenotype appear to be associated with the inhibitory effects of AGER1 on ferroptosis, which is dependent on the regulation of sirtuin 4. Finally, in vivo adeno-associated virus-mediated AGER1 overexpression effectively relieved liver fibrosis in a murine model. Collectively, these findings suggest that ferroptosis participates in the pathogenesis of liver fibrosis in NASH with T2DM by promoting hepatocyte EMT. AGER1 could reverse hepatocyte EMT to ameliorate liver fibrosis by inhibiting ferroptosis. The results also suggest that AGER1 may be a potential therapeutic target for the treatment of liver fibrosis in patients with NASH with T2DM. Chronic hyperglycemia is associated with increased advanced glycation end products, resulting in the downregulation of AGER1. AGER1 deficiency downregulates Sirt4, which disturbs key regulators of ferroptosis (TFR-1, FTH, GPX4, and SLC7A11). These lead to increased iron uptake, decreasing the antioxidative capacity and enhanced lipid ROS production, ultimately leading to ferroptosis, which further promotes hepatocyte epithelial-mesenchymal transition and fibrosis progression in NASH with T2DM.
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Affiliation(s)
- Yihui Gong
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Zijun Liu
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Yuanyuan Zhang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Jun Zhang
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China
| | - Yin Zheng
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
| | - Zhongming Wu
- NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300134, China.
- Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University, Tianjin, 300134, China.
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
- Shandong Institute of Endocrine and Metabolic Diseases, Jinan, Shandong, 250021, China.
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22
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Pucci M, Moschetti M, Urzì O, Loria M, Conigliaro A, Di Bella MA, Crescitelli R, Olofsson Bagge R, Gallo A, Santos MF, Puglisi C, Forte S, Lorico A, Alessandro R, Fontana S. Colorectal cancer-derived small extracellular vesicles induce TGFβ1-mediated epithelial to mesenchymal transition of hepatocytes. Cancer Cell Int 2023; 23:77. [PMID: 37072829 PMCID: PMC10114452 DOI: 10.1186/s12935-023-02916-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/31/2023] [Indexed: 04/20/2023] Open
Abstract
BACKGROUND Metastatic disease is the major cause of cancer-related deaths. Increasing evidence shows that primary tumor cells can promote metastasis by preparing the local microenvironment of distant organs, inducing the formation of the so-called "pre-metastatic niche". In recent years, several studies have highlighted that among the tumor-derived molecular components active in pre-metastatic niche formation, small extracellular vesicles (sEVs) play a crucial role. Regarding liver metastasis, the ability of tumor-derived sEVs to affect the activities of non-parenchymal cells such as Kupffer cells and hepatic stellate cells is well described, while the effects on hepatocytes, the most conspicuous and functionally relevant hepatic cellular component, remain unknown. METHODS sEVs isolated from SW480 and SW620 CRC cells and from clinical samples of CRC patients and healthy subjects were used to treat human healthy hepatocytes (THLE-2 cells). RT-qPCR, Western blot and confocal microscopy were applied to investigate the effects of this treatment. RESULTS Our study shows for the first time that TGFβ1-carrying CRC_sEVs impair the morphological and functional properties of healthy human hepatocytes by triggering their TGFβ1/SMAD-dependent EMT. These abilities of CRC_sEVs were further confirmed by evaluating the effects elicited on hepatocytes by sEVs isolated from plasma and biopsies from CRC patients. CONCLUSIONS Since it is known that EMT of hepatocytes leads to the formation of a fibrotic environment, a well-known driver of metastasis, these results suggest that CRC_sEV-educated hepatocytes could have an active and until now neglected role during liver metastasis formation.
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Affiliation(s)
- Marzia Pucci
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Marta Moschetti
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Ornella Urzì
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Marco Loria
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Alice Conigliaro
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Maria Antonietta Di Bella
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
| | - Rossella Crescitelli
- Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Roger Olofsson Bagge
- Sahlgrenska Center for Cancer Research, Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Alessia Gallo
- Department of Research, IRCCS ISMETT, Palermo, Italy
| | - Mark F Santos
- Touro University College of Medicine, Henderson, NV, USA
| | | | | | - Aurelio Lorico
- Touro University College of Medicine, Henderson, NV, USA
- IOM Ricerca, Viagrande, Catania, Italy
| | - Riccardo Alessandro
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy
- Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), Palermo, Italy
| | - Simona Fontana
- Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, Palermo, Italy.
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23
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Aguilar-Bravo B, Ariño S, Blaya D, Pose E, Martinez García de la Torre RA, Latasa MU, Martínez-Sánchez C, Zanatto L, Sererols-Viñas L, Cantallops P, Affo S, Coll M, Thillen X, Dubuquoy L, Avila MA, Argemi JM, Paz AL, Nevzorova YA, Cubero J, Bataller R, Lozano JJ, Ginès P, Mathurin P, Sancho-Bru P. Hepatocyte Dedifferentiation Profiling In Alcohol-Related Liver Disease Identifies CXCR4 As A Driver Of Cell Reprogramming. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.04.535566. [PMID: 37066245 PMCID: PMC10104068 DOI: 10.1101/2023.04.04.535566] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/18/2023]
Abstract
Background and Aims Loss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocytes markers and showing immature features. However, the mechanisms and the impact of hepatocyte dedifferentiation in liver disease are poorly understood. Methods HB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ALD). Hepatocyte- specific overexpression or deletion of CXCR4, and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity. Results Here we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness and cancer gene programs. CXCR4 pathway was highly enriched in HB cells, and correlated with disease severity and hepatocyte dedifferentiation. In vitro , CXCR4 was associated with biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased hepatocyte specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression. Conclusions This study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. Lay summary Here we describe that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis.
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24
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Akkız H. Emerging Role of Cancer-Associated Fibroblasts in Progression and Treatment of Hepatocellular Carcinoma. Int J Mol Sci 2023; 24:3941. [PMID: 36835352 PMCID: PMC9964606 DOI: 10.3390/ijms24043941] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/07/2023] [Accepted: 01/10/2023] [Indexed: 02/18/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death globally. Tumor cells recruit and remodel various types of stromal and inflammatory cells to form a tumor microenvironment (TME), which encompasses cellular and molecular entities, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), immune cells, myeloid-derived suppressor cells (MDSCs), immune checkpoint molecules and cytokines that promote cancer cell growth, as well as their drug resistance. HCC usually arises in the context of cirrhosis, which is always associated with an enrichment of activated fibroblasts that are owed to chronic inflammation. CAFs are a major component of the TME, providing physical support in it and secreting various proteins, such as extracellular matrices (ECMs), hepatocyte growth factor (HGF), insulin-like growth factor 1/2 (ILGF1/2) and cytokines that can modulate tumor growth and survival. As such, CAF-derived signaling may increase the pool of resistant cells, thus reducing the duration of clinical responses and increasing the degree of heterogeneity within tumors. Although CAFs are often implicated to be associated with tumor growth, metastasis and drug resistance, several studies have reported that CAFs have significant phenotypic and functional heterogeneity, and some CAFs display antitumor and drug-sensitizing properties. Multiple studies have highlighted the relevance of crosstalk between HCC cells, CAFs and other stromal cells in influence of HCC progression. Although basic and clinical studies partially revealed the emerging roles of CAFs in immunotherapy resistance and immune evasion, a better understanding of the unique functions of CAFs in HCC progression will contribute to development of more effective molecular-targeted drugs. In this review article, molecular mechanisms involved in crosstalk between CAFs, HCC cells and other stromal cells, as well as the effects of CAFs on HCC-cell growth, metastasis, drug resistance and clinical outcomes, are comprehensively discussed.
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Affiliation(s)
- Hikmet Akkız
- Department of Gastroenterology and Hepatology, The University of Bahçeşehir, Istanbul 34425, Turkey
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25
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Gromowski T, Lukacs-Kornek V, Cisowski J. Current view of liver cancer cell-of-origin and proposed mechanisms precluding its proper determination. Cancer Cell Int 2023; 23:3. [PMID: 36609378 PMCID: PMC9824961 DOI: 10.1186/s12935-022-02843-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/30/2022] [Indexed: 01/09/2023] Open
Abstract
Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are devastating primary liver cancers with increasing prevalence in many parts of the world. Despite intense investigation, many aspects of their biology are still largely obscure. For example, numerous studies have tackled the question of the cell-of-origin of primary liver cancers using different experimental approaches; they have not, however, provided a clear and undisputed answer. Here, we will review the evidence from animal models supporting the role of all major types of liver epithelial cells: hepatocytes, cholangiocytes, and their common progenitor as liver cancer cell-of-origin. Moreover, we will also propose mechanisms that promote liver cancer cell plasticity (dedifferentiation, transdifferentiation, and epithelial-to-mesenchymal transition) which may contribute to misinterpretation of the results and which make the issue of liver cancer cell-of-origin particularly complex.
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Affiliation(s)
- Tomasz Gromowski
- grid.5522.00000 0001 2162 9631Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Veronika Lukacs-Kornek
- grid.10388.320000 0001 2240 3300Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Jaroslaw Cisowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
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26
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Wei M, Yan X, Xin X, Chen H, Hou L, Zhang J. Hepatocyte-Specific Smad4 Deficiency Alleviates Liver Fibrosis via the p38/p65 Pathway. Int J Mol Sci 2022; 23:ijms231911696. [PMID: 36232998 PMCID: PMC9570188 DOI: 10.3390/ijms231911696] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 09/17/2022] [Accepted: 09/29/2022] [Indexed: 11/20/2022] Open
Abstract
Liver fibrosis is a wound-healing response caused by the abnormal accumulation of extracellular matrix, which is produced by activated hepatic stellate cells (HSCs). Most studies have focused on the activated HSCs themselves in liver fibrosis, and whether hepatocytes can modulate the process of fibrosis is still unclear. Sma mothers against decapentaplegic homologue 4 (Smad4) is a key intracellular transcription mediator of transforming growth factor-β (TGF-β) during the development and progression of liver fibrosis. However, the role of hepatocyte Smad4 in the development of fibrosis is poorly elucidated. Here, to explore the functional role of hepatocyte Smad4 and the molecular mechanism in liver fibrosis, a CCl4-induced liver fibrosis model was established in mice with hepatocyte-specific Smad4 deletion (Smad4Δhep). We found that hepatocyte-specific Smad4 deficiency reduced liver inflammation and fibrosis, alleviated epithelial-mesenchymal transition, and inhibited hepatocyte proliferation and migration. Molecularly, Smad4 deletion in hepatocytes suppressed the expression of inhibitor of differentiation 1 (ID1) and the secretion of connective tissue growth factor (CTGF) of hepatocytes, which subsequently activated the p38 and p65 signaling pathways of HSCs in an epidermal growth factor receptor-dependent manner. Taken together, our results clearly demonstrate that the Smad4 expression in hepatocytes plays an important role in promoting liver fibrosis and could therefore be a promising target for future anti-fibrotic therapy.
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Affiliation(s)
- Miaomiao Wei
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
| | - Xinlong Yan
- Faculty of Environmental and Life Sciences, Beijing University of Technology, Beijing 100124, China
| | - Xin Xin
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
| | - Haiqiang Chen
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
| | - Lingling Hou
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
| | - Jinhua Zhang
- The College of Life Science and Bioengineering, Beijing Jiaotong University, Beijing 100044, China
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27
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Peng H, Zhu E, Zhang Y. Advances of cancer-associated fibroblasts in liver cancer. Biomark Res 2022; 10:59. [PMID: 35971182 PMCID: PMC9380339 DOI: 10.1186/s40364-022-00406-z] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 08/01/2022] [Indexed: 12/24/2022] Open
Abstract
Liver cancer is one of the most common malignant tumors worldwide, it is ranked sixth in incidence and fourth in mortality. According to the distinct origin of malignant tumor cells, liver cancer is mainly divided into hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Since most cases are diagnosed at an advanced stage, the prognosis of liver cancer is poor. Tumor growth depends on the dynamic interaction of various cellular components in the tumor microenvironment (TME). As the most abundant components of tumor stroma, cancer-associated fibroblasts (CAFs) have been involved in the progression of liver cancer. The interplay between CAFs and tumor cells, immune cells, or vascular endothelial cells in the TME through direct cell-to-cell contact or indirect paracrine interaction, affects the initiation and development of tumors. Additionally, CAFs are not a homogeneous cell population in liver cancer. Recently, single-cell sequencing technology has been used to help better understand the diversity of CAFs in liver cancer. In this review, we mainly update the knowledge of CAFs both in HCC and CCA, including their cell origins, chemoresistance, tumor stemness induction, tumor immune microenvironment formation, and the role of tumor cells on CAFs. Understanding the context-dependent role of different CAFs subsets provides new strategies for precise liver cancer treatment.
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Affiliation(s)
- Hao Peng
- Medical School, Southeast University, Nanjing, 210009, China
| | - Erwei Zhu
- The Second People's Hospital of Lianyungang (The Oncology Hospital of Lianyungang), Lianyungang, 222006, China
| | - Yewei Zhang
- Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210009, China.
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28
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Liu L, Sun Q, Davis F, Mao J, Zhao H, Ma D. Epithelial-mesenchymal transition in organ fibrosis development: current understanding and treatment strategies. BURNS & TRAUMA 2022; 10:tkac011. [PMID: 35402628 PMCID: PMC8990740 DOI: 10.1093/burnst/tkac011] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 12/16/2021] [Indexed: 01/10/2023]
Abstract
Organ fibrosis is a process in which cellular homeostasis is disrupted and extracellular matrix is excessively deposited. Fibrosis can lead to vital organ failure and there are no effective treatments yet. Although epithelial–mesenchymal transition (EMT) may be one of the key cellular mechanisms, the underlying mechanisms of fibrosis remain largely unknown. EMT is a cell phenotypic process in which epithelial cells lose their cell-to-cell adhesion and polarization, after which they acquire mesenchymal features such as infiltration and migration ability. Upon injurious stimulation in different organs, EMT can be triggered by multiple signaling pathways and is also regulated by epigenetic mechanisms. This narrative review summarizes the current understanding of the underlying mechanisms of EMT in fibrogenesis and discusses potential strategies for attenuating EMT to prevent and/or inhibit fibrosis. Despite better understanding the role of EMT in fibrosis development, targeting EMT and beyond in developing therapeutics to tackle fibrosis is challenging but likely feasible.
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Affiliation(s)
- Lexin Liu
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK.,Department of Nephrology and Urology, Pediatric Urolith Center, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, Zhejiang Province, 310003, China
| | - Qizhe Sun
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK
| | - Frank Davis
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK
| | - Jianhua Mao
- Department of Nephrology, The Children Hospital of Zhejiang University, School of Medicine, Hangzhou, Zhejiang Province, 310003, China
| | - Hailin Zhao
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK
| | - Daqing Ma
- Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, SW10 9NH, UK
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29
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Czaja AJ. Immune Inhibitory Properties and Therapeutic Prospects of Transforming Growth Factor-Beta and Interleukin 10 in Autoimmune Hepatitis. Dig Dis Sci 2022; 67:1163-1186. [PMID: 33835375 DOI: 10.1007/s10620-021-06968-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 03/22/2021] [Indexed: 12/14/2022]
Abstract
Transforming growth factor-beta and interleukin 10 have diverse immune inhibitory properties that have restored homeostatic defense mechanisms in experimental models of autoimmune disease. The goals of this review are to describe the actions of each cytokine, review their investigational use in animal models and patients, and indicate their prospects as interventions in autoimmune hepatitis. English abstracts were identified in PubMed by multiple search terms. Full-length articles were selected for review, and secondary and tertiary bibliographies were developed. Transforming growth factor-beta expands the natural and inducible populations of regulatory T cells, limits the proliferation of natural killer cells, suppresses the activation of naïve CD8+ T cells, decreases the production of interferon-gamma, and stimulates fibrotic repair. Interleukin 10 selectively inhibits the CD28 co-stimulatory signal for antigen recognition and impairs antigen-specific activation of uncommitted CD4+ and CD8+ T cells. It also inhibits maturation of dendritic cells, suppresses Th17 cells, supports regulatory T cells, and limits production of diverse pro-inflammatory cytokines. Contradictory immune stimulatory effects have been associated with each cytokine and may relate to the dose and accompanying cytokine milieu. Experimental findings have not translated into successful early clinical trials. The recombinant preparation of each agent in low dosage has been safe in human studies. In conclusion, transforming growth factor-beta and interleukin 10 have powerful immune inhibitory actions of potential therapeutic value in autoimmune hepatitis. The keys to their therapeutic application will be to match their predominant non-redundant function with the pivotal pathogenic mechanism or cytokine deficiency and to avoid contradictory immune stimulatory actions.
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Affiliation(s)
- Albert J Czaja
- Professor Emeritus of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, 200 First Street S.W., Rochester, MN, 55905, USA.
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30
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Fuji H, Miller G, Nishio T, Koyama Y, Lam K, Zhang V, Loomba R, Brenner D, Kisseleva T. The role of Mesothelin signaling in Portal Fibroblasts in the pathogenesis of cholestatic liver fibrosis. Front Mol Biosci 2021; 8:790032. [PMID: 34966784 PMCID: PMC8710774 DOI: 10.3389/fmolb.2021.790032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/15/2021] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis develops in response to chronic toxic or cholestatic injury, and is characterized by apoptosis of damaged hepatocytes, development of inflammatory responses, and activation of Collagen Type I producing myofibroblasts that make liver fibrotic. Two major cell types, Hepatic Stellate Cells (HSCs) and Portal Fibroblasts (PFs) are the major source of hepatic myofibroblasts. Hepatotoxic liver injury activates Hepatic Stellate Cells (aHSCs) to become myofibroblasts, while cholestatic liver injury activates both aHSCs and Portal Fibroblasts (aPFs). aPFs comprise the major population of myofibroblasts at the onset of cholestatic injury, while aHSCs are increasingly activated with fibrosis progression. Here we summarize our current understanding of the role of aPFs in the pathogenesis of cholestatic fibrosis, their unique features, and outline the potential mechanism of targeting aPFs in fibrotic liver.
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Affiliation(s)
- Hiroaki Fuji
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Grant Miller
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Takahiro Nishio
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukinori Koyama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kevin Lam
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Vivian Zhang
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Rohit Loomba
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
| | - David Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
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31
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Wang C, He Q, Yin Y, Wu Y, Li X. Clonorchis sinensis Granulin Promotes Malignant Transformation of Hepatocyte Through EGFR-Mediated RAS/MAPK/ERK and PI3K/Akt Signaling Pathways. Front Cell Infect Microbiol 2021; 11:734750. [PMID: 34858869 PMCID: PMC8631275 DOI: 10.3389/fcimb.2021.734750] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/20/2021] [Indexed: 11/13/2022] Open
Abstract
The biological functions of growth factor, such as granulins, have been explored in parasites, and we elucidated that Clonorchis sinensis granulin (CsGRN) promoted the metastasis of hepatocellular carcinoma in our previous study. However, it is still unclear for the malignant transformation role of CsGRN in normal human hepatocytes. In this study, by transfecting pEGFP-C1-CsGRN eukaryotic expression plasmid, a cell line with stable overexpression of CsGRN in normal hepatocyte (LO2-GRN cells) was constructed. The effects on cell proliferation were detected by carrying out cell counting kit-8 (CCK8) assay and colony formation assay. Additionally, we conducted flow cytometry analysis to determine whether the proliferation of CsGRN was due to cell cycle arrest. Subsequently, the migration ability and the invasion ability of LO2-GRN cells were evaluated through wound-healing assay and transwell assay. Meanwhile, the levels of the markers of RAS/MAPK/ERK and PI3K/Akt signaling pathways activation in LO2-GRN cells were assessed by quantitative RT-PCR and Western blot. Our results indicated that CsGRN promoted the proliferation of LO2 cells by regulating the expression of cell-cycle-related genes. Moreover, the overexpression of CsGRN regulates malignant metastasis of liver cells by inducing the upregulation of epithelial-mesenchymal transition (EMT) marker proteins. Furthermore, both mRNA and protein expression levels of p-EGFR, RAS, p-ERK, p-AKT, p-PI3K, and p-braf have been enhanced by CsGRN. These results showed that CsGRN promoted the malignant transformation of hepatocytes by regulating epidermal growth factor receptor (EGFR)-mediated RAS/MAPK/ERK and PI3K/Akt signaling pathways, which suggested that CsGRN could serve as a novel oncoprotein during Clonorchis sinensis-associated malignant transformation of hepatocytes.
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Affiliation(s)
- Caiqin Wang
- Department of Medical Oncology, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.,Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China.,China Atomic Energy Authority (CAEA) Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, China
| | - Qing He
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China.,China Atomic Energy Authority (CAEA) Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, China
| | - Yingxuan Yin
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China.,China Atomic Energy Authority (CAEA) Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, China
| | - Yinjuan Wu
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China.,China Atomic Energy Authority (CAEA) Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, China
| | - Xuerong Li
- Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.,Key Laboratory for Tropical Diseases Control of Ministry of Education, Sun Yat-sen University, Guangzhou, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, China.,China Atomic Energy Authority (CAEA) Center of Excellence on Nuclear Technology Applications for Insect Control, Beijing, China
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Feng S, Tong H, Gao JH, Tang SH, Yang WJ, Wang GM, Zhou HY, Wen SL. Anti-inflammation treatment for protection of hepatocytes and amelioration of hepatic fibrosis in rats. Exp Ther Med 2021; 22:1213. [PMID: 34584558 PMCID: PMC8422404 DOI: 10.3892/etm.2021.10647] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 06/11/2021] [Indexed: 02/05/2023] Open
Abstract
Chronic inflammation is considered as an important pathophysiologic mechanism of hepatic cirrhosis, which induces hepatocyte injury and activates hepatic stellate cells (HSCs), thus resulting in hepatic fibrosis. Previous studies have reported that cyclooxygenase-2 (COX-2) inhibitor can effectively treat liver fibrosis, while somatostatin (SST) analogues inhibit the activation of HSCs. The present study aimed to investigate the effects of a COX-2 inhibitor, celecoxib, combined with a SST analogue, octreotide, for protection of hepatocytes and prevention of fibrosis in a rat model of hepatic fibrosis. Therefore, a hepatic fibrosis rat model was established following peritoneal injection of thioacetamide (TAA), and the rats were then treated with a combination of celecoxib and octreotide (TAA + C). Immunohistochemistry and western blotting assays were used to assess the expression levels of proteins associated with inflammation, epithelial-mesenchymal transition (EMT), proliferation, apoptosis and autophagy. H&E staining, transmission electron microscopy and scanning electron microscopy were used to evaluate the destruction of hepatocytes. Masson's Trichrome and Sirius Red were used to measure the degree of liver fibrosis. The results demonstrated that, compared with those of the control group, the degree of liver fibrosis and the expression of the intrahepatic inflammation factors were aggravated in the TAA group. Furthermore, the apoptosis rate, EMT and autophagy of hepatocytes were also increased in the TAA group. However, treatment with TAA + C restored the aforementioned increased levels compared with the TAA group. In conclusion, treatment of rats with the combination of celecoxib and octreotide could attenuate the progress of hepatic fibrosis via protection of hepatocytes by reducing apoptosis, EMT and autophagy in hepatocytes.
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Affiliation(s)
- Shi Feng
- Key Laboratory of Brain Science Research and Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou, Hainan 571199, P.R. China
| | - Huan Tong
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Jin-Hang Gao
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Shi-Hang Tang
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Wen-Juan Yang
- Division of Peptides Related with Human Diseases, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Gui-Ming Wang
- Department of Human Anatomy, West China School of Basic Medical Science and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Hong-Ying Zhou
- Department of Human Anatomy, West China School of Basic Medical Science and Forensic Medicine, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Shi-Lei Wen
- Key Laboratory of Brain Science Research and Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou, Hainan 571199, P.R. China
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Kim SM, Hur WH, Kang BY, Lee SW, Roh PR, Park DJ, Sung PS, Yoon SK. Death-Associated Protein 6 (Daxx) Alleviates Liver Fibrosis by Modulating Smad2 Acetylation. Cells 2021; 10:1742. [PMID: 34359912 PMCID: PMC8305094 DOI: 10.3390/cells10071742] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 07/06/2021] [Accepted: 07/06/2021] [Indexed: 12/27/2022] Open
Abstract
Transforming growth factor-β (TGF-β) has been identified as an inducer of hepatocyte epithelial-mesenchymal transition (EMT), which triggers liver fibrosis. Death-associated protein 6 (Daxx) is known to be associated with the TGF-β-induced apoptotic pathway, but the function of Daxx in liver fibrosis remains unknown. This study aimed to elucidate the role of Daxx in liver fibrosis. We used liver fibrosis tissues from humans and mice to assess Daxx expression. EMT properties and TGF-β signaling pathway activation were investigated in the Daxx-overexpressing FL83B cell line. The therapeutic effect of Daxx was investigated in a mouse model of liver fibrosis by the hydrodynamic injection of plasmids. The expression of Daxx was markedly decreased in hepatocytes from fibrotic human and mouse livers, as well as in hepatocytes treated with TGF-β in vitro. The overexpression of Daxx inhibited the EMT process by interfering with the TGF-β-induced phosphorylation of Smad2. Coimmunoprecipitation analysis confirmed that Daxx reduced the transcriptional activity of Smad2 by binding to its MH1 domain and interfering with Smad2 acetylation. In addition, the therapeutic delivery of Daxx alleviated liver fibrosis in a thioacetamide-induced fibrosis mouse model. Overall, our results indicate that Daxx could be a potential therapeutic target to modulate fibrogenesis, as well as a useful biomarker for liver fibrosis.
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Affiliation(s)
- Sung-Min Kim
- The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.-M.K.); (W.-H.H.); (B.-Y.K.); (S.-W.L.); (P.-R.R.); (D.-J.P.); (P.-S.S.)
| | - Won-Hee Hur
- The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.-M.K.); (W.-H.H.); (B.-Y.K.); (S.-W.L.); (P.-R.R.); (D.-J.P.); (P.-S.S.)
| | - Byung-Yoon Kang
- The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.-M.K.); (W.-H.H.); (B.-Y.K.); (S.-W.L.); (P.-R.R.); (D.-J.P.); (P.-S.S.)
| | - Sung-Won Lee
- The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.-M.K.); (W.-H.H.); (B.-Y.K.); (S.-W.L.); (P.-R.R.); (D.-J.P.); (P.-S.S.)
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea
| | - Pu-Reun Roh
- The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.-M.K.); (W.-H.H.); (B.-Y.K.); (S.-W.L.); (P.-R.R.); (D.-J.P.); (P.-S.S.)
| | - Dong-Jun Park
- The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.-M.K.); (W.-H.H.); (B.-Y.K.); (S.-W.L.); (P.-R.R.); (D.-J.P.); (P.-S.S.)
| | - Pil-Soo Sung
- The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.-M.K.); (W.-H.H.); (B.-Y.K.); (S.-W.L.); (P.-R.R.); (D.-J.P.); (P.-S.S.)
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea
| | - Seung-Kew Yoon
- The Catholic University Liver Research Centre, Department of Biomedicine & Health Sciences, POSTECH-Catholic Biomedical Engineering Institute, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea; (S.-M.K.); (W.-H.H.); (B.-Y.K.); (S.-W.L.); (P.-R.R.); (D.-J.P.); (P.-S.S.)
- Division of Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Korea
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Sun YL, Bai T, Zhou L, Zhu RT, Wang WJ, Liang RP, Li J, Zhang CX, Gou JJ. SOD3 deficiency induces liver fibrosis by promoting hepatic stellate cell activation and epithelial-mesenchymal transition. J Cell Physiol 2021; 236:4313-4329. [PMID: 33230845 DOI: 10.1002/jcp.30174] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/14/2020] [Accepted: 10/06/2020] [Indexed: 12/18/2022]
Abstract
Hepatic stellate cell (HSC) activation plays an important role in the pathogenesis of liver fibrosis, and epithelial-mesenchymal transition (EMT) is suggested to potentially promote HSC activation. Superoxide dismutase 3 (SOD3) is an extracellular antioxidant defense against oxidative damage. Here, we found downregulation of SOD3 in a mouse model of liver fibrosis induced by carbon tetrachloride (CCl4 ). SOD3 deficiency induced spontaneous liver injury and fibrosis with increased collagen deposition, and further aggravated CCl4 -induced liver injury in mice. Depletion of SOD3 enhanced HSC activation marked by increased α-smooth muscle actin and subsequent collagen synthesis primarily collagen type I in vivo, and promoted transforming growth factor-β1 (TGF-β1)-induced HSC activation in vitro. SOD3 deficiency accelerated EMT process in the liver and TGF-β1-induced EMT of AML12 hepatocytes, as evidenced by loss of E-cadherin and gain of N-cadherin and vimentin. Notably, SOD3 expression and its pro-fibrogenic effect were positively associated with sirtuin 1 (SIRT1) expression. SOD3 deficiency inhibited adenosine monophosphate-activated protein kinase (AMPK) signaling to downregulate SIRT1 expression and thus involving in liver fibrosis. Enforced expression of SIRT1 inhibited SOD3 deficiency-induced HSC activation and EMT, whereas depletion of SIRT1 counteracted the inhibitory effect of SOD3 in vitro. These findings demonstrate that SOD3 deficiency contributes to liver fibrogenesis by promoting HSC activation and EMT process, and suggest a possibility that SOD3 may function through modulating SIRT1 via the AMPK pathway in liver fibrosis.
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Affiliation(s)
- Yu-Ling Sun
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China
- Key Lab of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
| | - Tao Bai
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China
- Key Lab of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
- Department of Vascular and Endovascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Lin Zhou
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China
- Key Lab of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
- Department of Digestive, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Rong-Tao Zhu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China
- Key Lab of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
| | - Wei-Jie Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China
- Key Lab of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
| | - Ruo-Peng Liang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China
- Key Lab of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
| | - Jian Li
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China
- Key Lab of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
| | - Chi-Xian Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China
- Key Lab of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
| | - Jian-Jun Gou
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, China
- Key Lab of Hepatobiliary and Pancreatic Diseases, Zhengzhou, China
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Acharya P, Chouhan K, Weiskirchen S, Weiskirchen R. Cellular Mechanisms of Liver Fibrosis. Front Pharmacol 2021; 12:671640. [PMID: 34025430 PMCID: PMC8134740 DOI: 10.3389/fphar.2021.671640] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 04/21/2021] [Indexed: 12/12/2022] Open
Abstract
The liver is a central organ in the human body, coordinating several key metabolic roles. The structure of the liver which consists of the distinctive arrangement of hepatocytes, hepatic sinusoids, the hepatic artery, portal vein and the central vein, is critical for its function. Due to its unique position in the human body, the liver interacts with components of circulation targeted for the rest of the body and in the process, it is exposed to a vast array of external agents such as dietary metabolites and compounds absorbed through the intestine, including alcohol and drugs, as well as pathogens. Some of these agents may result in injury to the cellular components of liver leading to the activation of the natural wound healing response of the body or fibrogenesis. Long-term injury to liver cells and consistent activation of the fibrogenic response can lead to liver fibrosis such as that seen in chronic alcoholics or clinically obese individuals. Unidentified fibrosis can evolve into more severe consequences over a period of time such as cirrhosis and hepatocellular carcinoma. It is well recognized now that in addition to external agents, genetic predisposition also plays a role in the development of liver fibrosis. An improved understanding of the cellular pathways of fibrosis can illuminate our understanding of this process, and uncover potential therapeutic targets. Here we summarized recent aspects in the understanding of relevant pathways, cellular and molecular drivers of hepatic fibrosis and discuss how this knowledge impact the therapy of respective disease.
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Affiliation(s)
- Pragyan Acharya
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Komal Chouhan
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India
| | - Sabine Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, RWTH University Hospital Aachen, Aachen, Germany
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Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol 2021; 18:151-166. [PMID: 33128017 DOI: 10.1038/s41575-020-00372-7] [Citation(s) in RCA: 1080] [Impact Index Per Article: 270.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/23/2020] [Indexed: 01/18/2023]
Abstract
Chronic liver injury leads to liver inflammation and fibrosis, through which activated myofibroblasts in the liver secrete extracellular matrix proteins that generate the fibrous scar. The primary source of these myofibroblasts are the resident hepatic stellate cells. Clinical and experimental liver fibrosis regresses when the causative agent is removed, which is associated with the elimination of these activated myofibroblasts and resorption of the fibrous scar. Understanding the mechanisms of liver fibrosis regression could identify new therapeutic targets to treat liver fibrosis. This Review summarizes studies of the molecular mechanisms underlying the reversibility of liver fibrosis, including apoptosis and the inactivation of hepatic stellate cells, the crosstalk between the liver and the systems that orchestrate the recruitment of bone marrow-derived macrophages (and other inflammatory cells) driving fibrosis resolution, and the interactions between various cell types that lead to the intracellular signalling that induces fibrosis or its regression. We also discuss strategies to target hepatic myofibroblasts (for example, via apoptosis or inactivation) and the myeloid cells that degrade the matrix (for example, via their recruitment to fibrotic liver) to facilitate fibrosis resolution and liver regeneration.
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Affiliation(s)
- Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla, CA, USA.
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla, CA, USA
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Zhong Y, Xu M, Hu J, Huang X, Lin N, Deng M. Inhibiting Th1/2 cells influences hepatic capillarization by adjusting sinusoidal endothelial fenestrae through Rho-ROCK-myosin pathway. Aging (Albany NY) 2021; 13:5069-5086. [PMID: 33535174 PMCID: PMC7950229 DOI: 10.18632/aging.202425] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 11/10/2020] [Indexed: 12/24/2022]
Abstract
CD4+ T cells are considered to be vital in chronic liver diseases, but their exact roles in hepatic capillarization, the typical characteristic of liver fibrosis, are poorly understood. This study aimed to assess the roles of typical subtype of CD4+ T cells, named T helper 1 (Th1) and Th2 cells in liver fibrosis. Taking advantage of well established fibrotic rat model, we conducted in vitro and in vivo experiments to explore the interactions between liver sinusoidal endothelial cells (LSECs) and Th1/2 cells; meanwhile we evaluated the degree of hepatic capillarization when inhibiting these interactions with inhibitory antibodies. Our results showed that prohibiting interactions between Th2 cells and LSECs caused the restoration of fenestrae, increased cytokine level of Th1 cells and reduction of hepatic capillarization; inhibiting the interaction between Th1 cells and LSECs produced the opposite effects. Moreover, increased Rho and myosin light chain phosphorylation were observed when Th1 cells were inhibited with the corresponding inhibitory antibody; Th2 cell inhibition yielded the opposite results. This study indicated that Th1/2 cells steer the capillarization process in different directions and this effect is probably mediated by the Rho-Rho kinase (ROCK)-myosin signaling pathway.
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Affiliation(s)
- Yuesi Zhong
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Mingxing Xu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Jingxiong Hu
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Xi Huang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Nan Lin
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
| | - Meihai Deng
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, Guangdong, China
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Plekhanov AN, Tovarshinov AI. [Liver regeneration: resolved and problem issues]. Khirurgiia (Mosk) 2021:88-93. [PMID: 33570361 DOI: 10.17116/hirurgia202102188] [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] [Indexed: 06/12/2023]
Abstract
Liver is an exceptional organ due to unique anatomical and physiological features, as well as advanced regenerative ability. Discovery of molecular mechanisms governing liver regeneration allowed researchers to use them to enhance liver regeneration. However, significant progress in this area was achieved through the introduction of gene therapy. In this manuscript, the authors consider stem cells for cell therapy and tissue engineering, as well as an alternative to liver transplantation.
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Affiliation(s)
- A N Plekhanov
- Buryat State University, Ulan-Ude, Russia
- Irkutsk Scientific Center of Surgery and Traumatology, Irkutsk, Russia
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Berumen J, Baglieri J, Kisseleva T, Mekeel K. Liver fibrosis: Pathophysiology and clinical implications. WIREs Mech Dis 2021; 13:e1499. [PMID: 32713091 PMCID: PMC9479486 DOI: 10.1002/wsbm.1499] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 04/30/2020] [Accepted: 05/21/2020] [Indexed: 02/06/2023]
Abstract
Liver fibrosis is a clinically significant finding that has major impacts on patient morbidity and mortality. The mechanism of fibrosis involves many different cellular pathways, but the major cell type involved appears to be hepatic stellate cells. Many liver diseases, including Hepatitis B, C, and fatty liver disease cause ongoing hepatocellular damage leading to liver fibrosis. No matter the cause of liver disease, liver-related mortality increases exponentially with increasing fibrosis. The progression to cirrhosis brings more dramatic mortality and higher incidence of hepatocellular carcinoma. Fibrosis can also affect outcomes following liver transplantation in adult and pediatric patients and require retransplantation. Drugs exist to treat Hepatitis B and C that reverse fibrosis in patients with those viral diseases, but there are currently no therapies to directly treat liver fibrosis. Several mouse models of chronic liver diseases have been successfully reversed using novel drug targets with current therapies focusing mostly on prevention of myofibroblast activation. Further research in these areas could lead to development of drugs to treat fibrosis, which will have invaluable impact on patient survival. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology.
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Affiliation(s)
| | - Jacopo Baglieri
- Department of Surgery, University of California, San Diego
- Department of Medicine, University of California, San Diego
| | | | - Kristin Mekeel
- Department of Surgery, University of California, San Diego
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40
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Chen T, Oh S, Gregory S, Shen X, Diehl AM. Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration. JCI Insight 2020. [DOI: 10.1172/jci.insight.141024 33208554] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
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Chen T, Oh S, Gregory S, Shen X, Diehl AM. Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration. JCI Insight 2020; 5:141024. [PMID: 33208554 PMCID: PMC7710279 DOI: 10.1172/jci.insight.141024] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2020] [Accepted: 10/08/2020] [Indexed: 01/07/2023] Open
Abstract
Adult liver has enormous regenerative capacity; it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA- and ATAC-Seq to map state transitions in approximately 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with IHC, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers, whereas others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes, and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.
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Affiliation(s)
- Tianyi Chen
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
| | | | - Simon Gregory
- Department of Neurology, Duke University, Durham, North Carolina, USA
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA
| | - Xiling Shen
- Department of Biomedical Engineering, Pratt School of Engineering, Duke University, Durham, North Carolina, USA
| | - Anna Mae Diehl
- Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
- Department of Medicine and
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Leslie J, Macia MG, Luli S, Worrell JC, Reilly WJ, Paish HL, Knox A, Barksby BS, Gee LM, Zaki MYW, Collins AL, Burgoyne RA, Cameron R, Bragg C, Xu X, Chung GW, Brown CDA, Blanchard AD, Nanthakumar CB, Karsdal M, Robinson SM, Manas DM, Sen G, French J, White SA, Murphy S, Trost M, Zakrzewski JL, Klein U, Schwabe RF, Mederacke I, Nixon C, Bird T, Teuwen LA, Schoonjans L, Carmeliet P, Mann J, Fisher AJ, Sheerin NS, Borthwick LA, Mann DA, Oakley F. c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis. Nat Metab 2020; 2:1350-1367. [PMID: 33168981 PMCID: PMC7116435 DOI: 10.1038/s42255-020-00306-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 09/30/2020] [Indexed: 02/07/2023]
Abstract
Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-β1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in RelΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel-Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.
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Affiliation(s)
- Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
| | - Marina García Macia
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Saimir Luli
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Julie C Worrell
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - William J Reilly
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Hannah L Paish
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Amber Knox
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Ben S Barksby
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Lucy M Gee
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Marco Y W Zaki
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Biochemistry Department, Faculty of Pharmacy, Minia University, Minia, Egypt
| | - Amy L Collins
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rachel A Burgoyne
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Rainie Cameron
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Charlotte Bragg
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Xin Xu
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Git W Chung
- Newcells Biotech, The Biosphere, Newcastle Helix, Newcastle upon Tyne, UK
| | - Colin D A Brown
- Newcells Biotech, The Biosphere, Newcastle Helix, Newcastle upon Tyne, UK
| | - Andrew D Blanchard
- Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, UK
| | - Carmel B Nanthakumar
- Fibrosis Discovery Performance Unit, Respiratory Therapy Area, Medicines Research Centre, GlaxoSmithKline R&D, Stevenage, UK
| | - Morten Karsdal
- Nordic Bioscience A/S, Biomarkers & Research, Herlev, Denmark
| | - Stuart M Robinson
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Derek M Manas
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Gourab Sen
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Jeremy French
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Steven A White
- Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sandra Murphy
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Matthias Trost
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Johannes L Zakrzewski
- Center for Discovery and Innovation and John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ, USA
| | - Ulf Klein
- Division of Haematology & Immunology, Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | | | - Ingmar Mederacke
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK
| | - Tom Bird
- Cancer Research UK Beatson Institute, Garscube Estate, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
- MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Laure-Anne Teuwen
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Luc Schoonjans
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Jelena Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Andrew J Fisher
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Institute of Transplantation, The Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Neil S Sheerin
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Lee A Borthwick
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Fiona Oakley
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- Fibrofind, Medical School, Newcastle University, Newcastle upon Tyne, UK.
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Chen Y, Fan Y, Guo DY, Xu B, Shi XY, Li JT, Duan LF. Study on the relationship between hepatic fibrosis and epithelial-mesenchymal transition in intrahepatic cells. Biomed Pharmacother 2020; 129:110413. [PMID: 32570119 DOI: 10.1016/j.biopha.2020.110413] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 06/08/2020] [Accepted: 06/13/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatic fibrosis is a pathophysiological process, which causes excessive extracellular matrix (ECM) deposition resulting from persistent liver damage. Myofibroblasts are the core cells that produce ECM. It is known that epithelial-mesenchymal transition (EMT) is not a simple transition of cells from the epithelial to mesenchymal state. Instead, it is a process, in which epithelial cells temporarily lose cell polarity, transform into interstitial cell-like morphology, and acquire migration ability. Hepatocytes, hepatic stellate cells, and bile duct cells are the types of intrahepatic cells found in the liver. They can be transformed into myofibroblasts via EMT and play important roles in the development of hepatic fibrosis through a maze of regulations involving various pathways. The aim of the present study is to explore the relationship between the relevant regulatory factors and the EMT signaling pathways in the various intrahepatic cells.
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Affiliation(s)
- Yang Chen
- The Basic Medical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Yu Fan
- The Basic Medical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China; Shaanxi Province Key Laboratory of Basic and New Herbal Medicament Research, Xianyang 712046, China.
| | - Dong-Yan Guo
- Shaanxi Province Key Laboratory of Basic and New Herbal Medicament Research, Xianyang 712046, China.
| | - Bing Xu
- The Medical Technical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Xiao-Yan Shi
- The Basic Medical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China.
| | - Jing-Tao Li
- The First Affiliated Hospital of Shaanxi University of Chinese Medicine, Xianyang 712000, China.
| | - Li-Fang Duan
- The Basic Medical College of Shaanxi University of Chinese Medicine, Xianyang 712046, China.
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44
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MicroRNA-221: A Fine Tuner and Potential Biomarker of Chronic Liver Injury. Cells 2020; 9:cells9081767. [PMID: 32717951 PMCID: PMC7464779 DOI: 10.3390/cells9081767] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2020] [Revised: 07/10/2020] [Accepted: 07/10/2020] [Indexed: 12/12/2022] Open
Abstract
The last decade has witnessed significant advancements in our understanding of how small noncoding RNAs, such as microRNAs (miRNAs), regulate disease progression. One such miRNA, miR-221, has been shown to play a key role in the progression of liver fibrosis, a common feature of most liver diseases. Many reports have demonstrated the upregulation of miR-221 in liver fibrosis caused by multiple etiologies such as viral infections and nonalcoholic steatohepatitis. Inhibition of miR-221 via different strategies has shown promising results in terms of the suppression of fibrogenic gene signatures in vitro, as well as in vivo, in independent mouse models of liver fibrosis. In addition, miR-221 has also been suggested as a noninvasive serum biomarker for liver fibrosis and cirrhosis. In this review, we discuss the biology of miR-221, its significance and use as a biomarker during progression of liver fibrosis, and finally, potential and robust approaches that can be utilized to suppress liver fibrosis via inhibition of miR-221.
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45
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Zhao Y, Wang Z, Zhou J, Feng D, Li Y, Hu Y, Zhang F, Chen Z, Wang G, Ma X, Tian X, Yao J. LncRNA Mical2/miR-203a-3p sponge participates in epithelial-mesenchymal transition by targeting p66Shc in liver fibrosis. Toxicol Appl Pharmacol 2020; 403:115125. [PMID: 32659284 DOI: 10.1016/j.taap.2020.115125] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Revised: 06/18/2020] [Accepted: 06/20/2020] [Indexed: 12/13/2022]
Abstract
Epithelial-mesenchymal transition (EMT) is regulated by reactive oxygen species (ROS) in liver fibrosis. p66Shc is a redox enzyme, but its role of EMT is unclear in liver fibrosis. Long noncoding RNAs (lncRNAs) have been implicated as important regulators in numerous physiological and pathological processes and generally acting as a microRNA (miRNA) sponge to regulate gene expression. The aim of the current study was to evaluate the contribution of p66Shc to EMT in liver fibrosis and the regulation of p66Shc by lncRNA sponge. In vivo, p66Shc silencing prevented carbon tetrachloride (CCl4)-induced EMT as evidenced by the upregulation of E-cadherin, downregulation of Vimentin and N-cadherin, and inhibition of oxidative stress and extracellular matrix (ECM) components. Moreover, in vitro, TGF-β1 significantly enhanced ECM components, as well as the development of the EMT phenotype. These effects were abrogated by p66Shc downregulation and aggravated by p66Shc overexpression. Mechanistically, p66Shc contributed to EMT via mediating ROS, as evidenced by p66Shc downregulation inhibiting EMT under exogenous hydrogen peroxide (H2O2) stimulation. Furthermore, we found that molecule interacting with CasL2 (Mical2) lncRNA functioned as an endogenous miR-203a-3p sponge to regulate p66Shc expression. Both Mical2 silencing and miR-203a-3p agomiR treatment downregulated p66Shc expression, thus suppressing EMT in vivo and in vitro. Notably, the increased p66Shc and Mical2 levels and decreased miR-203a-3p levels in murine fibrosis were consistent with those in patients with liver fibrosis. In sum, our study reveals that p66Shc is critical for liver fibrosis and that Mical2, miR-203a-3p and p66Shc compose a novel regulatory pathway in liver fibrosis.
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Affiliation(s)
- Yan Zhao
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Zhecheng Wang
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Junjun Zhou
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Dongcheng Feng
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Yang Li
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Yan Hu
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Feng Zhang
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Zhao Chen
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Guangzhi Wang
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China
| | - Xiaodong Ma
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China
| | - Xiaofeng Tian
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian 116023, China.
| | - Jihong Yao
- Department of Pharmacology, Dalian Medical University, Dalian 116044, China.
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Ríos-López DG, Aranda-López Y, Sosa-Garrocho M, Macías-Silva M. La plasticidad del hepatocito y su relevancia en la fisiología y la patología hepática. TIP REVISTA ESPECIALIZADA EN CIENCIAS QUÍMICO-BIOLÓGICAS 2020. [DOI: 10.22201/fesz.23958723e.2020.0.225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
El hígado es uno de los principales órganos encargados de mantener la homeostasis en vertebrados, además de poseer una gran capacidad regenerativa. El hígado está constituido por diversos tipos celulares que de forma coordinada contribuyen para que el órgano funcione eficientemente. Los hepatocitos representan el tipo celular principal de este órgano y llevan a cabo la mayoría de sus actividades; además, constituyen una población heterogénea de células epiteliales con funciones especializadas en el metabolismo. El fenotipo de los hepatocitos está controlado por diferentes vías de señalización, como la vía del TGFβ/Smads, la ruta Hippo/YAP-TAZ y la vía Wnt/β-catenina, entre otras. Los hepatocitos son células que se encuentran normalmente en un estado quiescente, aunque cuentan con una plasticidad intrínseca que se manifiesta en respuesta a diversos daños en el hígado; así, estas células reactivan su capacidad proliferativa o cambian su fenotipo a través de procesos celulares como la transdiferenciación o la transformación, para contribuir a mantener la homeostasis del órgano en condiciones saludables o desarrollar diversas patologías.
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Roehlen N, Crouchet E, Baumert TF. Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives. Cells 2020; 9:cells9040875. [PMID: 32260126 PMCID: PMC7226751 DOI: 10.3390/cells9040875] [Citation(s) in RCA: 700] [Impact Index Per Article: 140.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/28/2020] [Accepted: 04/01/2020] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.
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Affiliation(s)
- Natascha Roehlen
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
| | - Emilie Crouchet
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
| | - Thomas F. Baumert
- Université de Strasbourg, 67000 Strasbourg, France; (N.R.); (E.C.)
- Institut de Recherche sur les Maladies Virales et Hépatiques U1110, 67000 Strasbourg, France
- Pôle Hepato-digestif, Institut Hopitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- Correspondence: ; Tel.: +33-366853703
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Origin and role of hepatic myofibroblasts in hepatocellular carcinoma. Oncotarget 2020; 11:1186-1201. [PMID: 32284794 PMCID: PMC7138168 DOI: 10.18632/oncotarget.27532] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Accepted: 03/03/2020] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.
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49
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Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the second leading cause of cancer-related death worldwide. Fibrosis and cirrhosis are important risk factors for the development of HCC. Hepatic myofibroblasts are the cells responsible for extracellular matrix deposition, which is the hallmark of liver fibrosis. It is believed that myofibroblasts are predominantly derived from hepatic stellate cells (HSCs), also known as Ito cells. Nevertheless, depending on the nature of insult to the liver, it is thought that myofibroblasts may also originate from a variety of other cell types such as the portal fibroblasts (PFs), fibrocytes, hepatocytes, hepatic progenitor cells (HPCs), and mesothelial cells. Liver myofibroblasts are believed to transform into cancer-associated fibroblasts (CAFs) while HCC is developing. There is substantial evidence suggesting that activated HSCs (aHSCs)/cancer-associated fibroblasts (CAFs) may play an important role in HCC initiation and progression. In this paper, we aim to review current literature on cellular origins of myofibroblasts with a focus on hepatitis B virus (HBV)- and hepatitis C virus (HCV)-induced hepatic fibrosis. We also address the role of aHSCs/CAFs in HCC progression through the regulation of immune cells as well as mechanisms of evolvement of drug resistance.
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50
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LeBleu VS, Neilson EG. Origin and functional heterogeneity of fibroblasts. FASEB J 2020; 34:3519-3536. [PMID: 32037627 DOI: 10.1096/fj.201903188r] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Revised: 01/21/2020] [Accepted: 01/23/2020] [Indexed: 12/12/2022]
Abstract
The inherent plasticity and resiliency of fibroblasts make this cell type a conventional tool for basic research. But where do they come from, are all fibroblasts the same, and how do they function in disease? The first fibroblast lineages in mammalian development emerge from the ooze of primary mesenchyme during gastrulation. They are cells that efficiently create and negotiate the extracellular matrix of the mesoderm in order to migrate and meet their developmental fate. Mature fibroblasts in epithelial tissues live in the interstitial spaces between basement membranes that spatially delimit complex organ structures. While the function of resident fibroblasts in healthy tissues is largely conjecture, the accumulation of fibroblasts in pathologic lesions offers insight into biologic mechanisms that control their function; fibroblasts are poised to coordinate fibrogenesis in tissue injury, neoplasia, and aging. Here, we examine the developmental origin and plasticity of fibroblasts, their molecular and functional definitions, the epigenetic control underlying their identity and activation, and the evolution of their immune regulatory functions. These topics are reviewed through the lens of fate mapping using genetically engineered mouse models and from the perspective of single-cell RNA sequencing. Recent observations suggest dynamic and heterogeneous functions for fibroblasts that underscore their complex molecular signatures and utility in injured tissues.
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Affiliation(s)
- Valerie S LeBleu
- Departments of Medicine and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Eric G Neilson
- Departments of Medicine and Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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