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Ma X, Huang T, Chen X, Li Q, Liao M, Fu L, Huang J, Yuan K, Wang Z, Zeng Y. Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics. Signal Transduct Target Ther 2025; 10:63. [PMID: 39920130 PMCID: PMC11806117 DOI: 10.1038/s41392-024-02104-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 09/02/2024] [Accepted: 12/12/2024] [Indexed: 02/09/2025] Open
Abstract
Liver repair and regeneration are crucial physiological responses to hepatic injury and are orchestrated through intricate cellular and molecular networks. This review systematically delineates advancements in the field, emphasizing the essential roles played by diverse liver cell types. Their coordinated actions, supported by complex crosstalk within the liver microenvironment, are pivotal to enhancing regenerative outcomes. Recent molecular investigations have elucidated key signaling pathways involved in liver injury and regeneration. Viewed through the lens of metabolic reprogramming, these pathways highlight how shifts in glucose, lipid, and amino acid metabolism support the cellular functions essential for liver repair and regeneration. An analysis of regenerative variability across pathological states reveals how disease conditions influence these dynamics, guiding the development of novel therapeutic strategies and advanced techniques to enhance liver repair and regeneration. Bridging laboratory findings with practical applications, recent clinical trials highlight the potential of optimizing liver regeneration strategies. These trials offer valuable insights into the effectiveness of novel therapies and underscore significant progress in translational research. In conclusion, this review intricately links molecular insights to therapeutic frontiers, systematically charting the trajectory from fundamental physiological mechanisms to innovative clinical applications in liver repair and regeneration.
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Affiliation(s)
- Xiao Ma
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Tengda Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xiangzheng Chen
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Qian Li
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Mingheng Liao
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Li Fu
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Jiwei Huang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Kefei Yuan
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Zhen Wang
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Yong Zeng
- Division of Liver Surgery, Department of General Surgery and Laboratory of Liver Surgery, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Mavila N, Siraganahalli Eshwaraiah M, Kennedy J. Ductular Reactions in Liver Injury, Regeneration, and Disease Progression-An Overview. Cells 2024; 13:579. [PMID: 38607018 PMCID: PMC11011399 DOI: 10.3390/cells13070579] [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: 02/01/2024] [Revised: 03/11/2024] [Accepted: 03/22/2024] [Indexed: 04/13/2024] Open
Abstract
Ductular reaction (DR) is a complex cellular response that occurs in the liver during chronic injuries. DR mainly consists of hyper-proliferative or reactive cholangiocytes and, to a lesser extent, de-differentiated hepatocytes and liver progenitors presenting a close spatial interaction with periportal mesenchyme and immune cells. The underlying pathology of DRs leads to extensive tissue remodeling in chronic liver diseases. DR initiates as a tissue-regeneration mechanism in the liver; however, its close association with progressive fibrosis and inflammation in many chronic liver diseases makes it a more complicated pathological response than a simple regenerative process. An in-depth understanding of the cellular physiology of DRs and their contribution to tissue repair, inflammation, and progressive fibrosis can help scientists develop cell-type specific targeted therapies to manage liver fibrosis and chronic liver diseases effectively.
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Affiliation(s)
- Nirmala Mavila
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (M.S.E.); (J.K.)
- Division of Applied Cell Biology and Physiology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mallikarjuna Siraganahalli Eshwaraiah
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (M.S.E.); (J.K.)
| | - Jaquelene Kennedy
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (M.S.E.); (J.K.)
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3
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He YH, Pan JX, Xu LM, Gu T, Chen YW. Ductular reaction in non-alcoholic fatty liver disease: When Macbeth is perverted. World J Hepatol 2023; 15:725-740. [PMID: 37397935 PMCID: PMC10308290 DOI: 10.4254/wjh.v15.i6.725] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/03/2023] [Accepted: 04/24/2023] [Indexed: 06/25/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) or metabolic (dysfunction)-associated fatty liver disease is the leading cause of chronic liver diseases defined as a disease spectrum comprising hepatic steatosis, non-alcoholic steatohepatitis (NASH), liver fibrosis, cirrhosis, and hepatic carcinoma. NASH, characterized by hepatocyte injury, steatosis, inflammation, and fibrosis, is associated with NAFLD prognosis. Ductular reaction (DR) is a common compensatory reaction associated with liver injury, which involves the hepatic progenitor cells (HPCs), hepatic stellate cells, myofibroblasts, inflammatory cells (such as macrophages), and their secreted substances. Recently, several studies have shown that the extent of DR parallels the stage of NASH and fibrosis. This review summarizes previous research on the correlation between DR and NASH, the potential interplay mechanism driving HPC differentiation, and NASH progression.
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Affiliation(s)
- Yang-Huan He
- Department of Gastroenterology and Department of Geriatrics, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Jia-Xing Pan
- Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Lei-Ming Xu
- Department of Gastroenterology, School of Medicine, Xinhua Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai 200092, China
| | - Ting Gu
- Department of Gastroenterology, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
| | - Yuan-Wen Chen
- Department of Gastroenterology and Department of Geriatrics, Huadong Hospital Affiliated to Fudan University, Shanghai 200040, China
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Zhao Y, Wang H, He T, Ma B, Chen G, Tzeng C. Knockdown of Yap attenuates TAA-induced hepatic fibrosis by interaction with hedgehog signals. J Cell Commun Signal 2023:10.1007/s12079-023-00775-6. [PMID: 37338798 DOI: 10.1007/s12079-023-00775-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 06/05/2023] [Indexed: 06/21/2023] Open
Abstract
Liver fibrosis is an aberrant wound healing response to tissue injury characterized by excessive extracellular matrix deposition and loss of normal liver architecture. Hepatic stellate cells (HSCs) activation is regards to be the major process in liver fibrogenesis which is dynamic and reversible. Both Hippo signaling core factor Yap and Hedgehog (Hh) signaling promote HSCs transdifferentiation thereby regulating the repair process of liver injury. However, the molecular function of YAP and the regulation between Yap and Hh during fibrogenesis remain uncertain. In this study, the essential roles of Yap in liver fibrosis were investigated. Yap was detected to be increased in liver fibrotic tissue by the thioacetamide (TAA)-induced zebrafish embryonic and adult models. Inhibition of Yap by both embryonic morpholino interference and adult's inhibitor treatment was proved to alleviate TAA-induced liver lesions by and histology and gene expression examination. Transcriptomic analysis and gene expression detection showed that Yap and Hh signaling pathway have a cross talking upon TAA-induced liver fibrosis. In addition, TAA induction promoted the nuclear colocalization of YAP and Hh signaling factor GLI2α. This study demonstrates that Yap and Hh play synergistic protective roles in liver fibrotic response and provides new theoretical insight concerning the mechanisms of fibrosis progression.
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Affiliation(s)
- Ye Zhao
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China.
| | - Huiling Wang
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China
| | - Tianhua He
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China
| | - Bo Ma
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China
| | - Guoguang Chen
- School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, 211800, China
| | - Chimeng Tzeng
- School of Pharmaceutical Sciences, Xiamen University, Xiamen, 361005, China.
- Translational Medicine Research Center-Key Laboratory for Cancer T-Cell Theragnostic and Clinical Translation, School of Pharmaceutical Sciences, Xiamen University, Xiamen, Fujian, China.
- Xiamen Chang Gung Hospital Medical Research Center, Xiamen, Fujian, China.
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Li X, Abdel-Moneim AME, Yang B. Signaling Pathways and Genes Associated with Hexavalent Chromium-Induced Hepatotoxicity. Biol Trace Elem Res 2023; 201:1888-1904. [PMID: 35648283 DOI: 10.1007/s12011-022-03291-7] [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: 03/09/2022] [Accepted: 05/17/2022] [Indexed: 11/02/2022]
Abstract
Exposure to hexavalent chromium [Cr(VI)] causes human and animal hepatotoxicity. However, it is unclear how Cr(VI) induces hepatotoxicity, nor is it clear which pathways and genes may be involved. This study aimed to identify the key molecular pathways and genes engaged in Cr(VI)-induced hepatotoxicity. Publicly available microarray GSE19662 was downloaded from the Gene Expression Omnibus database. GSE19662 consists of primary rat hepatocyte (PRH) groups treated with or without 0.10 ppm potassium dichromate (PD), with three samples per group. Compared to the control group, a total of 400 differentially expressed genes were obtained. Specially 262 and 138 genes were up- and downregulated in PD-treated PRHs, respectively. Gene ontology (GO) enrichment indicated that those DEGs were primarily engaged in many biological processes, including androgen biosynthetic process, the positive regulation of cell death, the response to activity, the toxic substance and hepatocyte growth factor stimulus, and others. Kyoto Encyclopedia of Genes and Genomes (KEGG) suggested that the DEGs are fundamentally enriched in hepatocellular carcinoma (HCC), hepatitis B, p53, PI3K-Akt, MAPK, AMPK, metabolic pathways, estrogen, cGMP-PKG, metabolic pathways, etc. Moreover, many genes, including UBE2C, TOP2A, PRC1, CENPF, and MKI67, might contribute to Cr(VI)-induced hepatotoxicity. Taken together, this study enhances our understanding of the regulation, prevention, and treatment strategies of Cr(VI)-induced hepatotoxicity.
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Affiliation(s)
- Xiaofeng Li
- College of Animal Science, Anhui Science and Technology University, Fengyang, 233100, China
| | - Abdel-Moneim Eid Abdel-Moneim
- Biological Applications Department, Nuclear Research Center, Egyptian Atomic Energy Authority, Abu-Zaabal, 13759, Egypt
| | - Bing Yang
- College of Animal Science, Anhui Science and Technology University, Fengyang, 233100, China.
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Xie Y, Hu B, Gao Y, Tang Y, Chen G, Shen J, Jiang Z, Jiang H, Han J, Yan J, Jin L. Yap signalling regulates ductular reactions in mice with CRISPR/Cas9-induced glycogen storage disease type Ia. Anim Cells Syst (Seoul) 2022; 26:300-309. [PMID: 36605584 PMCID: PMC9809376 DOI: 10.1080/19768354.2022.2139755] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the glucose-6-phosphatase (G6Pase, G6pc) enzyme, which catalyses the final step of gluconeogenesis and glycogenolysis. Accumulation of G6pc can lead to an increase in glycogen and development of fatty liver. Ductular reactions refer to the proliferation of cholangiocytes and hepatic progenitors, which worsen fatty liver progress. To date, however, ductular reactions in GSD-Ia remain poorly understood. Here, we studied the development and potential underlying mechanism of ductular reactions in GSD-Ia in mice. We first generated GSD-Ia mice using CRISPR/Cas9 to target the exon 3 region of the G6pc gene. The typical GSD-Ia phenotype in G6pc -/- mice was then analysed using biochemical and histological assays. Ductular reactions in G6pc -/- mice were tested based on the expression of cholangiocytic markers cytokeratin 19 (CK19) and epithelial cell adhesion molecule (EpCAM). Yes-associated protein 1 (Yap) signalling activity was measured using western blot (WB) analysis and quantitative real-time polymerase chain reaction (qRT-PCR). Verteporfin was administered to the G6pc -/- mice to inhibit Yap signalling. The CRISPR/Cas9 system efficiently generated G6pc -/- mice, which exhibited typical GSD-Ia characteristics, including retarded growth, hypoglycaemia, and fatty liver disease. In addition, CK19- and EpCAM-positive cells as well as Yap signalling activity were increased in the livers of G6pc -/- mice. However, verteporfin treatment ameliorated ductular reactions and decreased Yap signalling activity. This study not only improves our understanding of GSD-Ia pathophysiology, but also highlights the potential of novel therapeutic approaches for GSD-Ia such as drug targeting of ductular reactions.
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Affiliation(s)
- Yixia Xie
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China,Shaoxing Academy of Biomedicine of Zhejiang Sci-Tech University, Shaoxing, Zhejiang, China
| | - Baowei Hu
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Yue Gao
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Yaxin Tang
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Guohe Chen
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Jiayuan Shen
- Department of Pathology, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, China
| | - Zhikai Jiang
- The Second Clinical Medical College of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - He Jiang
- The First Clinical Medical School of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China
| | - Jiwei Han
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China
| | - Junyan Yan
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China, Junyan Yan School of Life Science, Shaoxing University, Shaoxing, Zhejiang312000, People’s Republic of China
| | - Lifang Jin
- School of Life Science, Shaoxing University, Shaoxing, Zhejiang, China,Shaoxing Academy of Biomedicine of Zhejiang Sci-Tech University, Shaoxing, Zhejiang, China,Lifang Jin School of Life Science, Shaoxing University, Shaoxing, Zhejiang312000, People’s Republic of China
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7
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Chen Y, Gao WK, Shu YY, Ye J. Mechanisms of ductular reaction in non-alcoholic steatohepatitis. World J Gastroenterol 2022; 28:2088-2099. [PMID: 35664038 PMCID: PMC9134136 DOI: 10.3748/wjg.v28.i19.2088] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/18/2022] [Accepted: 04/04/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease spectrum caused in part by insulin resistance and genetic predisposition. This disease is primarily characterized by excessive lipid accumulation in hepatocytes in the absence of alcohol abuse and other causes of liver damage. Histologically, NAFLD is divided into several periods: simple steatosis, non-alcoholic steatohepatitis (NASH), hepatic fibrosis, cirrhosis, and hepatocellular carcinoma. With the increasing prevalence of obesity and hyperlipidemia, NAFLD has become the main cause of chronic liver disease worldwide. As a result, the pathogenesis of this disease is drawing increasing attention. Ductular reaction (DR) is a reactive bile duct hyperplasia caused by liver injury that involves hepatocytes, cholangiocytes, and hepatic progenitor cells. Recently, DR is shown to play a pivotal role in simple steatosis progression to NASH or liver fibrosis, providing new research and treatment options. This study reviews several DR signaling pathways, including Notch, Hippo/YAP-TAZ, Wnt/β-catenin, Hedgehog, HGF/c-Met, and TWEAK/Fn14, and their role in the occurrence and development of NASH.
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Affiliation(s)
- Yue Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Wen-Kang Gao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Yan-Yun Shu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Jin Ye
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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Abstract
Yes-associated protein 1 (YAP1) is a transcriptional coactivator that activates transcriptional enhanced associate domain transcription factors upon inactivation of the Hippo signaling pathway, to regulate biological processes like proliferation, survival, and differentiation. YAP1 is most prominently expressed in biliary epithelial cells (BECs) in normal adult livers and during development. In the current review, we will discuss the multiple roles of YAP1 in the development and morphogenesis of bile ducts inside and outside the liver, as well as in orchestrating the cholangiocyte repair response to biliary injury. We will review how biliary repair can occur through the process of hepatocyte-to-BEC transdifferentiation and how YAP1 is pertinent to this process. We will also discuss the liver's capacity for metabolic reprogramming as an adaptive mechanism in extreme cholestasis, such as when intrahepatic bile ducts are absent due to YAP1 loss from hepatic progenitors. Finally, we will discuss the roles of YAP1 in the context of pediatric pathologies afflicting bile ducts, such as Alagille syndrome and biliary atresia. In conclusion, we will comprehensively discuss the spatiotemporal roles of YAP1 in biliary development and repair after biliary injury while describing key interactions with other well-known developmental pathways.
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Affiliation(s)
- Laura Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine
| | - Kari Nejak-Bowen
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine,Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Satdarshan P. Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine,Pittsburgh Liver Research Center, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania,Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh and UPMC, Pittsburgh, Pennsylvania
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