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1
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Büyük M, Berker N, Bağbudar S, Çavuş B, Güllüoğlu M. Hepatic progenitor cell activation and ductular reaction in metabolic dysfunction-associated steatotic liver disease (MASLD): Indicators for disease activity and the degree of fibrosis: The pilot study. Medicine (Baltimore) 2025; 104:e42108. [PMID: 40228280 PMCID: PMC11999437 DOI: 10.1097/md.0000000000042108] [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: 02/12/2025] [Accepted: 03/27/2025] [Indexed: 04/16/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) spectrum encompasses steatosis, metabolic dysfunction-associated steatohepatitis, fibrosis, cirrhosis and metabolic dysfunction-associated steatohepatitis-related hepatocellular carcinoma. We evaluated the histomorphologic findings, portal-periportal biliary epithelial cell changes, and factors that may be associated with the degree of fibrosis in liver biopsies of MASLD patients. Hematoxylin-eosin, masson-trichrome, keratin7, keratin19, CD34, and glutamine synthetase-stained biopsies of 34 patients and 10 healthy liver donors (as controls) were retrospectively analyzed. Lobular inflammation was significantly correlated to the ballooning degeneration (P = .023), portal inflammation (P = .003), ductular reaction (DR) grade (P = .027), and the degree of fibrosis (P = .003). Ballooning degeneration (P = .004), and NAS (P = .008) were significantly related to the degree of fibrosis. Portal inflammation had a significant relationship with both DR grade (P < .001) and the degree of fibrosis (P = .002). The presence of hepatic progenitor cells (HPCs) was related to NAS (P = .005) and correlated with the DR grade (P = .002) and the degree of fibrosis (P = .038). Both DR (P < .001) and biliary metaplasia (P = .024) were significantly correlated with the degree of fibrosis. In multivariate analysis, biliary metaplasia (P = .015) and DR (P = .02) were found to be independent factors related to degree of fibrosis. Our results showed that HPC and DR were closely associated with disease activity and degree of fibrosis and might be good indicators of disease progression in MASLD. As pathologists, we might integrate the degree of HPCs and the grade of DR in our pathology reports as these findings might contribute to the disease progression risk categorization of the patients.
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Affiliation(s)
- Melek Büyük
- Department of Pathology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Neslihan Berker
- Department of Pathology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Sidar Bağbudar
- Department of Pathology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Bilger Çavuş
- Department of Gastroenterology and Hepatology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
| | - Mine Güllüoğlu
- Department of Pathology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey
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2
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Sorrentino G. Microenvironmental control of the ductular reaction: balancing repair and disease progression. Cell Death Dis 2025; 16:246. [PMID: 40180915 PMCID: PMC11968979 DOI: 10.1038/s41419-025-07590-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 03/11/2025] [Accepted: 03/24/2025] [Indexed: 04/05/2025]
Abstract
The ductular reaction (DR) is a dynamic adaptive cellular response within the liver, triggered by various hepatic insults and characterized by an expansion of dysmorphic biliary epithelial cells and liver progenitors. This complex response presents a dual role, playing a pivotal function in liver regeneration but, paradoxically, contributing to the progression of liver diseases, depending upon specific contextual factors and signaling pathways involved. This comprehensive review aims to offer a holistic perspective on the DR, focusing into its intricate cellular and molecular mechanisms, highlighting its pathological significance, and exploring its potential therapeutic implications. An up-to-date understanding of the DR in the context of different liver injuries is provided, analyzing its contributions to liver regeneration, inflammation, fibrosis, and ultimately carcinogenesis. Moreover, the review highlights the role of multiple microenvironmental factors, including the influence of extracellular matrix, tissue mechanics and the interplay with the intricate hepatic cell ecosystem in shaping the DR's regulation. Finally, in vitro and in vivo experimental models of the DR will be discussed, providing insights into how researchers can study and manipulate this critical cellular response. By comprehensively addressing the multifaceted nature of the DR, this review contributes to a more profound understanding of its pathophysiological role in liver diseases, thus offering potential therapeutic avenues for hepatic disorders and improving patient outcomes.
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Affiliation(s)
- Giovanni Sorrentino
- Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy.
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3
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Li Z, Sun X, Zhao Z, Yang Q, Ren Y, Teng X, Tai DCS, Wanless IR, Schattenberg JM, Liu C. A machine learning based algorithm accurately stages liver disease by quantification of arteries. Sci Rep 2025; 15:3143. [PMID: 39856155 PMCID: PMC11759706 DOI: 10.1038/s41598-025-87427-4] [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: 05/06/2024] [Accepted: 01/20/2025] [Indexed: 01/27/2025] Open
Abstract
A major histologic feature of cirrhosis is the loss of liver architecture with collapse of tissue and vascular changes per unit. We developed qVessel to quantify the arterial density (AD) in liver biopsies with chronic disease of varied etiology and stage. 46 needle liver biopsy samples with chronic hepatitis B (CHB), 48 with primary biliary cholangitis (PBC) and 43 with metabolic dysfunction-associated steatotic liver disease (MASLD) were collected at the Shuguang Hospital. The METAVIR system was used to assess stage. The second harmonic generation (SHG)/two-photon images were generated from unstained slides. Collagen proportionate area (CPA) using SHG. AD was counted using qVessel (previously trained on manually labeled vessels by stained slides (CD34/a-SMA/CK19) and developed by a decision tree algorithm). As liver fibrosis progressed from F1 to F4, we observed that both AD and CPA gradually increases among the three etiologies (P < 0.05). However, at each stage of liver fibrosis, there was no significant difference in AD or CPA between CHB and PBC compared to MASLD (P > 0.05). AD and CPA performed similar diagnostic efficacy in liver cirrhosis (P > 0.05). Using the qVessel algorithm, we discovered a significant correlation between AD, CPA and METAVIR stages in all three etiologies. This suggests that AD could underpin a novel staging system.
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Affiliation(s)
- Zhengxin Li
- Gongli Hospital of Shanghai Pudong New Area, Shanghai, China
| | - Xin Sun
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203, China
| | - Zhimin Zhao
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Qiang Yang
- Hangzhou Choutu Tech. Co., Ltd., Hangzhou, China
| | - Yayun Ren
- Hangzhou Choutu Tech. Co., Ltd., Hangzhou, China
| | - Xiao Teng
- Histoindex Pte. Ltd, Singapore, Singapore
| | | | - Ian R Wanless
- Department of Pathology, Queen Elizabeth II Health Sciences Centre, Dalhousie University, Halifax, Canada
| | - Jörn M Schattenberg
- Department of Internal Medicine II, Saarland University Medical Center, Homburg, Germany
- Saarland University, Saarbrücken, Germany
| | - Chenghai Liu
- Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Pudong New Area, Shanghai, 201203, China.
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China.
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4
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Zhao X, Wang S, Liu Q, Wei W, Sun X, Song H, Xu J, Zhang S, Wang H, Fu J. Single-cell landscape of the intrahepatic ecosystem in alcohol-related liver disease. Clin Transl Med 2025; 15:e70198. [PMID: 39834100 PMCID: PMC11746962 DOI: 10.1002/ctm2.70198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 01/05/2025] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
Alcohol-related liver disease (ALD) is a common chronic liver disease caused by long-term excessive alcohol consumption and responsible for more than half of all liver-related deaths worldwide. The molecular mechanisms associated with ALD were not fully understood. In this study, we performed single-cell RNA sequencing on liver tissues obtained from ALD patients and healthy liver donors. We identified an ALB+KRT7+ epithelial population that expressed both hepatocyte and biliary markers significantly expanded in ALD livers. The ALB+KRT7+ epithelial cells were demonstrated to have stem cell properties and malignant transformation potentials. Moreover, ALB+KRT7+ epithelium-derived ALD organoids promote the tumour growth by activating Wnt/β-catenin signalling of liver cancer cells. Most importantly, blocking the Wnt protein secretion or knockdown the Wnt receptor suppressed the tumour promoting effect of ALD organoids. Our study provides important insights that Wnt signalling can be targeted in patients with advanced alcohol-related cirrhosis to prevent malignant transformation. In addition, our results also uncovered the important alterations of nonparenchymal cells, especially macrophages and T/NK populations that responsible for active inflammation responses in alcohol-related hepatitis and immunosuppressive microenvironment in advanced cirrhosis livers, which likely facilitated the malignant progression of ALD. KEY POINTS: This study provides single-cell landscape of human liver samples across different ALD stages. The ALB+ KRT7+ epithelium were enriched in ALD patients, and the function of this epithelial population varied significantly across ALD stages. ALB+KRT7+ epithelium from advanced alcohol-related cirrhosis had malignant transformation potential and tumour promotion activity. The comprehensive changes of parenchymal and nonparenchymal cells in the ALD livers lay a hidden danger for the further malignant progression.
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Affiliation(s)
- Xiaofang Zhao
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepatobiliary Tumor BiologyEastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical UniversityShanghaiChina
| | - Senyan Wang
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Qi Liu
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Wenjuan Wei
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Xiaoyan Sun
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Hao Song
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Jing Xu
- Translational Medicine CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Shuijun Zhang
- Department of Hepatobiliary and Pancreatic SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenanChina
| | - Hongyang Wang
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepatobiliary Tumor BiologyEastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical UniversityShanghaiChina
| | - Jing Fu
- International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepatobiliary Tumor BiologyEastern Hepatobiliary Surgery Hospital, Second Military Medical University/NAVAL Medical UniversityShanghaiChina
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5
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Kim M, Park Y, Kim YS, Ko S. Cellular Plasticity in Gut and Liver Regeneration. Gut Liver 2024; 18:949-960. [PMID: 39081200 PMCID: PMC11565004 DOI: 10.5009/gnl240005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/07/2024] [Accepted: 06/21/2024] [Indexed: 11/16/2024] Open
Abstract
The intestine and liver share a unique regenerative property that sets them apart from other mammalian visceral organs. The intestinal epithelium exhibits rapid renewal, making it one of the fastest renewing tissues in humans. Under physiological conditions, intestinal stem cells within each intestinal crypt continuously differentiate into the different types of intestinal epithelial cells to maintain intestinal homeostasis. However, when exposed to tissue damage or stressful conditions such as inflammation, intestinal epithelial cells in the gastrointestinal tract exhibit plasticity, allowing fully differentiated cells to regain their stem cell properties. Likewise, hepatic epithelial cells possess a remarkable regenerative capacity to restore lost liver mass through proliferation-mediated liver regeneration. When the proliferation-mediated regenerative capacity is impaired, hepatocytes and biliary epithelial cells (BECs) can undergo plasticity-mediated regeneration and replenish each other. The transition of mammalian liver progenitor cells to hepatocytes/BECs can be observed under tightly controlled experimental conditions such as severe hepatocyte injury accompanied by the loss of regenerative capacity. In this review, we will discuss the mechanism by which cellular plasticity contributes to the regeneration process and the potential therapeutic implications of understanding and harnessing cellular plasticity in the gut and liver.
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Affiliation(s)
- Minwook Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yoojeong Park
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - You Sun Kim
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Department of Internal Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
- Pittsburgh Liver Research Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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6
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Nishikawa Y. Aberrant differentiation and proliferation of hepatocytes in chronic liver injury and liver tumors. Pathol Int 2024; 74:361-378. [PMID: 38837539 PMCID: PMC11551836 DOI: 10.1111/pin.13441] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 04/29/2024] [Accepted: 05/12/2024] [Indexed: 06/07/2024]
Abstract
Chronic liver injury induces liver cirrhosis and facilitates hepatocarcinogenesis. However, the effects of this condition on hepatocyte proliferation and differentiation are unclear. We showed that rodent hepatocytes display a ductular phenotype when they are cultured within a collagenous matrix. This process involves transdifferentiation without the emergence of hepatoblastic features and is at least partially reversible. During the ductular reaction in chronic liver diseases with progressive fibrosis, some hepatocytes, especially those adjacent to ectopic ductules, demonstrate ductular transdifferentiation, but the majority of increased ductules originate from the existing bile ductular system that undergoes extensive remodeling. In chronic injury, hepatocyte proliferation is weak but sustained, and most regenerative nodules in liver cirrhosis are composed of clonally proliferating hepatocytes, suggesting that a small fraction of hepatocytes maintain their proliferative capacity in chronic injury. In mouse hepatocarcinogenesis models, hepatocytes activate the expression of various fetal/neonatal genes, indicating that these cells undergo dedifferentiation. Hepatocyte-specific somatic integration of various oncogenes in mice demonstrated that hepatocytes may be the cells of origin for a broad spectrum of liver tumors through transdifferentiation and dedifferentiation. In conclusion, the phenotypic plasticity and heterogeneity of mature hepatocytes are important for understanding the pathogenesis of chronic liver diseases and liver tumors.
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Affiliation(s)
- Yuji Nishikawa
- President's OfficeAsahikawa Medical UniversityAsahikawaHokkaidoJapan
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7
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Gribben C, Galanakis V, Calderwood A, Williams EC, Chazarra-Gil R, Larraz M, Frau C, Puengel T, Guillot A, Rouhani FJ, Mahbubani K, Godfrey E, Davies SE, Athanasiadis E, Saeb-Parsy K, Tacke F, Allison M, Mohorianu I, Vallier L. Acquisition of epithelial plasticity in human chronic liver disease. Nature 2024; 630:166-173. [PMID: 38778114 PMCID: PMC11153150 DOI: 10.1038/s41586-024-07465-2] [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: 11/17/2022] [Accepted: 04/25/2024] [Indexed: 05/25/2024]
Abstract
For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms are becoming well characterized1-4, but technical challenges and ethical aspects are limiting the validation of these results in humans. We decided to address this difficulty with respect to the liver. This organ displays the remarkable ability to regenerate after acute injury, although liver regeneration in the context of recurring injury remains to be fully demonstrated. Here we performed single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients with different stages of metabolic dysfunction-associated steatotic liver disease to establish a cellular map of the liver during disease progression. We then combined these single-cell-level data with advanced 3D imaging to reveal profound changes in the liver architecture. Hepatocytes lose their zonation and considerable reorganization of the biliary tree takes place. More importantly, our study uncovers transdifferentiation events that occur between hepatocytes and cholangiocytes without the presence of adult stem cells or developmental progenitor activation. Detailed analyses and functional validations using cholangiocyte organoids confirm the importance of the PI3K-AKT-mTOR pathway in this process, thereby connecting this acquisition of plasticity to insulin signalling. Together, our data indicate that chronic injury creates an environment that induces cellular plasticity in human organs, and understanding the underlying mechanisms of this process could open new therapeutic avenues in the management of chronic diseases.
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Affiliation(s)
- Christopher Gribben
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
- Open Targets, Wellcome Genome Campus, Hinxton, UK
| | - Vasileios Galanakis
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
- Open Targets, Wellcome Genome Campus, Hinxton, UK
- Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Alexander Calderwood
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Eleanor C Williams
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Ruben Chazarra-Gil
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Miguel Larraz
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
| | - Carla Frau
- Berlin Institute of Health Centre for Regenerative Therapies, Berlin, Germany
| | - Tobias Puengel
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Adrien Guillot
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | | | - Edmund Godfrey
- Department of Radiology, Addenbrooke's Hospital, Cambridge, UK
| | - Susan E Davies
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Emmanouil Athanasiadis
- Greek Genome Centre, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
- Medical Image and Signal Processing Laboratory, Department of Biomedical Engineering, University of West Attica, Athens, Greece
| | | | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Michael Allison
- Open Targets, Wellcome Genome Campus, Hinxton, UK.
- Liver Unit, Department of Medicine, Cambridge NIHR Biomedical Research Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
| | - Irina Mohorianu
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
| | - Ludovic Vallier
- Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
- Open Targets, Wellcome Genome Campus, Hinxton, UK.
- Berlin Institute of Health Centre for Regenerative Therapies, Berlin, Germany.
- Max Planck Institute for Molecular Genetics, Berlin, Germany.
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8
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Yoshizawa T, Lee JW, Hong SM, Jung D, Noë M, Zbijewski W, Kiemen A, Wu PH, Wirtz D, Hruban RH, Wood LD, Oshima K. Three-dimensional analysis of ductular reactions and their correlation with liver regeneration and fibrosis. Virchows Arch 2024; 484:753-763. [PMID: 37704824 DOI: 10.1007/s00428-023-03641-3] [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: 04/18/2023] [Revised: 08/24/2023] [Accepted: 08/30/2023] [Indexed: 09/15/2023]
Abstract
The liver has multiple regeneration modes, including hepatocellular hypertrophy and self-renewal of hepatocytes. When hepatocyte proliferation is impaired, hepatic progenitor cells may proliferate through ductular reaction (DR), differentiate into hepatocytes, and contribute to fibrosis. However, the three-dimensional spatial relationship between DR and regenerating hepatocytes and dynamic changes in DR associated with fibrosis remain poorly understood. Here, we performed three-dimensional (3D) imaging of cleared 42 liver explants with chronic and acute liver diseases and 4 normal livers to visualize DR. In chronic hepatic liver diseases, such as viral hepatitis, steatohepatitis, autoimmune hepatitis, and cryptogenic cirrhosis, the total length and number of branches of DR showed a significant positive correlation. We studied the spatial relationship between DR and GS-expressing cells using glutamine synthetase (GS) and cytokeratin 19 (CK19) as markers of liver regeneration and DR, respectively. The percentage of CK19-positive cells that co-expressed GS was less than 10% in chronic liver diseases. In contrast, nearly one-third of CK19-positive cells co-expressed GS in acute liver diseases, and chronic cholestatic liver diseases, including primary biliary cholangitis and primary sclerosing cholangitis, showed no co-expression. We also found that DR was longer and had more branching in livers with progressive fibrosis compared to those with regressive fibrosis. Our results suggest that DR displays varying degrees of spatial complexity and contribution to liver regeneration. DR may serve as hepatobiliary junctions that maintain continuity between hepatocytes and bile ducts rather than hepatocyte regeneration in chronic liver diseases.
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Affiliation(s)
- Tadashi Yoshizawa
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology and Bioscience, Hirosaki University Graduate School of Medicine, Hirosaki Aomori, Japan
| | - Jae W Lee
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Seung-Mo Hong
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - DongJun Jung
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Medicine, Graduate School, University of Ulsan, Seoul, Republic of Korea
| | - Michaël Noë
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Wojciech Zbijewski
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Ashley Kiemen
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Pei-Hsun Wu
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Denis Wirtz
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, USA
| | - Ralph H Hruban
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D Wood
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Kiyoko Oshima
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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9
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Rizvi F, Lee YR, Diaz-Aragon R, Bawa PS, So J, Florentino RM, Wu S, Sarjoo A, Truong E, Smith AR, Wang F, Everton E, Ostrowska A, Jung K, Tam Y, Muramatsu H, Pardi N, Weissman D, Soto-Gutierrez A, Shin D, Gouon-Evans V. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. Cell Stem Cell 2023; 30:1640-1657.e8. [PMID: 38029740 PMCID: PMC10843608 DOI: 10.1016/j.stem.2023.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/07/2023] [Accepted: 10/31/2023] [Indexed: 12/01/2023]
Abstract
The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial-cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via nonintegrative and safe nucleoside-modified mRNA encapsulated into lipid nanoparticles (mRNA-LNPs) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and elimination of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This work defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals unexpected therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases.
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Affiliation(s)
- Fatima Rizvi
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Yu-Ri Lee
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Ricardo Diaz-Aragon
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Pushpinder S Bawa
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Juhoon So
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Rodrigo M Florentino
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Susan Wu
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Arianna Sarjoo
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Emily Truong
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Anna R Smith
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Feiya Wang
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Elissa Everton
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA
| | - Alina Ostrowska
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Kyounghwa Jung
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Ying Tam
- Acuitas Therapeutics, Vancouver, BC V6T 1Z3, Canada
| | - Hiromi Muramatsu
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Norbert Pardi
- Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Drew Weissman
- Department of Medicine, Infectious Diseases Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 10104, USA
| | - Alejandro Soto-Gutierrez
- Department of Pathology, Center for Transcriptional Medicine, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA
| | - Donghun Shin
- Department of Developmental Biology, Pittsburgh Liver Research Center, McGowan Institute for Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15260, USA
| | - Valerie Gouon-Evans
- Center for Regenerative Medicine, Department of Medicine, Section of Gastroenterology, Boston University and Boston Medical Center, Boston, MA 02118, USA.
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10
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Wiethoff H, Mohr I, Fichtner A, Merle U, Schirmacher P, Weiss KH, Longerich T. Metallothionein: a game changer in histopathological diagnosis of Wilson disease. Histopathology 2023; 83:936-948. [PMID: 37661783 DOI: 10.1111/his.15041] [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: 04/12/2023] [Revised: 08/11/2023] [Accepted: 08/18/2023] [Indexed: 09/05/2023]
Abstract
AIMS Wilson disease (WD) is a genetic disorder of copper metabolism caused by mutations in the ATP7B gene. Toxic copper accumulation leads to hepatic, neurologic, and psychiatric disorders with variable presentation. Metallothionein (MT) immunohistochemistry was proposed as a diagnostic marker. METHODS MT immunohistochemistry was performed on liver specimens of WD patients (n = 64) and control cases (n = 160) including acute liver failure, steatotic liver disease, autoimmune hepatitis, normal liver, primary biliary cholangitis, primary and secondary sclerosing cholangitis, and progressive familial intrahepatic cholestasis. The optimal cutoff for detection of WD was determined by receiver operating characteristic (ROC) analysis. RESULTS At least moderate staining in >50% of hepatocytes was observed in 81% of analysed liver specimens (n = 56/69) of WD patients, while only five control cases showed this staining pattern. The sensitivity, specificity, and accuracy for a new diagnosis of WD were 85.7%, 96.9%, and 94.9%, respectively. Sensitivity in nonfibrotic patients was 70.6% and this MT pattern was robust in small biopsies. The hepatic copper concentration was similar between MT-positive and MT-negative liver samples (P > 0.05). Zinc treatment may induce hepatocellular MT expression. Kayser-Fleischer rings (50% versus 15%) and neurologic disorders (50% versus 13%) were significantly more prevalent in MT-negative compared to MT-positive WD patients, respectively. CONCLUSION MT immunostaining is an excellent biomarker for histological diagnosis of WD, should be incorporated in the diagnostic work-up of patients with potential WD, and is useful in a modified Leipzig score.
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Affiliation(s)
- Hendrik Wiethoff
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Isabelle Mohr
- Department of Gastroenterology, Infectious Diseases and Intoxication, Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany
| | - Alexander Fichtner
- Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany
| | - Uta Merle
- Department of Gastroenterology, Infectious Diseases and Intoxication, Internal Medicine IV, Heidelberg University Hospital, Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Karl H Weiss
- Department of Internal Medicine, Salem Medical Center, Heidelberg, Germany
| | - Thomas Longerich
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
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11
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Song Y, Lu Z, Shu W, Xiang Z, Wang Z, Wei X, Xu X. Arouse potential stemness: Intrinsic and acquired stem cell therapeutic strategies for advanced liver diseases. CELL INSIGHT 2023; 2:100115. [PMID: 37719773 PMCID: PMC10502372 DOI: 10.1016/j.cellin.2023.100115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/10/2023] [Accepted: 08/10/2023] [Indexed: 09/19/2023]
Abstract
Liver diseases are a major health issue, and prolonged liver injury always progresses. Advanced liver disorders impair liver regeneration. Millions of patients die yearly worldwide, even with the available treatments of liver transplantation and artificial liver support system. With its abundant cell resources and significant differentiative potential, stem cell therapy is a viable treatment for various disorders and offers hope to patients waiting for orthotopic liver transplantation. Considering such plight, stem cell therapeutic strategies deliver hope to the patients. Moreover, we conclude intrinsic and acquired perspectives based on stem cell sources. The properties and therapeutic uses of these stem cells' specific types or sources were then reviewed. Owing to the recent investigations of the above cells, a safe and effective therapy will emerge for advanced liver diseases soon.
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Affiliation(s)
- Yisu Song
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Zhengyang Lu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Zhejiang Chinese Medical University, Hangzhou, 310053, PR China
| | - Wenzhi Shu
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Ze Xiang
- Zhejiang University School of Medicine, Hangzhou, China
| | - Zhengxin Wang
- Department of General Surgery, Huashan Hospital, Fudan University Shanghai, 200040, China
| | - Xuyong Wei
- Department of Hepatobiliary and Pancreatic Surgery Affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine Hangzhou, Zhejiang, 310006, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
| | - Xiao Xu
- Zhejiang University School of Medicine, Hangzhou, China
- Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Hangzhou, 310006, China
- Institute of Organ Transplantation, Zhejiang University, Hangzhou, 310003, China
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12
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Cai P, Ni R, Lv M, Liu H, Zhao J, He J, Luo L. VEGF signaling governs the initiation of biliary-mediated liver regeneration through the PI3K-mTORC1 axis. Cell Rep 2023; 42:113028. [PMID: 37632748 DOI: 10.1016/j.celrep.2023.113028] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 07/12/2023] [Accepted: 08/10/2023] [Indexed: 08/28/2023] Open
Abstract
Biliary epithelial cells (BECs) are a potential source to repair the damaged liver when hepatocyte proliferation is compromised. Promotion of BEC-to-hepatocyte transdifferentiation could be beneficial to the clinical therapeutics of patients with end-stage liver diseases. However, mechanisms underlying the initiation of BEC transdifferentiation remain largely unknown. Here, we show that upon extreme hepatocyte injury, vegfaa and vegfr2/kdrl are notably induced in hepatic stellate cells and BECs, respectively. Pharmacological and genetic inactivation of vascular endothelial growth factor (VEGF) signaling would disrupt BEC dedifferentiation and proliferation, thus restraining hepatocyte regeneration. Mechanically, VEGF signaling regulates the activation of the PI3K-mammalian target of rapamycin complex 1 (mTORC1) axis, which is essential for BEC-to-hepatocyte transdifferentiation. In mice, VEGF signaling exerts conserved roles in oval cell activation and BEC-to-hepatocyte differentiation. Taken together, this study shows VEGF signaling as an initiator of biliary-mediated liver regeneration through activating the PI3K-mTORC1 axis. Modulation of VEGF signaling in BECs could be a therapeutic approach for patients with end-stage liver diseases.
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Affiliation(s)
- Pengcheng Cai
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Rui Ni
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Mengzhu Lv
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Huijuan Liu
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Jieqiong Zhao
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Jianbo He
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China
| | - Lingfei Luo
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Beibei, Chongqing 400715, China; School of Life Sciences, Fudan University, Shanghai 200438, China.
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13
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Barkin JM, Jin-Smith B, Torok K, Pi L. Significance of CCNs in liver regeneration. J Cell Commun Signal 2023; 17:321-332. [PMID: 37202628 PMCID: PMC10326177 DOI: 10.1007/s12079-023-00762-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Accepted: 05/01/2023] [Indexed: 05/20/2023] Open
Abstract
The liver has an inherent regenerative capacity via hepatocyte proliferation after mild-to-modest damage. When hepatocytes exhaust their replicative ability during chronic or severe liver damage, liver progenitor cells (LPC), also termed oval cells (OC) in rodents, are activated in the form of ductular reaction (DR) as an alternative pathway. LPC is often intimately associated with hepatic stellate cells (HSC) activation to promote liver fibrosis. The Cyr61/CTGF/Nov (CCN) protein family consists of six extracellular signaling modulators (CCN1-CCN6) with affinity to a repertoire of receptors, growth factors, and extracellular matrix proteins. Through these interactions, CCN proteins organize microenvironments and modulate cell signalings in a diverse variety of physiopathological processes. In particular, their binding to subtypes of integrin (αvβ5, αvβ3, α6β1, αvβ6, etc.) influences the motility and mobility of macrophages, hepatocytes, HSC, and LPC/OC during liver injury. This paper summarizes the current understanding of the significance of CCN genes in liver regeneration in relation to hepatocyte-driven or LPC/OC-mediated pathways. Publicly available datasets were also searched to compare dynamic levels of CCNs in developing and regenerating livers. These insights not only add to our understanding of the regenerative capability of the liver but also provide potential targets for the pharmacological management of liver repair in the clinical setting. Ccns in liver regeneration Restoring damaged or lost tissues requires robust cell growth and dynamic matrix remodeling. Ccns are matricellular proteins highly capable of influencing cell state and matrix production. Current studies have identified Ccns as active players in liver regeneration. Cell types, modes of action, and mechanisms of Ccn induction may vary depending on liver injuries. Hepatocyte proliferation is a default pathway for liver regeneration following mild-to-modest damages, working in parallel with the transient activation of stromal cells, such as macrophages and hepatic stellate cells (HSC). Liver progenitor cells (LPC), also termed oval cells (OC) in rodents, are activated in the form of ductular reaction (DR) and are associated with sustained fibrosis when hepatocytes lose their proliferative ability in severe or chronic liver damage. Ccns may facilitate both hepatocyte regeneration and LPC/OC repair via various mediators (growth factors, matrix proteins, integrins, etc.) for cell-specific and context-dependent functions.
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Affiliation(s)
- Joshua M Barkin
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Brady Jin-Smith
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Kendle Torok
- Department of Pathology, Tulane University, New Orleans, LA, USA
| | - Liya Pi
- Department of Pathology, Tulane University, New Orleans, LA, USA.
- Department of Pathology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA, USA.
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14
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Rodimova S, Mozherov A, Elagin V, Karabut M, Shchechkin I, Kozlov D, Krylov D, Gavrina A, Bobrov N, Zagainov V, Zagaynova E, Kuznetsova D. Effect of Hepatic Pathology on Liver Regeneration: The Main Metabolic Mechanisms Causing Impaired Hepatic Regeneration. Int J Mol Sci 2023; 24:ijms24119112. [PMID: 37298064 DOI: 10.3390/ijms24119112] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/15/2023] [Accepted: 05/17/2023] [Indexed: 06/12/2023] Open
Abstract
Liver regeneration has been studied for many decades, and the mechanisms underlying regeneration of normal liver following resection are well described. However, no less relevant is the study of mechanisms that disrupt the process of liver regeneration. First of all, a violation of liver regeneration can occur in the presence of concomitant hepatic pathology, which is a key factor reducing the liver's regenerative potential. Understanding these mechanisms could enable the rational targeting of specific therapies to either reduce the factors inhibiting regeneration or to directly stimulate liver regeneration. This review describes the known mechanisms of normal liver regeneration and factors that reduce its regenerative potential, primarily at the level of hepatocyte metabolism, in the presence of concomitant hepatic pathology. We also briefly discuss promising strategies for stimulating liver regeneration and those concerning methods for assessing the regenerative potential of the liver, especially intraoperatively.
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Affiliation(s)
- Svetlana Rodimova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
| | - Artem Mozherov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research, Institute of Clinical Medicine, N.I. Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Vadim Elagin
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
| | - Maria Karabut
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
| | - Ilya Shchechkin
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research, Institute of Clinical Medicine, N.I. Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Dmitry Kozlov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research, Institute of Clinical Medicine, N.I. Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Dmitry Krylov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research, Institute of Clinical Medicine, N.I. Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Alena Gavrina
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research, Institute of Clinical Medicine, N.I. Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
| | - Nikolai Bobrov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- The Volga District Medical Centre of Federal Medical and Biological Agency, 14 Ilinskaya St., 603000 Nizhny Novgorod, Russia
| | - Vladimir Zagainov
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Nizhny Novgorod Regional Clinical Oncologic Dispensary, Delovaya St., 11/1, 603126 Nizhny Novgorod, Russia
| | - Elena Zagaynova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
| | - Daria Kuznetsova
- Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, 10/1 Minin and Pozharsky Sq., 603000 Nizhny Novgorod, Russia
- Laboratory of Molecular Genetic Research, Institute of Clinical Medicine, N.I. Lobachevsky Nizhny Novgorod National Research State University, 23 Gagarina Ave., 603022 Nizhny Novgorod, Russia
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15
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Rizvi F, Lee YR, Diaz-Aragon R, So J, Florentino RM, Smith AR, Everton E, Ostrowska A, Jung K, Tam Y, Muramatsu H, Pardi N, Weissman D, Soto-Gutierrez A, Shin D, Gouon-Evans V. VEGFA mRNA-LNP promotes biliary epithelial cell-to-hepatocyte conversion in acute and chronic liver diseases and reverses steatosis and fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.17.537186. [PMID: 37131823 PMCID: PMC10153196 DOI: 10.1101/2023.04.17.537186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The liver is known for its remarkable regenerative ability through proliferation of hepatocytes. Yet, during chronic injury or severe hepatocyte death, proliferation of hepatocytes is exhausted. To overcome this hurdle, we propose vascular-endothelial-growth-factor A (VEGFA) as a therapeutic means to accelerate biliary epithelial cell (BEC)-to-hepatocyte conversion. Investigation in zebrafish establishes that blocking VEGF receptors abrogates BEC-driven liver repair, while VEGFA overexpression promotes it. Delivery of VEGFA via non-integrative and safe nucleoside-modified mRNA encapsulated into lipid-nanoparticles (mRNA-LNP) in acutely or chronically injured mouse livers induces robust BEC-to-hepatocyte conversion and reversion of steatosis and fibrosis. In human and murine diseased livers, we further identified VEGFA-receptor KDR-expressing BECs associated with KDR-expressing cell-derived hepatocytes. This defines KDR-expressing cells, most likely being BECs, as facultative progenitors. This study reveals novel therapeutic benefits of VEGFA delivered via nucleoside-modified mRNA-LNP, whose safety is widely validated with COVID-19 vaccines, for harnessing BEC-driven repair to potentially treat liver diseases. Highlights Complementary mouse and zebrafish models of liver injury demonstrate the therapeutic impact of VEGFA-KDR axis activation to harness BEC-driven liver regeneration.VEGFA mRNA LNPs restore two key features of the chronic liver disease in humans such as steatosis and fibrosis.Identification in human cirrhotic ESLD livers of KDR-expressing BECs adjacent to clusters of KDR+ hepatocytes suggesting their BEC origin.KDR-expressing BECs may represent facultative adult progenitor cells, a unique BEC population that has yet been uncovered.
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16
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Pu W, Zhu H, Zhang M, Pikiolek M, Ercan C, Li J, Huang X, Han X, Zhang Z, Lv Z, Li Y, Liu K, He L, Liu X, Heim MH, Terracciano LM, Tchorz JS, Zhou B. Bipotent transitional liver progenitor cells contribute to liver regeneration. Nat Genet 2023; 55:651-664. [PMID: 36914834 PMCID: PMC10101857 DOI: 10.1038/s41588-023-01335-9] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Accepted: 02/07/2023] [Indexed: 03/16/2023]
Abstract
Following severe liver injury, when hepatocyte-mediated regeneration is impaired, biliary epithelial cells (BECs) can transdifferentiate into functional hepatocytes. However, the subset of BECs with such facultative tissue stem cell potential, as well as the mechanisms enabling transdifferentiation, remains elusive. Here we identify a transitional liver progenitor cell (TLPC), which originates from BECs and differentiates into hepatocytes during regeneration from severe liver injury. By applying a dual genetic lineage tracing approach, we specifically labeled TLPCs and found that they are bipotent, as they either differentiate into hepatocytes or re-adopt BEC fate. Mechanistically, Notch and Wnt/β-catenin signaling orchestrate BEC-to-TLPC and TLPC-to-hepatocyte conversions, respectively. Together, our study provides functional and mechanistic insights into transdifferentiation-assisted liver regeneration.
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Affiliation(s)
- Wenjuan Pu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Huan Zhu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Mingjun Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Monika Pikiolek
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland
| | - Caner Ercan
- Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland
| | - Jie Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Xiuzhen Huang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Ximeng Han
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Zhenqian Zhang
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Zan Lv
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Yan Li
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Kuo Liu
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Lingjuan He
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Xiuxiu Liu
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China
| | - Markus H Heim
- Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.,Clarunis University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Luigi M Terracciano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IRCCS Humanitas Research Hospital, Milan, Italy
| | - Jan S Tchorz
- Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China. .,Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. .,School of Life Science and Technology, ShanghaiTech University, Shanghai, China. .,New Cornerstone Science Laboratory, Shenzhen, China.
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17
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Kim M, Rizvi F, Shin D, Gouon-Evans V. Update on Hepatobiliary Plasticity. Semin Liver Dis 2023; 43:13-23. [PMID: 36764306 PMCID: PMC10005859 DOI: 10.1055/s-0042-1760306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
Abstract
The liver field has been debating for decades the contribution of the plasticity of the two epithelial compartments in the liver, hepatocytes and biliary epithelial cells (BECs), to derive each other as a repair mechanism. The hepatobiliary plasticity has been first observed in diseased human livers by the presence of biphenotypic cells expressing hepatocyte and BEC markers within bile ducts and regenerative nodules or budding from strings of proliferative BECs in septa. These observations are not surprising as hepatocytes and BECs derive from a common fetal progenitor, the hepatoblast, and, as such, they are expected to compensate for each other's loss in adults. To investigate the cell origin of regenerated cell compartments and associated molecular mechanisms, numerous murine and zebrafish models with ability to trace cell fates have been extensively developed. This short review summarizes the clinical and preclinical studies illustrating the hepatobiliary plasticity and its potential therapeutic application.
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Affiliation(s)
- Minwook Kim
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Fatima Rizvi
- Department of Medicine, Gastroenterology Section, Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts
| | - Donghun Shin
- Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Valerie Gouon-Evans
- Department of Medicine, Gastroenterology Section, Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, Massachusetts
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18
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Dezső K, Paku S, Kóbori L, Thorgeirsson SS, Nagy P. What Makes Cirrhosis Irreversible?-Consideration on Structural Changes. Front Med (Lausanne) 2022; 9:876293. [PMID: 35572980 PMCID: PMC9091510 DOI: 10.3389/fmed.2022.876293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 04/04/2022] [Indexed: 11/17/2022] Open
Abstract
Several studies have shown that liver fibrosis, and even cirrhosis can be reversed, disproving the old “dogma” that cirrhosis is irreversible. In addition to scaring, vascular alterations appear to be critically important in the progression of chronic liver diseases. To overcome the “tipping-point” of cirrhosis, we need to understand in depth what might make it irreversible in some cases. Morphologically, the initial, as well as the advanced stages of cirrhosis are characterized by specific structural changes. The hallmark of the initial stage is the division of the original liver parenchyma by centro-central or porto-portal septa. No significant vascular changes are observed in this stage. The advanced stage is characterized by several morphological alterations: (i) The main feature is the parenchymal extinction, with intact portal vein branches, hepatic artery branches, and biliary ductules; (ii) In the extinct areas we observed numerous loops in the ductular network, indicating the disruption of the hepato-biliary junctions; (iii) Although the ductular progenitor cells are able to generate hepatocytes via the budding process, the newly formed hepatocyte nodules cannot re-establish the original lobular architecture due to their disorganized growth. In conclusion, this regenerative process characteristic for the advanced stage, contributes to circulatory disorders, perpetuates parenchymal injury and may lead to the irreversibility of cirrhosis.
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Affiliation(s)
- Katalin Dezső
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Sándor Paku
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - László Kóbori
- Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
| | - Snorri S Thorgeirsson
- Laboratory of Human Carcinogenesis, Center for Cancer Research (CCR), National Cancer Institute, National Institute of Health (NIH), Bethesda, MD, United States
| | - Péter Nagy
- Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
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19
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Lin T, Wang S, Munker S, Jung K, Macías-Rodríguez RU, Ruiz-Margáin A, Schierwagen R, Liu H, Shao C, Fan C, Feng R, Yuan X, Wang S, Wandrer F, Meyer C, Wimmer R, Liebe R, Kroll J, Zhang L, Schiergens T, Ten Dijke P, Teufel A, Marx A, Mertens PR, Wang H, Ebert MPA, Bantel H, N De Toni E, Trebicka J, Dooley S, Shin D, Ding H, Weng HL. Follistatin-controlled activin-HNF4α-coagulation factor axis in liver progenitor cells determines outcome of acute liver failure. Hepatology 2022; 75:322-337. [PMID: 34435364 DOI: 10.1002/hep.32119] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 07/01/2021] [Accepted: 08/15/2021] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIMS In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF. APPROACH AND RESULTS Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-β superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure. CONCLUSIONS These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.
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Affiliation(s)
- Tao Lin
- Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Shanshan Wang
- Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
- Beijing Institute of HepatologyBeijing You'an HospitalCapital Medical UniversityBeijingChina
| | - Stefan Munker
- Department of Medicine IIUniversity Hospital, Campus Großhadern, LMU MunichMunichGermany
| | - Kyounghwa Jung
- Department of Developmental BiologyMcGowan Institute for Regenerative MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Ricardo U Macías-Rodríguez
- Department of GastroenterologyInstituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico cityMexico
| | - Astrid Ruiz-Margáin
- Department of GastroenterologyInstituto Nacional de Ciencias Médicas y Nutrición Salvador ZubiránMexico cityMexico
| | - Robert Schierwagen
- Translational Hepatology, Medical Department IFrankfurt University HospitalFrankfurtGermany
| | - Hui Liu
- Department of PathologyBeijing You'an HospitalAffiliated with Capital Medical UniversityBeijingChina
| | - Chen Shao
- Department of PathologyBeijing You'an HospitalAffiliated with Capital Medical UniversityBeijingChina
| | - Chunlei Fan
- Department of Gastroenterology and HepatologyBeijing You'an HospitalAffiliated with Capital Medical UniversityBeijingChina
| | - Rilu Feng
- Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Xiaodong Yuan
- Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Sai Wang
- Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Franziska Wandrer
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Christoph Meyer
- Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Ralf Wimmer
- Department of Medicine IIUniversity Hospital, Campus Großhadern, LMU MunichMunichGermany
| | - Roman Liebe
- Clinic of Gastroenterology, Hepatology and Infectious DiseasesHeinrich Heine UniversityDüsseldorfGermany
- Department of Medicine IISaarland University Medical CenterSaarland UniversityHomburgGermany
| | - Jens Kroll
- Vascular Biology and Tumor AngiogenesisEuropean Center for AngioscienceMedical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Long Zhang
- Life Sciences Institute and Innovation Center for Cell Signaling NetworkHangzhouChina
| | - Tobias Schiergens
- Department of General, Visceral, Transplantation, Vascular and Thoracic SurgeryUniversity HospitalLMU MunichMunichGermany
| | - Peter Ten Dijke
- Oncode Institute and Department of Cell and Chemical BiologyLeiden University Medical CenterLeidenThe Netherlands
| | - Andreas Teufel
- Division of Hepatology, Division of Clinical Bioinformatics, Department of Medicine II, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
- Clinical Cooperation Unit Healthy MetabolismCenter for Preventive Medicine and Digital Health Baden-WürttembergMedical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Alexander Marx
- Institute of PathologyUniversity Medical Center MannheimHeidelberg UniversityMannheimGermany
| | - Peter R Mertens
- Clinic of Nephrology and Hypertension, Diabetes and EndocrinologyOtto-von-Guericke-UniversityMagdeburgGermany
| | - Hua Wang
- Department of Oncologythe First Affiliated Hospital of Anhui Medical UniversityHefeiChina
- Inflammation and Immune Mediated Disease Laboratory of Anhui ProvinceHefeiChina
| | - Matthias P A Ebert
- Mannheim Institute for Innate ImmunoscienceMannheimGermany
- Clinical Cooperation Unit Healthy MetabolismCenter of Preventive Medicine and Digital HealthMedical Faculty MannheimHeidelberg UniversityMannheimGermany
- Department of Medicine II, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Heike Bantel
- Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany
| | - Enrico N De Toni
- Department of Medicine IIUniversity Hospital, Campus Großhadern, LMU MunichMunichGermany
| | - Jonel Trebicka
- Translational Hepatology, Medical Department IFrankfurt University HospitalFrankfurtGermany
- European Foundation for Study of Chronic Liver FailureBarcelonaSpain
| | - Steven Dooley
- Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
| | - Donghun Shin
- Department of Developmental BiologyMcGowan Institute for Regenerative MedicineUniversity of PittsburghPittsburghPennsylvaniaUSA
| | - Huiguo Ding
- Department of Gastroenterology and HepatologyBeijing You'an HospitalAffiliated with Capital Medical UniversityBeijingChina
| | - Hong-Lei Weng
- Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty MannheimHeidelberg UniversityMannheimGermany
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20
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Denk H, Pabst D, Abuja PM, Reihs R, Tessaro B, Zatloukal K, Lackner C. Senescence markers in focal nodular hyperplasia of the liver: pathogenic considerations on the basis of immunohistochemical results. Mod Pathol 2022; 35:87-95. [PMID: 34645984 DOI: 10.1038/s41379-021-00940-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 02/07/2023]
Abstract
Focal nodular hyperplasia (FNH) is a polyclonal tumour-like hepatic lesion characterised by parenchymal nodules, connective tissue septa without interlobular bile ducts, pronounced ductular reaction and inflammation. It may represent a response to local arterial hyperperfusion and hyperoxygenation resulting in oxidative stress. We aimed at obtaining closer insight into the pathogenesis of FNH with its characteristic morphologic features. Immunohistochemistry and immunofluorescence microscopy was performed on FNH specimens using antibodies against keratins (K) 7 and 19, neural cell adhesion molecule (NCAM), lamin B1, senescence markers (CDK inhibitor 1/p21Cip1, CDK inhibitor /p16Ink4a, senescence-associated (SA) β- galactosidase activity), proliferation markers (Ki-67, proliferating-cell nuclear antigen (PCNA)), and the abnormally phosphorylated histone γ-H2AX, indicating DNA double strand breaks; moreover SA β- galactosidase activity was determined histochemically. Ductular metaplasia of hepatocytes indicated by K7 expression in the absence of K19 plays a major role in the development of ductular reaction in FNH. Moreover, the expression of senescence markers (p21Cip1, p16Ink4a, γ-H2AX, SA β-galactosidase activity) in hepatocytes and cholangiocytes suggests that stress-induced cellular senescence contributes to fibrosis and inflammation via production of components of the senescence-associated secretory phenotype. Expression of proliferation markers (Ki-67, PCNA) was not enhanced in hepatocytes and biliary cells. Senescence and ductular metaplasia of hepatocytes may thus be involved in inflammation, fibrosis and apoptosis resistance. Hence, fibrosis, inflammation and reduced apoptotic cell death, rather than proliferation (hyperplasia) may be responsible for increased tissue mass and tumour-like appearance of FNH.
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Affiliation(s)
- Helmut Denk
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria.
| | - Daniela Pabst
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Peter M Abuja
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Robert Reihs
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Brigitte Tessaro
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Kurt Zatloukal
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Carolin Lackner
- Diagnostic & Research Centre of Molecular Biomedicine, Institute of Pathology, Medical University of Graz, Graz, Austria
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21
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Aloia L. The influence of tissue spatial geometry and functional organisation on liver regeneration. Semin Cell Dev Biol 2021; 130:70-78. [PMID: 34563460 DOI: 10.1016/j.semcdb.2021.09.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 08/09/2021] [Accepted: 09/10/2021] [Indexed: 12/14/2022]
Abstract
The adult liver exerts crucial functions, including nutrient metabolism and storage, bile production and drug detoxification. These complex functions expose the liver to constant damage induced by toxins, metabolic intermediates and oxidative stress. However, the adult liver exhibits an exceptional regenerative potential, which allows fast and efficient restoration of tissue architecture and function both after tissue resection and toxic damage. To accomplish its vital role, the liver shows a peculiar tissue architecture into functional units, which follow the gradient of oxygen and nutrients within the parenchyma. Much less is known about the influence of tissue spatial geometry and functional organisation on adult liver regeneration. Here I examine the experimental evidence in mouse models showing that the spatial organisation of the epithelial and mesenchymal compartments plays a key role in liver regeneration and favours the establishment of regenerative adult liver progenitors following liver injury. I also discuss the advantages and limitations of human and mouse 3D hepatic organoid systems, which recapitulate key aspects of liver function and architecture, as models of liver regeneration and disease. Finally, I analyse the role of the YAP/TAZ transcriptional co-activators as a central hub sensing the extra-cellular matrix (ECM), metabolic and epigenetic remodelling that regulate liver regeneration and promote liver disease, such as fibrosis, chronic liver disease and liver cancer. Together, the findings summarised here demonstrate that local physical and functional cellular interactions determined by the liver peculiar spatial geometry, play a crucial role in liver regeneration, and that their alterations have important implications for human liver disease.
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Affiliation(s)
- Luigi Aloia
- MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
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22
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Jung K, Kim M, So J, Lee SH, Ko S, Shin D. Farnesoid X Receptor Activation Impairs Liver Progenitor Cell-Mediated Liver Regeneration via the PTEN-PI3K-AKT-mTOR Axis in Zebrafish. Hepatology 2021; 74:397-410. [PMID: 33314176 PMCID: PMC8605479 DOI: 10.1002/hep.31679] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 11/15/2020] [Accepted: 11/29/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS Following mild liver injury, pre-existing hepatocytes replicate. However, if hepatocyte proliferation is compromised, such as in chronic liver diseases, biliary epithelial cells (BECs) contribute to hepatocytes through liver progenitor cells (LPCs), thereby restoring hepatic mass and function. Recently, augmenting innate BEC-driven liver regeneration has garnered attention as an alternative to liver transplantation, the only reliable treatment for patients with end-stage liver diseases. Despite this attention, the molecular basis of BEC-driven liver regeneration remains poorly understood. APPROACH AND RESULTS By performing a chemical screen with the zebrafish hepatocyte ablation model, in which BECs robustly contribute to hepatocytes, we identified farnesoid X receptor (FXR) agonists as inhibitors of BEC-driven liver regeneration. Here we show that FXR activation blocks the process through the FXR-PTEN (phosphatase and tensin homolog)-PI3K (phosphoinositide 3-kinase)-AKT-mTOR (mammalian target of rapamycin) axis. We found that FXR activation blocked LPC-to-hepatocyte differentiation, but not BEC-to-LPC dedifferentiation. FXR activation also suppressed LPC proliferation and increased its death. These defects were rescued by suppressing PTEN activity with its chemical inhibitor and ptena/b mutants, indicating PTEN as a critical downstream mediator of FXR signaling in BEC-driven liver regeneration. Consistent with the role of PTEN in inhibiting the PI3K-AKT-mTOR pathway, FXR activation reduced the expression of pS6, a marker of mTORC1 activation, in LPCs of regenerating livers. Importantly, suppressing PI3K and mTORC1 activities with their chemical inhibitors blocked BEC-driven liver regeneration, as did FXR activation. CONCLUSIONS FXR activation impairs BEC-driven liver regeneration by enhancing PTEN activity; the PI3K-AKT-mTOR pathway controls the regeneration process. Given the clinical trials and use of FXR agonists for multiple liver diseases due to their beneficial effects on steatosis and fibrosis, the detrimental effects of FXR activation on LPCs suggest a rather personalized use of the agonists in the clinic.
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Affiliation(s)
- Kyounghwa Jung
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
| | - Minwook Kim
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
| | - Juhoon So
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
| | - Seung-Hoon Lee
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
| | - Sungjin Ko
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA;,Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Donghun Shin
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA
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23
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Parenchymal Extinction Mimicking Hepatocellular Carcinoma in a Patient with Chronic Hepatitis B-Related Liver Cirrhosis. Diagnostics (Basel) 2021; 11:diagnostics11071171. [PMID: 34203262 PMCID: PMC8306459 DOI: 10.3390/diagnostics11071171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 06/22/2021] [Accepted: 06/26/2021] [Indexed: 11/16/2022] Open
Abstract
Parenchymal extinction is characterized by the irreversible loss of hepatocytes and their eventual replacement by fibrous tissue, along with the alteration of the sinusoidal architecture and the obstruction of the small portal and hepatic veins. In clinical practice, radiologic modalities are not sufficient for differentiating between parenchymal extinction and hepatocellular carcinoma in patients with advanced fibrosis or cirrhosis. Herein, we present a case of parenchymal extinction mimicking hepatocellular carcinoma in a patient with chronic hepatitis B-related liver cirrhosis.
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24
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So J, Kim M, Lee SH, Ko S, Lee DA, Park H, Azuma M, Parsons MJ, Prober D, Shin D. Attenuating the Epidermal Growth Factor Receptor-Extracellular Signal-Regulated Kinase-Sex-Determining Region Y-Box 9 Axis Promotes Liver Progenitor Cell-Mediated Liver Regeneration in Zebrafish. Hepatology 2021; 73:1494-1508. [PMID: 32602149 PMCID: PMC7769917 DOI: 10.1002/hep.31437] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 06/02/2020] [Accepted: 06/03/2020] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver injury settings. In chronic liver diseases, the number of liver progenitor cells (LPCs) correlates proportionally to disease severity, implying that their inefficient differentiation into hepatocytes exacerbates the disease. Moreover, LPCs secrete proinflammatory cytokines; thus, their prolonged presence worsens inflammation and induces fibrosis. Promoting LPC-to-hepatocyte differentiation in patients with advanced liver disease, for whom liver transplantation is currently the only therapeutic option, may be a feasible clinical approach because such promotion generates more functional hepatocytes and concomitantly reduces inflammation and fibrosis. APPROACH AND RESULTS Here, using zebrafish models of LPC-mediated liver regeneration, we present a proof of principle of such therapeutics by demonstrating a role for the epidermal growth factor receptor (EGFR) signaling pathway in differentiation of LPCs into hepatocytes. We found that suppression of EGFR signaling promoted LPC-to-hepatocyte differentiation through the mitogen-activated ERK kinase (MEK)-extracellular signal-regulated kinase (ERK)-sex-determining region Y-box 9 (SOX9) cascade. Pharmacological inhibition of EGFR or MEK/ERK promoted LPC-to-hepatocyte differentiation as well as genetic suppression of the EGFR-ERK-SOX9 axis. Moreover, Sox9b overexpression in LPCs blocked their differentiation into hepatocytes. In the zebrafish liver injury model, both hepatocytes and biliary epithelial cells contributed to LPCs. EGFR inhibition promoted the differentiation of LPCs regardless of their origin. Notably, short-term treatment with EGFR inhibitors resulted in better liver recovery over the long term. CONCLUSIONS The EGFR-ERK-SOX9 axis suppresses LPC-to-hepatocyte differentiation during LPC-mediated liver regeneration. We suggest EGFR inhibitors as a proregenerative therapeutic drug for patients with advanced liver disease.
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Affiliation(s)
- Juhoon So
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Minwook Kim
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Seung-Hoon Lee
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
| | - Sungjin Ko
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
- Present address: Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Daniel A. Lee
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Hyewon Park
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA
| | - Mizuki Azuma
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS 66045, USA
| | - Michael J. Parsons
- Department of Developmental and Cell Biology, University of California Irvine, Irvine, CA 92697, USA
| | - David Prober
- Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA
| | - Donghun Shin
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15260, USA
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25
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Abstract
Intrahepatic ductular reaction is a pathologic proliferation of phenotypical biliary channels. Ductular reactions aim to restore compromised physiological function after liver injury and are one of the archetypal responses of the liver to a wide variety of etiologies, among them are parenchymal loss, biliary tract disease, neoplasms, after liver transplantation, and several pediatric liver diseases. The types and extent of ductular reactions can vary, according to the etiological insult. In this review, the authors will first consider the different mechanisms for ductular reactions and their relevance for liver regeneration. After, the authors will discuss our approach to differential diagnosis for ductular reactions in different patient groups, taking into account clinical history and potential pitfalls. The authors provide an algorithmic approach for practicing pathologists and trainees when confronted by a ductular reaction in a liver biopsy.
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26
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Silva DRS, Carreira ACO, Ferreira AO, da Silva MD, Sogayar MC, Miglino MA. Characterization of rat liver bud-derived cells. Tissue Cell 2021; 71:101510. [PMID: 33721789 DOI: 10.1016/j.tice.2021.101510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 02/03/2021] [Accepted: 02/06/2021] [Indexed: 10/22/2022]
Abstract
Cells derived from the fetal liver have been shown to be a rich source of progenitor stem cells, constituting a promising source for Tissue Engineering and Regenerative Medicine. In this study, embryo and fetal liver-bud derived cells from Fischer 344 rats were obtained at E12.5, E14.5 and E16.5 gestational days and evaluated for cell phenotype, survival and proliferation. Liver transaminase (AST and ALT) and AFP levels were lower in embryo liver-bud-derived cells on day 12.5. Markers for stem cells, cell cycle progression and cell death were differentially expressed in E12.5 cell cultures. Analysis of mitochondrial electric potential on 14.5 and 16.5 days showed a tendency for cells with lower functional or metabolic ability, in comparison to cultures derived from day 12.5. The results demonstrated that the majority of the E16.5 cells were in the G0 / G1 phase. The capacity of synthesis (S) and cellular division (G2 / M) of embryo and fetal liver bud-derived cells was constant over all gestational periods. In conclusion, embryo and fetal liver-bud-derived cells during the periods of 12.5 and 14.5 days, showed expression profile of progenitor cells, cell activity and hematopoietic function in culture.
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Affiliation(s)
- Dara Rúbia Souza Silva
- Department of Surgery, School of Veterinary Medicine and Animal Science (FMVZ), University of Sao Paulo (USP), Prof. Dr Orlando Marques de Paiva Avenue, 87, University City, Sao Paulo, SP 05508-270, Brazil
| | - Ana Claudia Oliveira Carreira
- Department of Surgery, School of Veterinary Medicine and Animal Science (FMVZ), University of Sao Paulo (USP), Prof. Dr Orlando Marques de Paiva Avenue, 87, University City, Sao Paulo, SP 05508-270, Brazil; Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of Sao Paulo (USP), Pangaré Street 100, University City, Butanta, SP 05360-130, Brazil
| | - Amanda Olivotti Ferreira
- Department of Surgery, School of Veterinary Medicine and Animal Science (FMVZ), University of Sao Paulo (USP), Prof. Dr Orlando Marques de Paiva Avenue, 87, University City, Sao Paulo, SP 05508-270, Brazil
| | - Mônica Duarte da Silva
- Department of Surgery, School of Veterinary Medicine and Animal Science (FMVZ), University of Sao Paulo (USP), Prof. Dr Orlando Marques de Paiva Avenue, 87, University City, Sao Paulo, SP 05508-270, Brazil
| | - Mari Cleide Sogayar
- Cell and Molecular Therapy Center (NUCEL), School of Medicine, University of Sao Paulo (USP), Pangaré Street 100, University City, Butanta, SP 05360-130, Brazil; Department of Biochemistry, Chemistry Institute, University of Sao Paulo (USP), São Paulo, SP 05508-900, Brazil
| | - Maria Angelica Miglino
- Department of Surgery, School of Veterinary Medicine and Animal Science (FMVZ), University of Sao Paulo (USP), Prof. Dr Orlando Marques de Paiva Avenue, 87, University City, Sao Paulo, SP 05508-270, Brazil.
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27
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Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol 2021; 18:40-55. [PMID: 32764740 DOI: 10.1038/s41575-020-0342-4] [Citation(s) in RCA: 546] [Impact Index Per Article: 136.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/24/2020] [Indexed: 02/08/2023]
Abstract
The liver is the only solid organ that uses regenerative mechanisms to ensure that the liver-to-bodyweight ratio is always at 100% of what is required for body homeostasis. Other solid organs (such as the lungs, kidneys and pancreas) adjust to tissue loss but do not return to 100% of normal. The current state of knowledge of the regenerative pathways that underlie this 'hepatostat' will be presented in this Review. Liver regeneration from acute injury is always beneficial and has been extensively studied. Experimental models that involve partial hepatectomy or chemical injury have revealed extracellular and intracellular signalling pathways that are used to return the liver to equivalent size and weight to those prior to injury. On the other hand, chronic loss of hepatocytes, which can occur in chronic liver disease of any aetiology, often has adverse consequences, including fibrosis, cirrhosis and liver neoplasia. The regenerative activities of hepatocytes and cholangiocytes are typically characterized by phenotypic fidelity. However, when regeneration of one of the two cell types fails, hepatocytes and cholangiocytes function as facultative stem cells and transdifferentiate into each other to restore normal liver structure. Liver recolonization models have demonstrated that hepatocytes have an unlimited regenerative capacity. However, in normal liver, cell turnover is very slow. All zones of the resting liver lobules have been equally implicated in the maintenance of hepatocyte and cholangiocyte populations in normal liver.
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Affiliation(s)
- George K Michalopoulos
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
| | - Bharat Bhushan
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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28
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Abstract
Following injury, the liver's epithelial cells regenerate efficiently with rapid proliferation of hepatocytes and biliary cells. However, when proliferation of resident epithelial cells is impaired, alternative regeneration mechanisms can occur. Intricate lineage-tracing strategies and experimental models of regenerative stress have revealed a degree of plasticity between hepatocytes and biliary cells. New technologies such as single-cell omics, in combination with functional studies, will be instrumental to uncover the remaining unknowns in the field. In this review, we evaluate the experimental and clinical evidence for epithelial plasticity in the liver and how this influences the development of therapeutic strategies for chronic liver disease.
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Affiliation(s)
- Victoria L Gadd
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Niya Aleksieva
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK
| | - Stuart J Forbes
- Centre for Regenerative Medicine, Edinburgh BioQuarter, University of Edinburgh, Edinburgh, EH16 4UU, UK.
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29
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Safarikia S, Carpino G, Overi D, Cardinale V, Venere R, Franchitto A, Onori P, Alvaro D, Gaudio E. Distinct EpCAM-Positive Stem Cell Niches Are Engaged in Chronic and Neoplastic Liver Diseases. Front Med (Lausanne) 2020; 7:479. [PMID: 32984373 PMCID: PMC7492539 DOI: 10.3389/fmed.2020.00479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 07/15/2020] [Indexed: 12/12/2022] Open
Abstract
In normal human livers, EpCAMpos cells are mostly restricted in two distinct niches, which are (i) the bile ductules and (ii) the mucous glands present inside the wall of large intrahepatic bile ducts (the so-called peribiliary glands). These EpCAMpos cell niches have been proven to harbor stem/progenitor cells with great importance in liver and biliary tree regeneration and in the pathophysiology of human diseases. The EpCAMpos progenitor cells within bile ductules are engaged in driving regenerative processes in chronic diseases affecting hepatocytes or interlobular bile ducts. The EpCAMpos population within peribiliary glands is activated when regenerative needs are finalized to repair large intra- or extra-hepatic bile ducts affected by chronic pathologies, including primary sclerosing cholangitis and ischemia-induced cholangiopathies after orthotopic liver transplantation. Finally, the presence of distinct EpCAMpos cell populations may explain the histological and molecular heterogeneity characterizing cholangiocarcinoma, based on the concept of multiple candidate cells of origin. This review aimed to describe the precise anatomical distribution of EpCAMpos populations within the liver and the biliary tree and to discuss their contribution in the pathophysiology of human liver diseases, as well as their potential role in regenerative medicine of the liver.
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Affiliation(s)
- Samira Safarikia
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico," Rome, Italy
| | - Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
| | - Rosanna Venere
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
| | - Domenico Alvaro
- Department of Precision and Translational Medicine, Sapienza University of Rome, Rome, Italy
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
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So J, Kim A, Lee SH, Shin D. Liver progenitor cell-driven liver regeneration. Exp Mol Med 2020; 52:1230-1238. [PMID: 32796957 PMCID: PMC8080804 DOI: 10.1038/s12276-020-0483-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 06/08/2020] [Accepted: 06/17/2020] [Indexed: 12/28/2022] Open
Abstract
The liver is a highly regenerative organ, but its regenerative capacity is compromised in severe liver diseases. Hepatocyte-driven liver regeneration that involves the proliferation of preexisting hepatocytes is a primary regeneration mode. On the other hand, liver progenitor cell (LPC)-driven liver regeneration that involves dedifferentiation of biliary epithelial cells or hepatocytes into LPCs, LPC proliferation, and subsequent differentiation of LPCs into hepatocytes is a secondary mode. This secondary mode plays a significant role in liver regeneration when the primary mode does not effectively work, as observed in severe liver injury settings. Thus, promoting LPC-driven liver regeneration may be clinically beneficial to patients with severe liver diseases. In this review, we describe the current understanding of LPC-driven liver regeneration by exploring current knowledge on the activation, origin, and roles of LPCs during regeneration. We also describe animal models used to study LPC-driven liver regeneration, given their potential to further deepen our understanding of the regeneration process. This understanding will eventually contribute to developing strategies to promote LPC-driven liver regeneration in patients with severe liver diseases.
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Affiliation(s)
- Juhoon So
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
| | - Angie Kim
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Seung-Hoon Lee
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA
| | - Donghun Shin
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15260, USA.
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Konishi T, Schuster RM, Goetzman HS, Caldwell CC, Lentsch AB. Fibrotic liver has prompt recovery after ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol 2020; 318:G390-G400. [PMID: 31961717 PMCID: PMC7099490 DOI: 10.1152/ajpgi.00137.2019] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 12/19/2019] [Accepted: 01/09/2020] [Indexed: 01/31/2023]
Abstract
Hepatic ischemia-reperfusion (I/R) is a major complication of liver resection, trauma, and liver transplantation; however, liver repair after I/R in diseased liver has not been studied. The present study sought to determine the manner in which the fibrotic liver repairs itself after I/R. Liver fibrosis was established in mice by CCl4 administration for 6 wk, and then liver I/R was performed to investigate liver injury and subsequent liver repair in fibrotic and control livers. After I/R, fibrotic liver had more injury compared with nonfibrotic, control liver; however, fibrotic liver showed rapid resolution of liver necrosis and reconstruction of liver parenchyma. Marked accumulation of hepatic stellate cells and macrophages were observed specifically in the fibrotic septa in early reparative phase. Fibrotic liver had higher numbers of hepatic stellate cells, macrophages, and hepatic progenitor cells during liver recovery after I/R than did control liver, but hepatocyte proliferation was unchanged. Fibrotic liver also had significantly greater number of phagocytic macrophages than control liver. Clodronate liposome injection into fibrotic mice after I/R caused decreased macrophage accumulation and delay of liver recovery. Conversely, CSF1-Fc injection into normal mice after I/R resulted in increased macrophage accumulation and concomitant decrease in necrotic tissue during liver recovery. In conclusion, fibrotic liver clears necrotic areas and restores normal parenchyma faster than normal liver after I/R. This beneficial response appears to be directly related to the increased numbers of nonparenchymal cells, particularly phagocytic macrophages, in the fibrotic liver.NEW & NOTEWORTHY This study is the first to reveal how diseased liver recovers after ischemia-reperfusion (I/R) injury. Although it was not completely unexpected that fibrotic liver had increased hepatic injury after I/R, a novel finding was that fibrotic liver had accelerated recovery and repair compared with normal liver. Enhanced repair after I/R in fibrotic liver was associated with increased expansion of phagocytic macrophages, hepatic stellate cells, and progenitor cells.
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Affiliation(s)
- Takanori Konishi
- Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio
| | - Rebecca M Schuster
- Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio
| | - Holly S Goetzman
- Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio
| | - Charles C Caldwell
- Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio
| | - Alex B Lentsch
- Department of Surgery, University of Cincinnati, College of Medicine, Cincinnati, Ohio
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Hadi R, Shin K, Reder N, Alpert L, Koch L, Choi WT, Swanson PE, Hart J, Westerhoff M. Utility of glutamine synthetase immunohistochemistry in identifying features of regressed cirrhosis. Mod Pathol 2020; 33:448-455. [PMID: 31391527 DOI: 10.1038/s41379-019-0346-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 07/13/2019] [Indexed: 02/07/2023]
Abstract
The prevailing view that cirrhosis is irreversible has been challenged. It has been proposed that varying degrees of fibrosis regression can be achieved if the injurious agent is removed. In the normal liver, glutamine synthetase immunostaining is present around central veins. In regressed cirrhosis, although fibrous bands between portal tracts and central veins may largely be resorbed, the abnormal portal tract-central vein adherence often remains. Hence, we hypothesized that aberrant glutamine synthetase positivity adjacent to portal tracts would help identify regressed cirrhosis. We performed glutamine synthetase immunohistochemistry on 49 liver specimens (16 regressed cirrhosis, 18 cirrhotic, and 15 normal livers). Qualification for regressed cirrhosis required the following histologic features: curved, delicate incomplete septa, portal tract-central vein adhesions, and portal tract "remnants" (portal tracts with no venous branch). Out of 16, 14 regressed cirrhosis cases had baseline cirrhosis established based on previous biopsy or signs of cirrhosis based on physical exam, laboratory, and radiological findings. All regressed cirrhosis cases (100%) had areas of aberrant glutamine synthetase positivity adjacent to portal tracts, indicating that portal tract-central vein approximation had occurred (p < 0.001 compared to all other categories). No normal cases had glutamine synthetase positivity adjacent to portal tracts, and half of cirrhosis cases had areas showing features of regression, with focal glutamine synthetase positivity adjacent to portal tracts. Overall, glutamine synthetase expression showed highly significant differences among the three categories (p < 0.001). This study shows that aberrant glutamine synthetase positivity adjacent to portal tracts is present in regressed cirrhosis and can be useful in identifying regressed cirrhosis when it is histologically suspected.
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Affiliation(s)
- Rouba Hadi
- Department of Anatomic Pathology, University of Washington Medical Center, 1959 NE Pacific St, NE 110, Seattle, WA, 98195, USA.
| | - Kseniya Shin
- Department of Anatomic Pathology, University of Washington Medical Center, 1959 NE Pacific St, NE 110, Seattle, WA, 98195, USA
| | - Nicholas Reder
- Department of Anatomic Pathology, University of Washington Medical Center, 1959 NE Pacific St, NE 110, Seattle, WA, 98195, USA
| | - Lindsay Alpert
- Department of Anatomic Pathology, University of Chicago, A27 S Maryland Ave, Chicago, IL, 60637, USA
| | - Lisa Koch
- Department of Anatomic Pathology, University of Washington Medical Center, 1959 NE Pacific St, NE 110, Seattle, WA, 98195, USA
| | - Won-Tak Choi
- Department of Anatomic Pathology, University of California San Francisco, 505 Parnassus Avenue, Room M-552, San Francisco, CA, 94143, USA
| | - Paul E Swanson
- Department of Anatomic Pathology, University of Washington Medical Center, 1959 NE Pacific St, NE 110, Seattle, WA, 98195, USA
| | - John Hart
- Department of Anatomic Pathology, University of Chicago, A27 S Maryland Ave, Chicago, IL, 60637, USA
| | - Maria Westerhoff
- Department of Anatomic Pathology, University of Michigan Health System, NCRC building 35 2800 Plymouth Road, Ann Arbor, MI, 48109, USA
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The Role of Vascular Injury and Congestion in the Pathogenesis of Cirrhosis: the Congestive Escalator and the Parenchymal Extinction Sequence. ACTA ACUST UNITED AC 2020. [DOI: 10.1007/s11901-020-00508-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
AbstractPurpose of ReviewCurrent research into the pathogenesis of cirrhosis is largely dominated by investigations of hepatocellular injury and fibrogenesis, mostly in short-term experimental models. Cirrhosis in the human evolves for decades with histologic features that are very different from the models studied, dominated by hepatic vein obstruction and congestion. This is a clue that the mechanisms operating in the human are different from those in most animal models.Recent FindingsThis paper presents an updated “vascular hypothesis” with previously unpublished observations that provide a more complete understanding of the pathogenesis of chronic liver disease in the human: (1) a definition of parenchymal extinction emphasizing the importance of sinusoidal destruction, (2) analysis of the temporal evolution of parenchymal extinction lesions, (3) new data to quantify hepatic vein obstruction, (4) a “congestive escalator” hypothesis to explain how vascular obstruction occurs, beginning with sinusoidal endothelial cell injury, fluid translocation, and vascular compression by mechanics known as “compartment syndrome,” (5) a “nested cone model” of hepatic vein anatomy that predisposes to compartment syndrome in the human, and (6) a proposal for the mechanism of collagen formation in response to congestion (“congestive fibrosis”).SummaryThe guiding principle in this model is that flow has to be vented to keep pressure gradients within the physiological range. Vascular obstruction causes tissue congestion which induces further vascular obstruction that drives a congestive escalator leading to progressive parenchymal extinction. This model may be applicable to all types of cirrhosis found in the human.
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Ko S, Russell JO, Molina LM, Monga SP. Liver Progenitors and Adult Cell Plasticity in Hepatic Injury and Repair: Knowns and Unknowns. ANNUAL REVIEW OF PATHOLOGY 2020; 15:23-50. [PMID: 31399003 PMCID: PMC7212705 DOI: 10.1146/annurev-pathmechdis-012419-032824] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The liver is a complex organ performing numerous vital physiological functions. For that reason, it possesses immense regenerative potential. The capacity for repair is largely attributable to the ability of its differentiated epithelial cells, hepatocytes and biliary epithelial cells, to proliferate after injury. However, in cases of extreme acute injury or prolonged chronic insult, the liver may fail to regenerate or do so suboptimally. This often results in life-threatening end-stage liver disease for which liver transplantation is the only effective treatment. In many forms of liver injury, bipotent liver progenitor cells are theorized to be activated as an additional tier of liver repair. However, the existence, origin, fate, activation, and contribution to regeneration of liver progenitor cells is hotly debated, especially since hepatocytes and biliary epithelial cells themselves may serve as facultative stem cells for one another during severe liver injury. Here, we discuss the evidence both supporting and refuting the existence of liver progenitor cells in a variety of experimental models. We also debate the validity of developing therapies harnessing the capabilities of these cells as potential treatments for patients with severe and chronic liver diseases.
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Affiliation(s)
- Sungjin Ko
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Jacquelyn O Russell
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Laura M Molina
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
| | - Satdarshan P Monga
- Division of Experimental Pathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA;
- Pittsburgh Liver Research Center, University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA
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Dezső K, Nagy P, Paku S. Human liver regeneration following massive hepatic necrosis: Two distinct patterns. J Gastroenterol Hepatol 2020; 35:124-134. [PMID: 31090096 DOI: 10.1111/jgh.14721] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Revised: 05/04/2019] [Accepted: 05/07/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIM Massive hepatic necrosis is a rare but often fatal complication of various liver injuries. Nevertheless, some patients can survive by spontaneous hepatic regeneration. It is known that surviving hepatocytes and/or progenitor cells can participate in this process but the mechanism of hepatic recovery is vague. METHODS We examined 13 explanted human livers removed for acute liver failure. Combined immunohistochemistry, digital image analysis, and three-dimensional reconstruction of serial sections were applied. RESULTS Two patterns of regeneration could be distinguished. In livers with centrilobular necrosis, the surviving injured periportal hepatocytes started to proliferate and arrange into acinar structures and expressed α-fetoprotein. If the injury wiped out almost all hepatocytes, large areas of parenchymal loss were invaded by an intense ductular reaction. The cells at the distal pole of the ductules differentiated into hepatocytes and formed foci organized by the branches of the portal vein. The expanding foci often containing complete portal triads were arranged around surviving central veins. Their fusion eventually could be an attempt to re-establish the hepatic lobules. CONCLUSIONS Regeneration of human livers following massive hepatic necrosis can occur in two ways-either through proliferation of α-fetoprotein-positive acinary-arranged hepatocytes or through ductular progenitor cells, with the latter being less efficient. Further investigation of these regenerative pathways may help identify biomarkers for likelihood of complete regeneration and hence have therapeutic implications.
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Affiliation(s)
- Katalin Dezső
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Péter Nagy
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Sándor Paku
- First Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
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Wanless IR. Pathology of Budd–Chiari Syndrome and Hepatic Vein Obstruction. BUDD-CHIARI SYNDROME 2020:27-38. [DOI: 10.1007/978-981-32-9232-1_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Majo J, Klinkhammer BM, Boor P, Tiniakos D. Pathology and natural history of organ fibrosis. Curr Opin Pharmacol 2019; 49:82-89. [PMID: 31671319 DOI: 10.1016/j.coph.2019.09.009] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 09/24/2019] [Indexed: 02/08/2023]
Abstract
Histopathological assessment of fibrosis focusing on morphological patterns provides important information for the management of patients with chronic diseases of the kidney, liver and the lung. This review summarizes key histopathological features of pulmonary, renal and hepatic fibrosis and discusses advances in the understanding of the pathogenesis of pulmonary fibrosis and pathogenetic insights with translational implications for renal fibrosis. The review also tackles new staging approaches based on liver fibrosis dynamics and evaluation of fibrosis regression, digital pathology and second harmonic generation microscopy methods for hepatic fibrosis assessment and critical appraisal of non-invasive tests for liver and renal fibrosis evaluation.
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Affiliation(s)
- Joaquim Majo
- Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom
| | - Barbara Mara Klinkhammer
- Institute of Pathology & Department of Nephrology, University Clinic of RWTH, Aachen, Aachen, Germany
| | - Peter Boor
- Institute of Pathology & Department of Nephrology, University Clinic of RWTH, Aachen, Aachen, Germany
| | - Dina Tiniakos
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, United Kingdom; Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece.
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Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis. PLoS One 2019; 14:e0222840. [PMID: 31644538 PMCID: PMC6808498 DOI: 10.1371/journal.pone.0222840] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Accepted: 09/08/2019] [Indexed: 12/15/2022] Open
Abstract
Background Prostanoids are important regulators of platelet aggregation and thrombotic arterial diseases. Their involvement in the development of portal vein thrombosis, frequent in decompensated liver cirrhosis, is still not investigated. Methods Therefore, we used pro-thrombotic venous milieu generation by bare metal stent transjugular intrahepatic portosystemic shunt insertion, to study the role of prostanoids in decompensated liver cirrhosis. Here, 89 patients receiving transjugular intrahepatic portosystemic shunt insertion were included in the study, and baseline levels of thromboxane B2, prostaglandin D2 and prostaglandin E2 were measured in the portal and the hepatic vein. Results While the hepatic vein contained higher levels of thromboxane B2 than the portal vein, levels of prostaglandin E2 and D2 were higher in the portal vein (all P<0.0001). Baseline concentrations of thromboxane B2 in the portal vein were independently associated with an increase of portal hepatic venous pressure gradient during short term follow-up, as an indirect sign of thrombogenic potential (multivariable P = 0.004). Moreover, severity of liver disease was inversely correlated with portal as well as hepatic vein levels of prostaglandin D2 and E2 (all P<0.0001). Conclusions Elevated portal venous thromboxane B2 concentrations are possibly associated with the extent of thrombogenic potential in patients with decompensated liver cirrhosis. Trial registration ClinicalTrials.gov identifier: NCT03584204.
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Bizzaro D, Russo FP, Burra P. New Perspectives in Liver Transplantation: From Regeneration to Bioengineering. Bioengineering (Basel) 2019; 6:81. [PMID: 31514475 PMCID: PMC6783848 DOI: 10.3390/bioengineering6030081] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/09/2019] [Accepted: 09/10/2019] [Indexed: 12/18/2022] Open
Abstract
Advanced liver diseases have very high morbidity and mortality due to associated complications, and liver transplantation represents the only current therapeutic option. However, due to worldwide donor shortages, new alternative approaches are mandatory for such patients. Regenerative medicine could be the more appropriate answer to this need. Advances in knowledge of physiology of liver regeneration, stem cells, and 3D scaffolds for tissue engineering have accelerated the race towards efficient therapies for liver failure. In this review, we propose an update on liver regeneration, cell-based regenerative medicine and bioengineering alternatives to liver transplantation.
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Affiliation(s)
- Debora Bizzaro
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, University/Hospital Padua, 35128 Padua, Italy.
| | - Francesco Paolo Russo
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, University/Hospital Padua, 35128 Padua, Italy.
| | - Patrizia Burra
- Department of Surgery, Oncology and Gastroenterology, Gastroenterology/Multivisceral Transplant Section, University/Hospital Padua, 35128 Padua, Italy.
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Manco R, Clerbaux LA, Verhulst S, Bou Nader M, Sempoux C, Ambroise J, Bearzatto B, Gala JL, Horsmans Y, van Grunsven L, Desdouets C, Leclercq I. Reactive cholangiocytes differentiate into proliferative hepatocytes with efficient DNA repair in mice with chronic liver injury. J Hepatol 2019; 70:1180-1191. [PMID: 30794890 DOI: 10.1016/j.jhep.2019.02.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 02/01/2019] [Accepted: 02/04/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND & AIM Chronic liver diseases are characterized by expansion of the small immature cholangiocytes - a mechanism named ductular reaction (DR) - which have the capacity to differentiate into hepatocytes. We investigated the kinetics of this differentiation, as well as analyzing several important features of the newly formed hepatocytes, such as functional maturity, clonal expansion and resistance to stress in mice with long-term liver damage. METHODS We tracked cholangiocytes using osteopontin-iCreERT2 and hepatocytes with AAV8-TBG-Cre. Mice received carbon tetrachloride (CCl4) for >24 weeks to induce chronic liver injury. Livers were collected for the analysis of reporter proteins, cell proliferation and death, DNA damage, and nuclear ploidy; hepatocytes were also isolated for RNA sequencing. RESULTS During liver injury we observed a transient DR and the differentiation of DR cells into hepatocytes as clones that expanded to occupy 12% of the liver parenchyma by week 8. By lineage tracing, we confirmed that these new hepatocytes derived from cholangiocytes but not from native hepatocytes. They had all the features of mature functional hepatocytes. In contrast to the exhausted native hepatocytes, these newly formed hepatocytes had higher proliferative capability, less apoptosis, a lower proportion of highly polyploid nuclei and were better at eliminating DNA damage. CONCLUSIONS In chronic liver injury, DR cells differentiate into stress-resistant hepatocytes that repopulate the liver. The process might account for the observed parenchymal reconstitution in livers of patients with advanced-stage hepatitis and could be a target for regenerative purposes. LAY SUMMARY During chronic liver disease, while native hepatocytes are exhausted and genetically unstable, a subset of cholangiocytes clonally expand to differentiate into young, functional and robust hepatocytes. This cholangiocyte cell population is a promising target for regenerative therapies in patients with chronic liver insufficiency.
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Affiliation(s)
- Rita Manco
- Laboratory of Hepato-gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Laure-Alix Clerbaux
- Laboratory of Hepato-gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Stefaan Verhulst
- Liver Cell Biology Laboratory, Vrije Universiteit Brussels (VUB), Brussels, Belgium
| | - Myriam Bou Nader
- Inserm, U1016, Institut Cochin, Paris, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Christine Sempoux
- Institute of Pathology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Jerome Ambroise
- Centre de Technologies Moléculaires Appliquées, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Bertrand Bearzatto
- Centre de Technologies Moléculaires Appliquées, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Jean Luc Gala
- Centre de Technologies Moléculaires Appliquées, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Yves Horsmans
- Laboratory of Hepato-gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium; Hepato-gastroenterology Unit, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Leo van Grunsven
- Liver Cell Biology Laboratory, Vrije Universiteit Brussels (VUB), Brussels, Belgium
| | - Chantal Desdouets
- Inserm, U1016, Institut Cochin, Paris, France; CNRS, UMR 8104, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France
| | - Isabelle Leclercq
- Laboratory of Hepato-gastroenterology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium.
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Di Giorgio A, D'Adda A, Marseglia A, Sonzogni A, Licini L, Nicastro E, D'Antiga L. Biliary features in liver histology of children with autoimmune liver disease. Hepatol Int 2019; 13:510-518. [PMID: 31069759 DOI: 10.1007/s12072-019-09948-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Accepted: 04/20/2019] [Indexed: 12/23/2022]
Abstract
OBJECTIVES AND STUDY Various degrees of biliary changes are considered to be part of the histological picture of children with pediatrics autoimmune liver disease (AILD), but the literature is scarce and confusing. We aimed to describe the characteristics of children with AILD (autoimmune hepatitis, AIH, and autoimmune sclerosing cholangitis, ASC) focusing on the prevalence and type of biliary abnormalities on initial biopsy to see whether ASC was predictable on histological ground. METHODS The files of children diagnosed with AILD were reviewed. The Ishak score was used to grade inflammation and fibrosis on biopsy; a biliary score was built to grade bile duct injury. Demographic, laboratory and histological features at diagnosis were reported and compared between the two groups (AIH vs ASC). RESULTS Forty-one patients were diagnosed with AIH (n = 24), ASC (n = 13) and PSC (n = 4) between 2009 and 2018. Twenty-nine patients [F = 76%, AIH = 20, ASC = 9, median age at diagnosis 11.7 (range 2.2-17.8)] were included in the study; 12 (4 with PSC) were excluded. Prevalence of inflammatory bowel disease was higher in ASC group (56% vs 10% in AIH, p < 0.05). On histology 17% had cirrhosis. The grade of biliopathy with AILD was moderate in 72% and severe in 31%, and overall more prominent in ASC (p = 0.031). The inflammation of the bile ducts was classified as "multifocal" or "diffuse" mainly in ASC patients (89% vs 45% in AIH, p = 0.043). Periductular fibrosis was reported in 52% of AILD patients, with a higher mean score in ASC group (p < 0.05). However, ductular reaction, biliary metaplasia and granulomatous cholangitis were equally reported in AIH and ASC, providing no clear-cut for the distinction of the two entities in the global histological evaluation. CONCLUSIONS Majority of patients with pediatrics AILD have "moderate" or "severe" features of biliopathy; AIH and ASC are not easily distinguishable on histological ground at diagnosis, and therefore, the cholangiogram remains the only effective tool to differentiate patients with AIH from those with ASC. Further prospective studies are needed to better define histological biliary features in AILD, assess if the biliopathy responds to immunosuppressive treatment and evaluate its impact on long-term outcome.
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Affiliation(s)
- Angelo Di Giorgio
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy.
| | - A D'Adda
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy
| | - A Marseglia
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy
| | - A Sonzogni
- Liver Pathology, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - L Licini
- Liver Pathology, Hospital Papa Giovanni XXIII, Bergamo, Italy
| | - E Nicastro
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy
| | - L D'Antiga
- Paediatric Hepatology, Gastroenterology and Transplantation, Hospital Papa Giovanni XXIII, Piazza Oms 1, 24127, Bergamo, Italy
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Paradis V, Quaglia A. Digital pathology, what is the future? J Hepatol 2019; 70:1016-1018. [PMID: 30857782 DOI: 10.1016/j.jhep.2018.03.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 03/26/2018] [Accepted: 03/27/2018] [Indexed: 12/04/2022]
Affiliation(s)
- V Paradis
- Pathology Department, Beaujon Hospital, Clichy, France.
| | - A Quaglia
- Institute of Liver Studies, King's College Hospital, United Kingdom
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43
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Russell JO, Ko S, Monga SP, Shin D. Notch Inhibition Promotes Differentiation of Liver Progenitor Cells into Hepatocytes via sox9b Repression in Zebrafish. Stem Cells Int 2019; 2019:8451282. [PMID: 30992706 PMCID: PMC6434270 DOI: 10.1155/2019/8451282] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 01/12/2019] [Indexed: 02/08/2023] Open
Abstract
Liver regeneration after most forms of injury is mediated through the proliferation of hepatocytes. However, when hepatocyte proliferation is impaired, such as during chronic liver disease, liver progenitor cells (LPCs) arising from the biliary epithelial cell (BEC) compartment can give rise to hepatocytes to mediate hepatic repair. Promotion of LPC-to-hepatocyte differentiation in patients with chronic liver disease could serve as a potentially new therapeutic option, but first requires the identification of the molecular mechanisms driving this process. Notch signaling has been identified as an important signaling pathway promoting the BEC fate during development and has also been implicated in regulating LPC differentiation during regeneration. SRY-related HMG box transcription factor 9 (Sox9) is a direct target of Notch signaling in the liver, and Sox9 has also been shown to promote the BEC fate during development. We have recently shown in a zebrafish model of LPC-driven liver regeneration that inhibition of Hdac1 activity through MS-275 treatment enhances sox9b expression in LPCs and impairs LPC-to-hepatocyte differentiation. Therefore, we hypothesized that inhibition of Notch signaling would promote LPC-to-hepatocyte differentiation by repressing sox9b expression in zebrafish. We ablated the hepatocytes of Tg(fabp10a:CFP-NTR) larvae and blocked Notch activation during liver regeneration through treatment with γ-secretase inhibitor LY411575 and demonstrated enhanced induction of Hnf4a in LPCs. Alternatively, enhancing Notch signaling via Notch3 intracellular domain (N3ICD) overexpression impaired Hnf4a induction. Hepatocyte ablation in sox9b heterozygous mutant embryos enhanced Hnf4a induction, while BEC-specific Sox9b overexpression impaired LPC-to-hepatocyte differentiation. Our results establish the Notch-Sox9b signaling axis as inhibitory to LPC-to-hepatocyte differentiation in a well-established in vivo LPC-driven liver regeneration model.
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Affiliation(s)
| | - Sungjin Ko
- Department of Pathology, University of Pittsburgh, Pittsburgh, USA
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
| | - Satdarshan P. Monga
- Department of Pathology, University of Pittsburgh, Pittsburgh, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, USA
- Department of Medicine, University of Pittsburgh, Pittsburgh, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, USA
| | - Donghun Shin
- Department of Developmental Biology, University of Pittsburgh, Pittsburgh, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, USA
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Liu W, Wang Y, Sun Y, Wu Y, Ma Q, Shi Y, He R, Zhang T, Ma Y, Zuo W, Wu Z. Clonal expansion of hepatic progenitor cells and differentiation into hepatocyte-like cells. Dev Growth Differ 2019; 61:203-211. [PMID: 30786319 DOI: 10.1111/dgd.12596] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 12/14/2018] [Accepted: 12/28/2018] [Indexed: 12/13/2022]
Abstract
Hepatic progenitor cells (HPCs) in adult liver are promising for treatment of liver diseases. A biliary-derived HPC population in adult mice has been characterized by co-expression of stem cell marker Sry (sex determining region Y)-box 9 (SOX9) and biliary marker cytokeratin 7 (CK7). However, isolation of these HPCs in adult healthy liver without any selection procedures remains a big challenge in this field. Here, by establishing a simple and efficient method to isolate and expand the CK7+ SOX9+ HPCs in vitro as clones, we acquired a stable and largely scalable cell source. The CK7+ SOX9+ progenitor cells were then further induced to differentiate into hepatocyte-like cells with expression of mature hepatocyte markers albumin (Alb) and hepatocyte nuclear factor 4 alpha (HNF4α), both in vitro and in vivo in the presence of hepatocyte growth factor (HGF) and fibroblast growth factor 9 (FGF9). Furthermore, we found that the HPCs are highly responsive to transforming growth factor-beta (TGF-β) signals. Collectively, we identified and harvested a CK7+ SOX9+ progenitor cell population from adult mouse liver by a simple and efficient approach. The exploration of this HPC population offers an alternative strategy of generating hepatocyte-like cells for cell-based therapies of acute and chronic liver disorders.
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Affiliation(s)
- Wenbin Liu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Kiangnan Stem Cell Institute, Hangzhou, China
| | - Yujia Wang
- Kiangnan Stem Cell Institute, Hangzhou, China.,Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yufen Sun
- Kiangnan Stem Cell Institute, Hangzhou, China.,Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yingchuan Wu
- Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Qiwang Ma
- Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yun Shi
- Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ruoxu He
- Kiangnan Stem Cell Institute, Hangzhou, China
| | - Ting Zhang
- Kiangnan Stem Cell Institute, Hangzhou, China
| | - Yu Ma
- Kiangnan Stem Cell Institute, Hangzhou, China.,Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Wei Zuo
- Kiangnan Stem Cell Institute, Hangzhou, China.,Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China.,Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhongjun Wu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Russell JO, Lu W, Okabe H, Abrams M, Oertel M, Poddar M, Singh S, Forbes SJ, Monga SP. Hepatocyte-Specific β-Catenin Deletion During Severe Liver Injury Provokes Cholangiocytes to Differentiate Into Hepatocytes. Hepatology 2019; 69:742-759. [PMID: 30215850 PMCID: PMC6351199 DOI: 10.1002/hep.30270] [Citation(s) in RCA: 111] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Accepted: 08/14/2018] [Indexed: 12/28/2022]
Abstract
Liver regeneration after injury is normally mediated by proliferation of hepatocytes, although recent studies have suggested biliary epithelial cells (BECs) can differentiate into hepatocytes during severe liver injury when hepatocyte proliferation is impaired. We investigated the effect of hepatocyte-specific β-catenin deletion in recovery from severe liver injury and BEC-to-hepatocyte differentiation. To induce liver injury, we administered choline-deficient, ethionine-supplemented (CDE) diet to three different mouse models, the first being mice with deletion of β-catenin in both BECs and hepatocytes (Albumin-Cre; Ctnnb1flox/flox mice). In our second model, we performed hepatocyte lineage tracing by injecting Ctnnb1flox/flox ; Rosa-stopflox/flox -EYFP mice with the adeno-associated virus serotype 8 encoding Cre recombinase under the control of the thyroid binding globulin promoter, a virus that infects only hepatocytes. Finally, we performed BEC lineage tracing via Krt19-CreERT ; Rosa-stopflox/flox -tdTomato mice. To observe BEC-to-hepatocyte differentiation, mice were allowed to recover on normal diet following CDE diet-induced liver injury. Livers were collected from all mice and analyzed by quantitative real-time polymerase chain reaction, western blotting, immunohistochemistry, and immunofluorescence. We show that mice with lack of β-catenin in hepatocytes placed on the CDE diet develop severe liver injury with impaired hepatocyte proliferation, creating a stimulus for BECs to differentiate into hepatocytes. In particular, we use both hepatocyte and BEC lineage tracing to show that BECs differentiate into hepatocytes, which go on to repopulate the liver during long-term recovery. Conclusion: β-catenin is important for liver regeneration after CDE diet-induced liver injury, and BEC-derived hepatocytes can permanently incorporate into the liver parenchyma to mediate liver regeneration.
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Affiliation(s)
- Jacquelyn O. Russell
- Department of PathologyUniversity of PittsburghPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Wei‐Yu Lu
- MRC Centre for Regenerative MedicineUniversity of EdinburghEdinburghUK
- Centre for Liver ResearchUniversity of BirminghamBirminghamUK
| | - Hirohisa Okabe
- Department of MedicineUniversity of Pittsburgh School of Medicine and University of Pittsburgh Medical CenterPittsburghPA
- Department of Gastroenterological SurgeryKumamoto UniversityKumamotoJapan
| | | | - Michael Oertel
- Department of PathologyUniversity of PittsburghPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Minakshi Poddar
- Department of PathologyUniversity of PittsburghPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Sucha Singh
- Department of PathologyUniversity of PittsburghPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
| | - Stuart J. Forbes
- MRC Centre for Regenerative MedicineUniversity of EdinburghEdinburghUK
| | - Satdarshan P. Monga
- Department of PathologyUniversity of PittsburghPittsburghPA
- Pittsburgh Liver Research CenterUniversity of Pittsburgh and University of Pittsburgh Medical CenterPittsburghPA
- Department of MedicineUniversity of Pittsburgh School of Medicine and University of Pittsburgh Medical CenterPittsburghPA
- Department of Gastroenterological SurgeryKumamoto UniversityKumamotoJapan
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Ko S, Russell JO, Tian J, Gao C, Kobayashi M, Feng R, Yuan X, Shao C, Ding H, Poddar M, Singh S, Locker J, Weng HL, Monga SP, Shin D. Hdac1 Regulates Differentiation of Bipotent Liver Progenitor Cells During Regeneration via Sox9b and Cdk8. Gastroenterology 2019; 156:187-202.e14. [PMID: 30267710 PMCID: PMC6309465 DOI: 10.1053/j.gastro.2018.09.039] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 09/17/2018] [Accepted: 09/18/2018] [Indexed: 01/06/2023]
Abstract
BACKGROUND & AIMS Upon liver injury in which hepatocyte proliferation is compromised, liver progenitor cells (LPCs), derived from biliary epithelial cells (BECs), differentiate into hepatocytes. Little is known about the mechanisms of LPC differentiation. We used zebrafish and mouse models of liver injury to study the mechanisms. METHODS We used transgenic zebrafish, Tg(fabp10a:CFP-NTR), to study the effects of compounds that alter epigenetic factors on BEC-mediated liver regeneration. We analyzed zebrafish with disruptions of the histone deacetylase 1 gene (hdac1) or exposed to MS-275 (an inhibitor of Hdac1, Hdac2, and Hdac3). We also analyzed zebrafish with mutations in sox9b, fbxw7, kdm1a, and notch3. Zebrafish larvae were collected and analyzed by whole-mount immunostaining and in situ hybridization; their liver tissues were collected for quantitative reverse transcription polymerase chain reaction. We studied mice in which hepatocyte-specific deletion of β-catenin (Ctnnb1flox/flox mice injected with Adeno-associated virus serotype 8 [AAV8]-TBG-Cre) induces differentiation of LPCs into hepatocytes after a choline-deficient, ethionine-supplemented (CDE) diet. Liver tissues were collected and analyzed by immunohistochemistry and immunoblots. We performed immunohistochemical analyses of liver tissues from patients with compensated or decompensated cirrhosis or acute on chronic liver failure (n = 15). RESULTS Loss of Hdac1 activity in zebrafish blocked differentiation of LPCs into hepatocytes by increasing levels of sox9b mRNA and reduced differentiation of LPCs into BECs by increasing levels of cdk8 mRNA, which encodes a negative regulator gene of Notch signaling. We identified Notch3 as the receptor that regulates differentiation of LPCs into BECs. Loss of activity of Kdm1a, a lysine demethylase that forms repressive complexes with Hdac1, produced the same defects in differentiation of LPCs into hepatocytes and BECs as observed in zebrafish with loss of Hdac1 activity. Administration of MS-275 to mice with hepatocyte-specific loss of β-catenin impaired differentiation of LPCs into hepatocytes after the CDE diet. HDAC1 was expressed in reactive ducts and hepatocyte buds of liver tissues from patients with cirrhosis. CONCLUSIONS Hdac1 regulates differentiation of LPCs into hepatocytes via Sox9b and differentiation of LPCs into BECs via Cdk8, Fbxw7, and Notch3 in zebrafish with severe hepatocyte loss. HDAC1 activity was also required for differentiation of LPCs into hepatocytes in mice with liver injury after the CDE diet. These pathways might be manipulated to induce LPC differentiation for treatment of patients with advanced liver diseases.
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Affiliation(s)
- Sungjin Ko
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania; Department of Pathology, Pittsburgh, Pennsylvania.
| | | | - Jianmin Tian
- Department of Pathology, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania
| | - Ce Gao
- Ministry of Education Key Laboratory for Molecular Animal Nutrition, College of Animal Sciences, Zhejiang University, Hangzhou, China
| | - Makoto Kobayashi
- Department of Molecular and Developmental Biology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Rilu Feng
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Xiaodong Yuan
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Chen Shao
- Department of Pathology, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | - Huiguo Ding
- Department of Gastroenterology and Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China
| | | | - Sucha Singh
- Department of Pathology, Pittsburgh, Pennsylvania
| | - Joseph Locker
- Department of Pathology, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania
| | - Hong-Lei Weng
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Satdarshan P Monga
- Department of Pathology, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania; Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Donghun Shin
- Department of Developmental Biology, McGowan Institute for Regenerative Medicine, Pittsburgh, Pennsylvania; Pittsburgh Liver Research Center, Pittsburgh, Pennsylvania.
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Sato K, Marzioni M, Meng F, Francis H, Glaser S, Alpini G. Ductular Reaction in Liver Diseases: Pathological Mechanisms and Translational Significances. Hepatology 2019; 69:420-430. [PMID: 30070383 PMCID: PMC6324973 DOI: 10.1002/hep.30150] [Citation(s) in RCA: 272] [Impact Index Per Article: 45.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 06/20/2018] [Indexed: 12/12/2022]
Abstract
Ductular reaction (DR) is characterized by the proliferation of reactive bile ducts induced by liver injuries. DR is pathologically recognized as bile duct hyperplasia and is commonly observed in biliary disorders. It can also be identified in various liver disorders including nonalcoholic fatty liver disease. DR is associated with liver fibrosis and damage, and the extent of DR parallels to patient mortality. DR raises scientific interests because it is associated with transdifferentiation of liver cells and may play an important role in hepatic regeneration. The origin of active cells during DR can be cholangiocytes, hepatocytes, or hepatic progenitor cells, and associated signaling pathways could differ depending on the specific liver injury or animal models used in the study. Although further studies are needed to elucidate detailed mechanisms and the functional roles in liver diseases, DR can be a therapeutic target to inhibit liver fibrosis and to promote liver regeneration. This review summarizes previous studies of DR identified in patients and animal models as well as currently understood mechanisms of DR.
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Affiliation(s)
- Keisaku Sato
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
| | - Marco Marzioni
- Clinic of Gastroenterology and Hepatology, Università Politecnica delle Marche, Ospedali Riuniti - University Hospital, Ancona, Italy
| | - Fanyin Meng
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
- Academic Research Integration, Baylor Scott & White Healthcare, Temple, TX 76504
| | - Heather Francis
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
| | - Shannon Glaser
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
| | - Gianfranco Alpini
- Research, Central Texas Veterans Health Care System, Temple, TX 76504
- Department of Medical Physiology, Texas A&M College of Medicine, Temple, TX 76504
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Healthcare, Temple, TX 76504
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Brosch M, Kattler K, Herrmann A, von Schönfels W, Nordström K, Seehofer D, Damm G, Becker T, Zeissig S, Nehring S, Reichel F, Moser V, Thangapandi RV, Stickel F, Baretton G, Röcken C, Muders M, Matz-Soja M, Krawczak M, Gasparoni G, Hartmann H, Dahl A, Schafmayer C, Walter J, Hampe J. Epigenomic map of human liver reveals principles of zonated morphogenic and metabolic control. Nat Commun 2018; 9:4150. [PMID: 30297808 PMCID: PMC6175862 DOI: 10.1038/s41467-018-06611-5] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Accepted: 09/14/2018] [Indexed: 12/21/2022] Open
Abstract
A deeper epigenomic understanding of spatial organization of cells in human tissues is an important challenge. Here we report the first combined positional analysis of transcriptomes and methylomes across three micro-dissected zones (pericentral, intermediate and periportal) of human liver. We identify pronounced anti-correlated transcriptional and methylation gradients including a core of 271 genes controlling zonated metabolic and morphogen networks and observe a prominent porto-central gradient of DNA methylation at binding sites of 46 transcription factors. The gradient includes an epigenetic and transcriptional Wnt signature supporting the concept of a pericentral hepatocyte regeneration pathway under steady-state conditions. While donors with non-alcoholic fatty liver disease show consistent gene expression differences corresponding to the severity of the disease across all zones, the relative zonated gene expression and DNA methylation patterns remain unchanged. Overall our data provide a wealth of new positional insights into zonal networks controlled by epigenetic and transcriptional gradients in human liver. Spatial mapping of genomic programs in tissue cells is an important step in the understanding of organ function and disease. Here, the authors provide a spatially resolved epigenomic and transcriptomic map of human liver and show porto-central gradients in metabolic and morphogen networks and transcription factor binding sites as a basis to better understand liver regeneration and function.
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Affiliation(s)
- Mario Brosch
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.,Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Kathrin Kattler
- Department of Genetics and Epigenetics, Universität des Saarlandes, Saarbrücken, Germany
| | - Alexander Herrmann
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.,Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Witigo von Schönfels
- Department of Visceral Surgery, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Karl Nordström
- Department of Genetics and Epigenetics, Universität des Saarlandes, Saarbrücken, Germany
| | - Daniel Seehofer
- Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, Leipzig, Germany
| | - Georg Damm
- Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, Leipzig, Germany
| | - Thomas Becker
- Department of Visceral Surgery, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Sebastian Zeissig
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Sophie Nehring
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Fabian Reichel
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Vincent Moser
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Raghavan Veera Thangapandi
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Felix Stickel
- Department of Gastroenterology, University of Zürich, Zürich, Switzerland
| | - Gustavo Baretton
- Institute of Pathology, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Christoph Röcken
- Institute of Pathology, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Michael Muders
- Institute of Pathology, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Madlen Matz-Soja
- Rudolf-Schönheimer-Institute for Biochemistry, University of Leipzig, Leipzig, Germany
| | - Michael Krawczak
- Institute of Medical Informatics and Statistics, Christian-Albrechts University, Kiel, Germany
| | - Gilles Gasparoni
- Department of Genetics and Epigenetics, Universität des Saarlandes, Saarbrücken, Germany
| | - Hella Hartmann
- Center for Molecular and Cellular Bioengineering (CMCB), Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Andreas Dahl
- Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Clemens Schafmayer
- Department of Visceral Surgery, University Hospital Schleswig-Holstein, Christian-Albrechts-University Kiel, Kiel, Germany
| | - Jörn Walter
- Department of Genetics and Epigenetics, Universität des Saarlandes, Saarbrücken, Germany
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany. .,Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden (TU Dresden), Dresden, Germany.
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Wendum D, Layese R, Ganne-Carrié N, Bourcier V, Merabtene F, Cagnot C, Sauce E, Barget N, Bedossa P, Terris B, Selves J, Bioulac-Sage P, Sturm N, Sattonnet C, Nahon P, Roudot-Thoraval F, Ziol M. Influence of Progenitor-Derived Regeneration Markers on Hepatitis C Virus-Related Cirrhosis Outcome (ANRS CO12 CirVir Cohort). Hepatology 2018; 68:1534-1548. [PMID: 29637581 DOI: 10.1002/hep.29927] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 08/22/2016] [Accepted: 10/31/2016] [Indexed: 12/20/2022]
Abstract
UNLABELLED Progenitor-derived regeneration gives rise to the aberrant expression of biliary markers such as cytokeratin 7 (K7) and epithelial cell adhesion molecule (EpCAM) in hepatocytes. We aimed to describe the expression of these molecules in patients with compensated hepatitis C virus (HCV)-related cirrhosis and to investigate its potential influence on cirrhosis complications. Among patients with Child-Pugh A uncomplicated HCV-related cirrhosis enrolled in the prospective ANRS CO12 CirVir cohort, we selected individuals with a liver biopsy collected within 2 years before inclusion in the study. K7 and EpCAM immunostaining identified intermediate hepatobiliary cells. The influence of biliary marker expres-sion in hepatocytes on decompensation events and the occurrence of hepatocellular carcinoma (HCC) was studied using a multivariate Cox proportional hazards regression model. Among the 337 patients eligible for the study (men, 67%; median age, 52 years), 198 (58.8%) had biopsies with K7-positive hepatocytes including extensive staining in 40 (11.9%) and 203 had EpCAM-positive hepatocytes (60.6%). During follow-up (median, 54.2 months), 47 patients (14%) experienced a decompensation event, and HCC was diagnosed in 37 patients (11%). Extensive K7 staining was independently associated with the occurrence of a decompensation event (hazard ratio [HR], 3.00; 95% confidence interval [CI], 1.30-6.89; P = 0.010). EpCAM expression was independently associated with HCC occurrence (HR, 2.37; 95% CI, 1.07-5.23; P =0.033) along with age and a low prothrombin ratio. CONCLUSION Progenitor-derived regeneration depicted by K7 and EpCAM immunostaining of hepatocytes in liver biopsies of patients with compensated HCV-related cirrhosis marks a cirrhosis stage more prone to develop complications. (HEPATOLOGY 2018; 68:1534-1548).
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Affiliation(s)
- Dominique Wendum
- APHP, Hôpital St. Antoine, Anatomie Pathologiques.,Sorbonne Universités, UPMC Université Paris 06, INSERM UMRS_938 Centre de Recherche St. Antoine (CRSA), Paris, France
| | - Richard Layese
- APHP, Hôpital Henri Mondor, Unité de recherche clinique (URC-Mondor), Service de Santé Publique, AP-HP, Hôpital Henri-Mondor, Créteil, France.,Université Paris Est (UPEC), IMRB, A-TVB DHU, CEpiA EA 7376 (Clinical Epidemiology and Ageing Unit), Créteil, France
| | - Nathalie Ganne-Carrié
- APHP, Hôpital Jean Verdier, Service d'hépatologie, Bondy, France.,Université Paris 13, Sorbonne Paris-Cité, Bobigny, France.,INSERM UMR 1162, Génomique fonctionnelle des tumeurs solides, Université Paris Descartes, Université Paris Diderot, France
| | - Valérie Bourcier
- APHP, Hôpital Jean Verdier, Service d'hépatologie, Bondy, France
| | - Fatiha Merabtene
- Sorbonne Universités, UPMC Université Paris 06, INSERM UMRS_938 Centre de Recherche St. Antoine (CRSA), Paris, France.,Sorbonne Universités, UMS 30 LUMIC plateforme d'histomorphologie St. Antoine
| | | | - Emmanuel Sauce
- APHP, Hôpital Jean Verdier, Anatomie Pathologique et CRB BB-0033-00027, Bondy, France
| | - Nathalie Barget
- APHP, Hôpital Jean Verdier, Anatomie Pathologique et CRB BB-0033-00027, Bondy, France
| | - Pierre Bedossa
- APHP, Hôpital Beaujon, Département de Pathologie, Clichy, France
| | - Benoit Terris
- APHP, Hôpital Cochin, Anatomie Pathologique, Paris, France
| | - Janick Selves
- IUCT-Oncopole Toulouse, Departement d'Anatomie Pathologique, Toulouse, France
| | - Paulette Bioulac-Sage
- Pathology Department, Pellegrin Hospital, CHU Bordeaux.,Inserm, UMR1053 Bordeaux Research in Translational Oncology BaRITOn.,Université Bordeaux, UMR1053 Bordeaux Research in Translational Oncology BaRITOn, Bordeaux, France
| | - Nathalie Sturm
- CHU Grenoble, Département de Pathologie, Grenoble, France
| | | | - Pierre Nahon
- APHP, Hôpital Jean Verdier, Service d'hépatologie, Bondy, France.,Université Paris 13, Sorbonne Paris-Cité, Bobigny, France.,INSERM UMR 1162, Génomique fonctionnelle des tumeurs solides, Université Paris Descartes, Université Paris Diderot, France
| | - Françoise Roudot-Thoraval
- APHP, Hôpital Henri Mondor, Unité de recherche clinique (URC-Mondor), Service de Santé Publique, AP-HP, Hôpital Henri-Mondor, Créteil, France.,Université Paris Est (UPEC), IMRB, A-TVB DHU, CEpiA EA 7376 (Clinical Epidemiology and Ageing Unit), Créteil, France
| | - Marianne Ziol
- Université Paris 13, Sorbonne Paris-Cité, Bobigny, France.,INSERM UMR 1162, Génomique fonctionnelle des tumeurs solides, Université Paris Descartes, Université Paris Diderot, France.,APHP, Hôpital Jean Verdier, Anatomie Pathologique et CRB BB-0033-00027, Bondy, France
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Overi D, Carpino G, Cardinale V, Franchitto A, Safarikia S, Onori P, Alvaro D, Gaudio E. Contribution of Resident Stem Cells to Liver and Biliary Tree Regeneration in Human Diseases. Int J Mol Sci 2018; 19:ijms19102917. [PMID: 30257529 PMCID: PMC6213374 DOI: 10.3390/ijms19102917] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 09/18/2018] [Accepted: 09/19/2018] [Indexed: 12/13/2022] Open
Abstract
Two distinct stem/progenitor cell populations of biliary origin have been identified in the adult liver and biliary tree. Hepatic Stem/progenitor Cells (HpSCs) are bipotent progenitor cells located within the canals of Hering and can be differentiated into mature hepatocytes and cholangiocytes; Biliary Tree Stem/progenitor Cells (BTSCs) are multipotent stem cells located within the peribiliary glands of large intrahepatic and extrahepatic bile ducts and able to differentiate into hepatic and pancreatic lineages. HpSCs and BTSCs are endowed in a specialized niche constituted by supporting cells and extracellular matrix compounds. The actual contribution of these stem cell niches to liver and biliary tree homeostatic regeneration is marginal; this is due to the high replicative capabilities and plasticity of mature parenchymal cells (i.e., hepatocytes and cholangiocytes). However, the study of human liver and biliary diseases disclosed how these stem cell niches are involved in the regenerative response after extensive and/or chronic injuries, with the activation of specific signaling pathways. The present review summarizes the contribution of stem/progenitor cell niches in human liver diseases, underlining mechanisms of activation and clinical implications, including fibrogenesis and disease progression.
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Affiliation(s)
- Diletta Overi
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome "Foro Italico", Piazza Lauro de Bosis 6, 00135 Rome, Italy.
| | - Vincenzo Cardinale
- Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Corso della Repubblica 79, 04100 Latina, Italy.
| | - Antonio Franchitto
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.
| | - Samira Safarikia
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy.
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.
| | - Domenico Alvaro
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Viale del Policlinico 151, 00161 Rome, Italy.
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Via Borelli 50, 00161 Rome, Italy.
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