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Kim HY, Sakane S, Eguileor A, Carvalho Gontijo Weber R, Lee W, Liu X, Lam K, Ishizuka K, Rosenthal SB, Diggle K, Brenner DA, Kisseleva T. The Origin and Fate of Liver Myofibroblasts. Cell Mol Gastroenterol Hepatol 2023; 17:93-106. [PMID: 37743012 PMCID: PMC10665929 DOI: 10.1016/j.jcmgh.2023.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 09/26/2023]
Abstract
Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts.
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Affiliation(s)
- Hyun Young Kim
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sadatsugu Sakane
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Alvaro Eguileor
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Raquel Carvalho Gontijo Weber
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Wonseok Lee
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Xiao Liu
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - Kevin Lam
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California
| | - Sara Brin Rosenthal
- Center for Computational Biology and Bioinformatics, University of California San Diego, La Jolla, California
| | - Karin Diggle
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Department of Surgery, University of California San Diego School of Medicine, La Jolla, California
| | - David A Brenner
- Department of Medicine, University of California San Diego School of Medicine, La Jolla, California; Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California.
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego School of Medicine, La Jolla, California.
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Borkham-Kamphorst E, Meurer SK, Weiskirchen R. Expression and biological function of the cellular communication network factor 5 (CCN5) in primary liver cells. J Cell Commun Signal 2023:10.1007/s12079-023-00757-8. [PMID: 37166689 DOI: 10.1007/s12079-023-00757-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Accepted: 04/28/2023] [Indexed: 05/12/2023] Open
Abstract
The cellular (centralized) communication network (CCN) factor protein family contains six small secreted cysteine-rich proteins sharing high structural similarity. These matricellular proteins have vital biological functions in cell adhesion, migration, cell cycle progression, and control of production and degradation of extracellular matrix. However, in liver the biological functions of CCN proteins become most visible during hepatic injury, disease, and remodeling. In particular, most of the hepatic functions of CCN proteins were derived from CCN2/CTGF, which becomes highly expressed in damaged hepatocytes and acts as a profibrogenic molecule. On the contrary, CCN1/CYR61 seems to have opposite effects, while the biological activity during hepatic fibrosis is somewhat controversially discussed for other CCN family members. In the present study, we analyzed the expression of CCN5/WISP2 in cultures of different types of primary liver cells and in an experimental model of hepatic fibrosis. We found that CCN5 is expressed in hepatic stellate cells, myofibroblasts and portal myofibroblasts, while CCN5 expression is virtually absent in hepatocytes. During hepatic fibrogenesis, CCN5 is significantly upregulated. Overexpression of CCN5 in portal myofibroblasts reduced expression of transforming growth factor-β receptor I (ALK5) and concomitant Smad2 activation, whereas JunB expression is upregulated. Moreover, elevated expression of CCN5 induces endoplasmic reticulum stress, unfolded protein response and apoptosis in portal myofibroblasts. We suggest that upregulated expression of CCN5 might be an intrinsic control mechanism that counteracts overshooting fibrotic responses in profibrogenic liver cells.
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Affiliation(s)
- Erawan Borkham-Kamphorst
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Pauwelsstr. 30, 52074, Aachen, Germany
| | - Steffen K Meurer
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Pauwelsstr. 30, 52074, Aachen, Germany
| | - Ralf Weiskirchen
- Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry (IFMPEGKC), RWTH University Hospital Aachen, Pauwelsstr. 30, 52074, Aachen, Germany.
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Nishio T, Koyama Y, Fuji H, Ishizuka K, Iwaisako K, Taura K, Hatano E, Brenner DA, Kisseleva T. The Role of Mesothelin in Activation of Portal Fibroblasts in Cholestatic Liver Injury. BIOLOGY 2022; 11:1589. [PMID: 36358290 PMCID: PMC9687690 DOI: 10.3390/biology11111589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/18/2022] [Accepted: 10/27/2022] [Indexed: 11/05/2022]
Abstract
Fibrosis is a common consequence of abnormal wound healing, which is characterized by infiltration of myofibroblasts and formation of fibrous scar. In liver fibrosis, activated Hepatic Stellate Cells (aHSCs) and activated Portal Fibroblasts (aPFs) are the major contributors to the origin of hepatic myofibroblasts. aPFs are significantly involved in the pathogenesis of cholestatic fibrosis, suggesting that aPFs may be a primary target for anti-fibrotic therapy in cholestatic injury. aPFs are distinguishable from aHSCs by specific markers including mesothelin (Msln), Mucin 16 (Muc16), and Thymus cell antigen 1 (Thy1, CD90) as well as fibulin 2, elastin, Gremlin 1, ecto-ATPase nucleoside triphosphate diphosphohydrolase 2. Msln plays a critical role in activation of PFs, via formation of Msln-Muc16-Thy1 complex that regulates TGFβ1/TGFβRI-mediated fibrogenic signaling. The opposing pro- and anti-fibrogenic effects of Msln and Thy1 are key components of the TGFβ1-induced activation pathway in aPFs. In addition, aPFs and activated lung and kidney fibroblasts share similarities across different organs with expression of common markers and activation cascade including Msln-Thy1 interaction. Here, we summarize the potential function of Msln in activation of PFs and development of cholestatic fibrosis, offering a novel perspective for anti-fibrotic therapy targeting Msln.
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Affiliation(s)
- Takahiro Nishio
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yukinori Koyama
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hiroaki Fuji
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Kei Ishizuka
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Keiko Iwaisako
- Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Tataramiyakodani, Kyotanabe 610-0394, Japan
| | - Kojiro Taura
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
- Department of Gastroenterological Surgery and Oncology, Kitano Hospital Medical Research Institute, 2-4-20 Ogimachi, Kita-ku, Osaka 530-8480, Japan
| | - Etsuro Hatano
- Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan
| | - David A. Brenner
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, 9500 Gilman Drive, #0063, La Jolla, CA 92093, USA
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4
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Fuji H, Miller G, Nishio T, Koyama Y, Lam K, Zhang V, Loomba R, Brenner D, Kisseleva T. The role of Mesothelin signaling in Portal Fibroblasts in the pathogenesis of cholestatic liver fibrosis. Front Mol Biosci 2021; 8:790032. [PMID: 34966784 PMCID: PMC8710774 DOI: 10.3389/fmolb.2021.790032] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 11/15/2021] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis develops in response to chronic toxic or cholestatic injury, and is characterized by apoptosis of damaged hepatocytes, development of inflammatory responses, and activation of Collagen Type I producing myofibroblasts that make liver fibrotic. Two major cell types, Hepatic Stellate Cells (HSCs) and Portal Fibroblasts (PFs) are the major source of hepatic myofibroblasts. Hepatotoxic liver injury activates Hepatic Stellate Cells (aHSCs) to become myofibroblasts, while cholestatic liver injury activates both aHSCs and Portal Fibroblasts (aPFs). aPFs comprise the major population of myofibroblasts at the onset of cholestatic injury, while aHSCs are increasingly activated with fibrosis progression. Here we summarize our current understanding of the role of aPFs in the pathogenesis of cholestatic fibrosis, their unique features, and outline the potential mechanism of targeting aPFs in fibrotic liver.
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Affiliation(s)
- Hiroaki Fuji
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Grant Miller
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Takahiro Nishio
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yukinori Koyama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kevin Lam
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Vivian Zhang
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
| | - Rohit Loomba
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
| | - David Brenner
- Department of Medicine, University of California San Diego, La Jolla, CA, United States
| | - Tatiana Kisseleva
- Department of Surgery, University of California San Diego, La Jolla, CA, United States
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5
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Immunotherapy-based targeting of MSLN + activated portal fibroblasts is a strategy for treatment of cholestatic liver fibrosis. Proc Natl Acad Sci U S A 2021; 118:2101270118. [PMID: 34253615 DOI: 10.1073/pnas.2101270118] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln-/- mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1-/- mice are more susceptible to fibrosis, suggesting that a Msln-Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)-injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.
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Yamashita T, Kaneko S. Liver cancer stem cells: Recent progress in basic and clinical research. Regen Ther 2021; 17:34-37. [PMID: 33816720 PMCID: PMC7988346 DOI: 10.1016/j.reth.2021.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 03/02/2021] [Indexed: 12/15/2022] Open
Abstract
The cancer stem cell (CSC) hypothesis was proposed over 4 decades ago and states that tumor growth is maintained by a small subset of cancer cells analogous to normal tissue stem cells in terms of self-renewal and differentiation capacity. Advances in CSC isolation were initially achieved in hematological malignancies and later in solid tumors, including hepatocellular carcinoma (HCC), the major histological type of liver cancer. Increasing evidence suggests the importance of liver CSCs for tumor growth, metastasis, and chemo/radiation resistance in HCC, but the application of the liver CSC concept for the clinical diagnosis and treatment of HCC has not yet been achieved to the extent initially expected. Furthermore, the heterogeneity and plasticity of liver CSCs has recently been noted and might be related to drug resistance and the rapid growth and/or metastasis of the tumor after treatment. Here, we introduce our recent advancement in liver CSC research and discuss the clinical implications, which may lead to the development of improved diagnostics and treatment in HCC.
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Affiliation(s)
- Taro Yamashita
- Department of General Medicine, Kanazawa University Hospital, Kanazawa, Ishikawa, Japan
- Corresponding author. Department of General Medicine, Kanazawa University Hospital, 13-1 Takara-Machi, Kanazawa, Ishikawa 920-8641, Japan.
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, Japan
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7
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Crema A, Ledda M, Fioretti D, Lolli MG, Sanchez M, Carico E, Marchese R, Rinaldi M, Lisi A. Combination of cord blood-derived human hepatic progenitors and hepatogenic factors strongly improves recovery after acute liver injury in mice through modulation of the Wnt/β-catenin signaling. J Tissue Eng Regen Med 2019; 13:1031-1043. [PMID: 30942524 DOI: 10.1002/term.2854] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 03/15/2019] [Accepted: 03/15/2019] [Indexed: 01/10/2023]
Abstract
Cell therapy represents a promising alternative strategy for end-stage liver disease, and hepatic progenitors are the best candidates. The possibility to maximize the paracrine effects of transplanted cells represents a great potential benefit for cell therapy success. We studied how cell type and microenvironment modulate the Wnt/β-catenin signaling in vitro and in vivo. In vitro, the onset of hepatocyte commitment was characterized by the presence of nuclear truncated β-catenin. In vivo, we analyzed the effect of human hepatic progenitors on damage recovery and functional regeneration in a mouse model of acute liver injury, either in combination or in absence of a selected mix of hepatogenic factors. Animals injected with human hepatic progenitors and hepatogenic factors showed improved engraftment triggering the Wnt/β-catenin signaling cascade. Human hepatic progenitors expressing the human oval cell marker OV6 displayed a consistent colocalization with β-catenin and colocalized with Wnt1 main ligand of the canonical pathway. Wnt5a, on the contrary, was expressed in distinct liver cell populations. Epithelial mesenchymal transition-related markers showed enhanced expression and wider distribution, and the hepato-mesenchymal population Thy1 + CK19- was also present. Control animals injected with hepatogenic factors alone exhibited higher β-catenin, decreased Wnt5a levels, and persistent proliferation of the hepato-mesenchymal population. In conclusion, the combination of human hepatic progenitors with selected hepatogenic factors creates a positive synergy with local microenvironment, ameliorates cell engraftment, stimulates and accelerates regenerative process, and improves the rescue of hepatic function by modulating the Wnt/βcatenin signaling and activating hepato-mesenchymal population.
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Affiliation(s)
- Annalisa Crema
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Mario Ledda
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Daniela Fioretti
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Maria Grazia Lolli
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Massimo Sanchez
- Core Facilities, Cytometry Unit, Istituto Superiore di Sanità, Rome, Italy
| | - Elisabetta Carico
- Department of Clinical and Molecular Medicine, Sapienza University, Sant'Andrea Hospital, Rome, Italy
| | | | - Monica Rinaldi
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Antonella Lisi
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
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8
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Katsumata LW, Miyajima A, Itoh T. Portal fibroblasts marked by the surface antigen Thy1 contribute to fibrosis in mouse models of cholestatic liver injury. Hepatol Commun 2017; 1:198-214. [PMID: 29404454 PMCID: PMC5721447 DOI: 10.1002/hep4.1023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2016] [Accepted: 02/09/2017] [Indexed: 12/23/2022] Open
Abstract
Liver fibrosis, a condition that is characterized by excessive production and accumulation of extracellular matrix, including collagen, is the most common outcome of chronic liver injuries of different etiologies. Vitamin A‐storing hepatic stellate cells (HSCs) are considered to be the main source of this collagen production, with activation in response to liver injury. In contrast, the contribution of other cell types to this fibrogenic response remains largely elusive due to the lack of specific surface markers to identify and isolate these cells for detailed analysis. Here, we identify a mesenchymal population of thymus cell antigen 1 (Thy1)+ CD45− cells (Thy1 MCs) in the mouse liver; these cells reside near the portal vein in vivo and indicate profibrogenic characteristics in vitro, shown by their expression of collagen and α‐smooth muscle actin. Flow cytometric analysis of mouse liver nonparenchymal cells revealed that vitamin A storage and Thy1 expression were mutually exclusive, indicating that Thy1 MCs are distinct from HSCs. Importantly, Thy1 MCs reacted and contributed to the development of liver fibrosis specifically in mouse models of cholestatic liver injury. With the occurrence of cholestatic liver injury, collagen‐producing Thy1 MCs expanded in cell number and inhibited collagen degradation through up‐regulation of matrix metalloproteinase inhibitor Timp1 expression, thereby promoting the accumulation of extracellular matrix in the periportal area. Conclusion: This study establishes Thy1 as a useful cell surface marker to prospectively identify and isolate periportal fibroblasts and further highlights a significant contribution of these cells to the pathogenesis of liver fibrosis caused by cholestatic liver injuries. We suggest that Thy1 MCs may be an interesting therapeutic target for treating liver fibrosis in addition to the well‐characterized HSCs. (Hepatology Communications 2017;1:198‐214)
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Affiliation(s)
- Len William Katsumata
- Laboratory of Cell Growth and Differentiation Institute of Molecular and Cellular Biosciences, University of Tokyo Tokyo Japan
| | - Atsushi Miyajima
- Laboratory of Cell Growth and Differentiation Institute of Molecular and Cellular Biosciences, University of Tokyo Tokyo Japan
| | - Tohru Itoh
- Laboratory of Cell Growth and Differentiation Institute of Molecular and Cellular Biosciences, University of Tokyo Tokyo Japan
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Tan EK, Shuh M, Francois-Vaughan H, Sanders JA, Cohen AJ. Negligible Oval Cell Proliferation Following Ischemia-Reperfusion Injury With and Without Partial Hepatectomy. Ochsner J 2017; 17:31-37. [PMID: 28331445 PMCID: PMC5349633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023] Open
Abstract
BACKGROUND Hepatic oval cells proliferate to replace hepatocytes and restore liver function when hepatocyte proliferation is compromised or inadequate. Exposure to chemical carcinogens, severe liver steatosis, and partial hepatectomy has been used in animal models to demonstrate the role of oval cells in liver regeneration. Ischemia-reperfusion injury (IRI) causes hepatocellular damage and death in the absence of confounding chemical toxicity; however, oval cell induction by IRI has not been demonstrated in vivo. We examine oval cell induction following partial IRI. METHODS Wistar rats were subjected to 2 IRI protocols: 70% warm liver ischemia for 30 minutes followed by reperfusion or 70% warm liver ischemia for 30 minutes with partial hepatectomy of the nonischemic lobes followed by reperfusion. Liver injury was monitored by serum alanine aminotransferase (ALT) at 1 day and 7 days of reperfusion. Oval cell proliferation was monitored by indirect immunofluorescence staining using the surface markers BD.2 and Thy-1. Cellular proliferation was quantified by 5-ethynyl-2'-deoxyuridine (EdU) incorporation in vivo. RESULTS Serum ALT elevation was only observed at the 1-day time point in the IRI with partial hepatectomy model. Oval cell marker expression was restricted to the biliary structures in both the ischemic and the nonischemic control lobes. Oval cell induction, measured by changes in the frequency of BD.2 and Thy-1 expression and EdU incorporation, was not significantly altered by IRI. CONCLUSION In both mild and moderate IRI models, we did not find evidence of oval cell induction or proliferation. EdU staining was restricted to hepatocytes, suggesting that liver regeneration following IRI is mediated by hepatocyte proliferation.
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Affiliation(s)
- Ek Khoon Tan
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA
- Department of General Surgery, Singapore General Hospital, Singapore
| | - Maureen Shuh
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA
| | | | - Jennifer A. Sanders
- Department of Pediatrics, Rhode Island Hospital and Brown University, Providence, RI
- Department of Pathology and Laboratory Medicine, Rhode Island Hospital and Brown University, Providence, RI
| | - Ari J. Cohen
- Institute of Translational Research, Ochsner Clinic Foundation, New Orleans, LA
- Multi-Organ Transplant Institute, Ochsner Clinic Foundation, New Orleans, LA
- The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA
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10
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Karin D, Koyama Y, Brenner D, Kisseleva T. The characteristics of activated portal fibroblasts/myofibroblasts in liver fibrosis. Differentiation 2016; 92:84-92. [PMID: 27591095 PMCID: PMC5079826 DOI: 10.1016/j.diff.2016.07.001] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 06/08/2016] [Accepted: 07/11/2016] [Indexed: 12/12/2022]
Abstract
Liver fibrosis results from chronic injury of hepatocytes and activation of Collagen Type I producing myofibroblasts that produce fibrous scar in liver fibrosis. Myofibroblasts are not present in the normal liver but rapidly appear early in experimental and clinical liver injury. The origin of the myofibroblast in liver fibrosis is still unresolved. The possibilities include activation of liver resident cells including portal fibroblasts, hepatic stellate cells, mesenchymal progenitor cells, and fibrocytes recruited from the bone marrow. It is considered that hepatic stellate cells and portal fibroblasts are the major source of hepatic myofibroblasts. In fact, the origin of myofibroblasts differs significantly for chronic liver diseases of different etiologies, such as cholestatic liver disease or hepatotoxic liver disease. Depending on etiology of hepatic injury, the fibrogenic foci might initiate within the hepatic lobule as seen in chronic hepatitis, or primarily affect the portal areas as in most biliary diseases. It has been suggested that activated portal fibroblasts/myofibroblasts work as "myofibroblasts for cholangiocytes" while hepatic stellate cells work as "myofibroblast for hepatocytes". This review will focus on our current understanding of the activated portal fibroblasts/myofibroblasts in cholestatic liver fibrosis.
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Affiliation(s)
- Daniel Karin
- Department of Surgery, University of California, San Diego, La Jolla CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla CA 92093, USA
| | - Yukinori Koyama
- Department of Surgery, University of California, San Diego, La Jolla CA 92093, USA; Department of Medicine, University of California, San Diego, La Jolla CA 92093, USA; Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Pediatrics, University of California, San Diego, La Jolla CA 92093, USA
| | - David Brenner
- Department of Medicine, University of California, San Diego, La Jolla CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla CA 92093, USA
| | - Tatiana Kisseleva
- Department of Surgery, University of California, San Diego, La Jolla CA 92093, USA; Department of Pediatrics, University of California, San Diego, La Jolla CA 92093, USA.
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11
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Liu WH, Ren LN, Wang T, Navarro-Alvarez N, Tang LJ. The Involving Roles of Intrahepatic and Extrahepatic Stem/Progenitor Cells (SPCs) to Liver Regeneration. Int J Biol Sci 2016; 12:954-963. [PMID: 27489499 PMCID: PMC4971734 DOI: 10.7150/ijbs.15715] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 05/09/2016] [Indexed: 12/17/2022] Open
Abstract
Liver regeneration is usually attributed to mature hepatocytes, which possess a remarkable potential to proliferate under mild to moderate injury. However, when the liver is severely damaged or hepatocyte proliferation is greatly inhibited, liver stem/progenitor cells (LSPCs) will contribute to the liver regeneration process. LSPCs in the developing liver have been extensively characterized, however, their contributing role to liver regeneration has not been completely understood. In addition to the restoration of the liver parenchymal tissue by hepatocytes or/and LSPCs, or in some cases bone marrow (BM) derived cells, such as hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), the wound healing after injury in terms of angiopoiesis by liver sinusoidal endothelial cells (LSECs) or/and sinusoidal endothelial progenitor cells (SEPCs) is another important aspect taking place during regeneration. To conclude, liver regeneration can be mainly divided into three distinct restoring levels according to the cause and severity of injury: hepatocyte dominant regeneration, LSPCs mediated regeneration, extrahepatic stem cells participative regeneration. In this review, we focus on the recent findings of liver regeneration, especially on those related to stem/progenitor cells (SPCs)-mediated regeneration and their potential clinical applications and challenges.
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Affiliation(s)
- Wei-hui Liu
- 1. General Surgery Center, Chengdu Military General Hospital; Chengdu, Sichuan Province, 610083
| | - Li-na Ren
- 1. General Surgery Center, Chengdu Military General Hospital; Chengdu, Sichuan Province, 610083
| | - Tao Wang
- 1. General Surgery Center, Chengdu Military General Hospital; Chengdu, Sichuan Province, 610083
| | - Nalu Navarro-Alvarez
- 2. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Li-jun Tang
- 1. General Surgery Center, Chengdu Military General Hospital; Chengdu, Sichuan Province, 610083
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12
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Eckert C, Kim YO, Julich H, Heier EC, Klein N, Krause E, Tschernig T, Kornek M, Lammert F, Schuppan D, Lukacs-Kornek V. Podoplanin discriminates distinct stromal cell populations and a novel progenitor subset in the liver. Am J Physiol Gastrointest Liver Physiol 2016; 310:G1-12. [PMID: 26564718 PMCID: PMC4698439 DOI: 10.1152/ajpgi.00344.2015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 11/05/2015] [Indexed: 01/31/2023]
Abstract
Podoplanin/gp38(+) stromal cells present in lymphoid organs play a central role in the formation and reorganization of the extracellular matrix and in the functional regulation of immune responses. Gp38(+) cells are present during embryogenesis and in human livers of primary biliary cirrhosis. Since little is known about their function, we studied gp38(+) cells during chronic liver inflammation in models of biliary and parenchymal liver fibrosis and steatohepatitis. Gp38(+) cells were analyzed using flow cytometry and confocal microscopy, and the expression of their steady state and inflammation-associated genes was evaluated from healthy and inflamed livers. Gp38(+) cells significantly expanded in all three models of liver injury and returned to baseline levels during regression of inflammation. Based on CD133 and gp38 expression in the CD45(-)CD31(-)Asgpr1(-) liver cell fraction, numerous subsets could be identified that were negative for CD133 (gp38(hi)CD133(-), gp38(low)CD133(-), and gp38(-)CD133(-)). Moreover, among the CD133(+) cells, previously identified as progenitor population in injured liver, two subpopulations could be distinguished based on their gp38 expression (gp38(-)CD133(+) and CD133(+)gp38(+)). Importantly, the distribution of the identified subsets in inflammation illustrated injury-specific changes. Moreover, the gp38(+)CD133(+) cells exhibited liver progenitor cell characteristics similar to the gp38(-)CD133(+) population, thus representing a novel subset within the classical progenitor cell niche. Additionally, these cells expressed distinct sets of inflammatory genes during liver injury. Our study illuminates a novel classification of the stromal/progenitor cell compartment in the liver and pinpoints a hitherto unrecognized injury-related alteration in progenitor subset composition in chronic liver inflammation and fibrosis.
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MESH Headings
- AC133 Antigen
- ATP Binding Cassette Transporter, Subfamily B/deficiency
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Animals
- Antigens, CD/metabolism
- Biomarkers/metabolism
- Cell Separation/methods
- Cells, Cultured
- Chemical and Drug Induced Liver Injury/genetics
- Chemical and Drug Induced Liver Injury/metabolism
- Chemical and Drug Induced Liver Injury/pathology
- Flow Cytometry
- Gene Expression Regulation
- Glycoproteins/metabolism
- Inflammation Mediators/metabolism
- Liver/metabolism
- Liver/pathology
- Liver Cirrhosis, Biliary/genetics
- Liver Cirrhosis, Biliary/metabolism
- Liver Cirrhosis, Biliary/pathology
- Liver Cirrhosis, Experimental/genetics
- Liver Cirrhosis, Experimental/metabolism
- Liver Cirrhosis, Experimental/pathology
- Male
- Membrane Glycoproteins/metabolism
- Mice, Inbred C57BL
- Mice, Knockout
- Microscopy, Confocal
- Non-alcoholic Fatty Liver Disease/genetics
- Non-alcoholic Fatty Liver Disease/metabolism
- Non-alcoholic Fatty Liver Disease/pathology
- Peptides/metabolism
- Phenotype
- Stem Cells/metabolism
- Stem Cells/pathology
- Stromal Cells/metabolism
- Stromal Cells/pathology
- ATP-Binding Cassette Sub-Family B Member 4
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Affiliation(s)
- Christoph Eckert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Yong Ook Kim
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany
| | - Henrike Julich
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Eva-Carina Heier
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Niklas Klein
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Elmar Krause
- Department of Physiology, Center for Integrative Physiology and Molecular Medicine, University of Saarland, Saarland, Germany
| | - Thomas Tschernig
- Insitute of Anatomy and Cell Biology, University of Saarland, Saarland, Germany; and
| | - Miroslaw Kornek
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Homburg, Germany
| | - Detlef Schuppan
- Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Johannes Gutenberg University, Mainz, Germany
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Best J, Manka P, Syn WK, Dollé L, van Grunsven LA, Canbay A. Role of liver progenitors in liver regeneration. Hepatobiliary Surg Nutr 2015; 4:48-58. [PMID: 25713804 DOI: 10.3978/j.issn.2304-3881.2015.01.16] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2014] [Accepted: 01/20/2015] [Indexed: 12/16/2022]
Abstract
During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.
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Affiliation(s)
- Jan Best
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Paul Manka
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Wing-Kin Syn
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Laurent Dollé
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Leo A van Grunsven
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
| | - Ali Canbay
- 1 Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany ; 2 Liver Cell Biology Lab, Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel (VUB), Brussels, Belgium ; 3 Regeneration and Repair, The Institute of Hepatology, Foundation for Liver Research, London, UK ; 4 Liver Unit, Barts Health NHS Trust, London, UK ; 5 Department of Surgery, Loyola University Chicago, USA
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Koyama Y, Wang P, Brenner DA, Kisseleva T. Stellate Cells, Portal Myofibroblasts, and Epithelial-to-Mesenchymal Transition. STELLATE CELLS IN HEALTH AND DISEASE 2015:87-106. [DOI: 10.1016/b978-0-12-800134-9.00006-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Liu D, Yovchev MI, Zhang J, Alfieri AA, Tchaikovskaya T, Laconi E, Dabeva MD. Identification and characterization of mesenchymal-epithelial progenitor-like cells in normal and injured rat liver. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 185:110-28. [PMID: 25447047 DOI: 10.1016/j.ajpath.2014.08.029] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Revised: 08/22/2014] [Accepted: 08/27/2014] [Indexed: 01/07/2023]
Abstract
In normal rat liver, thymocyte antigen 1 (Thy1) is expressed in fibroblasts/myofibroblasts and in some blood progenitor cells. Thy1-expressing cells also accumulate in the liver during impaired liver regeneration. The origin and nature of these cells are not well understood. By using RT-PCR analysis and immunofluorescence microscopy, we describe the presence of rare Thy1(+) cells in the liver lobule of normal animals, occasionally forming small collections of up to 20 cells. These cells constitute a small portion (1.7% to 1.8%) of nonparenchymal cells and reveal a mixed mesenchymal-epithelial phenotype, expressing E-cadherin, cytokeratin 18, and desmin. The most potent mitogens for mesenchymal-epithelial Thy1(+) cells in vitro are the inflammatory cytokines interferon γ, IL-1, and platelet-derived growth factor-BB, which are not produced by Thy1(+) cells. Thy1(+) cells express all typical mesenchymal stem cell and hepatic progenitor cell markers and produce growth factor and cytokine mRNA (Hgf, Il6, Tgfa, and Tweak) for proteins that maintain oval cell growth and differentiation. Under appropriate conditions, mesenchymal-epithelial cells differentiate in vitro into hepatocyte-like cells. In this study, we show that the adult rat liver harbors a small pool of endogenous mesenchymal-epithelial cells not recognized previously. In the quiescent state, these cells express both mesenchymal and epithelial cell markers. They behave like hepatic stem cells/progenitors with dual phenotype, exhibiting high plasticity and long-lasting proliferative activity.
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Affiliation(s)
- Daqing Liu
- Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York
| | - Mladen I Yovchev
- Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York
| | - Jinghang Zhang
- Flow Cytometry Core Facility, Albert Einstein College of Medicine, Bronx, New York
| | - Alan A Alfieri
- Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York
| | - Tatyana Tchaikovskaya
- Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York
| | - Ezio Laconi
- Section of Experimental Pathology, Department of Sciences and Biomedical Technology, University of Cagliari, Cagliari, Italy
| | - Mariana D Dabeva
- Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York.
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16
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Xu J, Liu X, Koyama Y, Wang P, Lan T, Kim IG, Kim IH, Ma HY, Kisseleva T. The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies. Front Pharmacol 2014; 5:167. [PMID: 25100997 PMCID: PMC4105921 DOI: 10.3389/fphar.2014.00167] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 06/25/2014] [Indexed: 01/18/2023] Open
Abstract
Liver fibrosis results from dysregulation of normal wound healing, inflammation, activation of myofibroblasts, and deposition of extracellular matrix (ECM). Chronic liver injury causes death of hepatocytes and formation of apoptotic bodies, which in turn, release factors that recruit inflammatory cells (neutrophils, monocytes, macrophages, and lymphocytes) to the injured liver. Hepatic macrophages (Kupffer cells) produce TGFβ1 and other inflammatory cytokines that activate Collagen Type I producing myofibroblasts, which are not present in the normal liver. Secretion of TGFβ1 and activation of myofibroblasts play a critical role in the pathogenesis of liver fibrosis of different etiologies. Although the composition of fibrogenic myofibroblasts varies dependent on etiology of liver injury, liver resident hepatic stellate cells and portal fibroblasts are the major source of myofibroblasts in fibrotic liver in both experimental models of liver fibrosis and in patients with liver disease. Several studies have demonstrated that hepatic fibrosis can reverse upon cessation of liver injury. Regression of liver fibrosis is accompanied by the disappearance of fibrogenic myofibroblasts followed by resorption of the fibrous scar. Myofibroblasts either apoptose or inactivate into a quiescent-like state (e.g., stop collagen production and partially restore expression of lipogenic genes). Resolution of liver fibrosis is associated with recruitment of macrophages that secrete matrix-degrading enzymes (matrix metalloproteinase, collagenases) and are responsible for fibrosis resolution. However, prolonged/repeated liver injury may cause irreversible crosslinking of ECM and formation of uncleavable collagen fibers. Advanced fibrosis progresses to cirrhosis and hepatocellular carcinoma. The current review will summarize the role and contribution of different cell types to populations of fibrogenic myofibroblasts in fibrotic liver.
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Affiliation(s)
- Jun Xu
- School of Medicine, University of California at San Diego La Jolla, CA, USA
| | - Xiao Liu
- School of Medicine, University of California at San Diego La Jolla, CA, USA
| | - Yukinori Koyama
- School of Medicine, University of California at San Diego La Jolla, CA, USA
| | - Ping Wang
- School of Medicine, University of California at San Diego La Jolla, CA, USA
| | - Tian Lan
- School of Medicine, University of California at San Diego La Jolla, CA, USA
| | - In-Gyu Kim
- School of Medicine, University of California at San Diego La Jolla, CA, USA
| | - In H Kim
- School of Medicine, University of California at San Diego La Jolla, CA, USA
| | - Hsiao-Yen Ma
- School of Medicine, University of California at San Diego La Jolla, CA, USA
| | - Tatiana Kisseleva
- School of Medicine, University of California at San Diego La Jolla, CA, USA
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17
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Elpek G&O. Cellular and molecular mechanisms in the pathogenesis of liver fibrosis: An update. World J Gastroenterol 2014; 20:7260-7276. [PMID: 24966597 PMCID: PMC4064072 DOI: 10.3748/wjg.v20.i23.7260] [Citation(s) in RCA: 285] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2013] [Revised: 02/08/2014] [Accepted: 05/23/2014] [Indexed: 02/06/2023] Open
Abstract
There have been considerable recent advances towards a better understanding of the complex cellular and molecular network underlying liver fibrogenesis. Recent data indicate that the termination of fibrogenic processes and the restoration of deficient fibrolytic pathways may allow the reversal of advanced fibrosis and even cirrhosis. Therefore, efforts have been made to better clarify the cellular and molecular mechanisms that are involved in liver fibrosis. Activation of hepatic stellate cells (HSCs) remains a central event in fibrosis, complemented by other sources of matrix-producing cells, including portal fibroblasts, fibrocytes and bone marrow-derived myofibroblasts. These cells converge in a complex interaction with neighboring cells to provoke scarring in response to persistent injury. Defining the interaction of different cell types, revealing the effects of cytokines on these cells and characterizing the regulatory mechanisms that control gene expression in activated HSCs will enable the discovery of new therapeutic targets. Moreover, the characterization of different pathways associated with different etiologies aid in the development of disease-specific therapies. This article outlines recent advances regarding the cellular and molecular mechanisms involved in liver fibrosis that may be translated into future therapies. The pathogenesis of liver fibrosis associated with alcoholic liver disease, non-alcoholic fatty liver disease and viral hepatitis are also discussed to emphasize the various mechanisms involved in liver fibrosis.
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18
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Itoh T, Miyajima A. Liver regeneration by stem/progenitor cells. Hepatology 2014; 59:1617-26. [PMID: 24115180 DOI: 10.1002/hep.26753] [Citation(s) in RCA: 113] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2013] [Accepted: 09/11/2013] [Indexed: 12/12/2022]
Abstract
UNLABELLED The liver is renowned for its strong, robust regenerative capacity, employing different modes of regeneration according to type and extent of injury. The process of compensatory hypertrophy of the liver upon partial hepatectomy has been standing as a classical model for studying organ regeneration in mammals and a subject of exhaustive analyses. Meanwhile, in view of the physiological relevance for many of the human liver pathologies induced upon toxic insults or hepatitis, other injury models have recently drawn increasing attention. In those damaged livers where hepatocyte proliferation is compromised, adult liver stem/progenitor cells (LPCs) are activated and differentiate to hepatocytes and cholangiocytes, leading to functional recovery of the organ. Here, we summarize and discuss recent findings on the mechanisms underlying the regeneration process of the liver. Whereas the primary focus of this article is on those related to LPC-mediated regeneration, we also introduce topics on compensatory hypertrophy, where application of new technologies and molecular genetics approaches in mice has gained a paradigm shift. Identification of various markers for LPC populations has expedited their characterization and enabled us to examine their differentiation potential in vivo using genetic lineage-tracing approaches. Comprehensive studies regarding intercellular signaling pathways and their modes of action have succeeded in elucidating novel frameworks for the LPC-niche interaction functioning in the regenerating liver. CONCLUSION Advancing our understanding of the cellular and molecular mechanisms for liver regeneration should provide a basis for developing therapeutic strategies to treat patients with liver disease.
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Affiliation(s)
- Tohru Itoh
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
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19
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Ding ZY, Jin GN, Liang HF, Wang W, Chen WX, Datta PK, Zhang MZ, Zhang B, Chen XP. Transforming growth factor β induces expression of connective tissue growth factor in hepatic progenitor cells through Smad independent signaling. Cell Signal 2013; 25:1981-1992. [PMID: 23727026 DOI: 10.1016/j.cellsig.2013.05.027] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 05/14/2013] [Accepted: 05/15/2013] [Indexed: 12/27/2022]
Abstract
Hepatic progenitor cells (HPCs) are activated in the chronic liver injury and are found to participate in the progression of liver fibrosis, while the precise role of HPCs in liver fibrosis remains largely elusive. In this study, by immunostaining of human liver sections, we confirmed that HPCs were activated in the cirrhotic liver and secreted transforming growth factor β (TGF-β) and connective tissue growth factor (CTGF), both of which were important inducers of liver fibrosis. Besides, we used HPC cell lines LE/6 and WB-F344 as in vitro models and found that TGF-β induced secretion of CTGF in HPCs. Moreover, TGF-β signaling was intracrine activated and contributed to autonomous secretion of CTGF in HPCs. Furthermore, we found that TGF-β induced expression of CTGF was not mediated by TGF-β activated Smad signaling but mediated by TGF-β activated Erk, JNK and p38 MAPK signaling. Taken together, our results provide evidence for the role of HPCs in liver fibrosis and suggest that the production of CTGF by TGF-β activated MAPK signaling in HPCs may be a therapeutic target of liver fibrosis.
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Affiliation(s)
- Ze-yang Ding
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
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20
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Yovchev MI, Dabeva MD, Oertel M. Isolation, characterization, and transplantation of adult liver progenitor cells. Methods Mol Biol 2013; 976:37-51. [PMID: 23400433 DOI: 10.1007/978-1-62703-317-6_4] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Many chronic liver diseases are life-threatening. When the liver loses the ability to repair itself the only treatment currently available is liver transplant. However, there are not enough donors to treat all the patients. This requires the search of alternative therapies utilizing stem and progenitor cells for treatment of these patients and restoration of their normal liver function.Hepatic progenitor cells can be isolated from livers at different developmental stages including adult liver. In the adult rat liver, there is clear evidence that progenitor cells (also called "oval cells") derive from precursors in the canals of Herring that are capable to differentiate into hepatocytes and bile duct cells. In experimental models, hepatic progenitor cells can be isolated and propagated in vitro and used for restoration of the diseased liver. The first step in utilization of progenitor cells is their identification in the liver, isolation of purified progenitor cell fractions, which are subsequently transplanted in the diseased liver for evaluation of liver repopulation by transplanted cells, and evaluation their potentials for clinical application.The present protocol describes the isolation of non-parenchymal cells (NPCs) from wt DPPIV(+) F344 rats, followed by purification of "oval cells", immunohistochemical staining techniques to characterize these cells, their transplantation into retrorsine-treated mutant DPPIV(-) rats, as well as the enzyme histochemical staining for DPPIV to detect transplanted cells in the host liver.
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Affiliation(s)
- Mladen I Yovchev
- Division of Gastroenterology and Liver Diseases, Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, USA
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21
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Takase HM, Itoh T, Ino S, Wang T, Koji T, Akira S, Takikawa Y, Miyajima A. FGF7 is a functional niche signal required for stimulation of adult liver progenitor cells that support liver regeneration. Genes Dev 2013; 27:169-81. [PMID: 23322300 DOI: 10.1101/gad.204776.112] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The liver is a unique organ with a remarkably high potential to regenerate upon injuries. In severely damaged livers where hepatocyte proliferation is impaired, facultative liver progenitor cells (LPCs) proliferate and are assumed to contribute to regeneration. An expansion of LPCs is often observed in patients with various types of liver diseases. However, the underlying mechanism of LPC activation still remains largely unknown. Here we show that a member of the fibroblast growth factor (FGF) family, FGF7, is a critical regulator of LPCs. Its expression was induced concomitantly with LPC response in the liver of mouse models as well as in the serum of patients with acute liver failure. Fgf7-deficient mice exhibited markedly depressed LPC expansion and higher mortality upon toxin-induced hepatic injury. Transgenic expression of FGF7 in vivo led to the induction of cells with characteristics of LPCs and ameliorated hepatic dysfunction. We revealed that Thy1(+) mesenchymal cells produced FGF7 and appeared in close proximity to LPCs, implicating a role for those cells as the functional LPC niche in the regenerating liver. These findings provide new insights into the cellular and molecular basis for LPC regulation and identify FGF7 as a potential therapeutic target for liver diseases.
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Affiliation(s)
- Hinako M Takase
- Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan
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22
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Liver Stem Cells. Regen Med 2013. [DOI: 10.1007/978-94-007-5690-8_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
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Abstract
Chronic liver injury of many etiologies produces liver fibrosis and may eventually lead to the formation of cirrhosis. Fibrosis is part of a dynamic process associated with the continuous deposition and resorption of extracellular matrix, mainly fibrillar collagen. Studies of fibrogenesis conducted in many organs including the liver demonstrate that the primary source of the extracellular matrix in fibrosis is the myofibroblast. Hepatic myofibroblasts are not present in the normal liver but transdifferentiate from heterogeneous cell populations in response to a variety of fibrogenic stimuli. Debate still exists regarding the origin of hepatic myofibroblasts. It is considered that hepatic stellate cells and portal fibroblasts have fibrogenic potential and are the major origin of hepatic myofibroblasts. Depending on the primary site of injury the fibrosis may be present in the hepatic parenchyma as seen in chronic hepatitis or may be restricted to the portal areas as in most biliary diseases. It is suggested that hepatic injury of different etiology triggers the transdifferentiation to myofibroblasts from distinct cell populations. Here we discuss the origin and fate of myofibroblast in liver fibrosis.
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Affiliation(s)
- Keiko Iwaisako
- Department of Medicine, University of California, San Diego, La Jolla, California 92093-0602, USA
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24
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Abstract
Liver fibrosis is the result of the entire organism responding to a chronic injury. Every cell type in the liver contributes to the fibrosis. This paper first discusses key intracellular signaling pathways that are induced during liver fibrosis. The paper then examines the effects of these signaling pathways on the major cell types in the liver. This will provide insights into the molecular pathophysiology of liver fibrosis and should identify therapeutic targets.
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25
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Kisseleva T, Brenner DA. Anti-fibrogenic strategies and the regression of fibrosis. Best Pract Res Clin Gastroenterol 2011; 25:305-17. [PMID: 21497747 PMCID: PMC3086317 DOI: 10.1016/j.bpg.2011.02.011] [Citation(s) in RCA: 136] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2011] [Revised: 02/18/2011] [Accepted: 02/23/2011] [Indexed: 01/31/2023]
Abstract
Liver fibrosis is an outcome of many chronic diseases, and often results in cirrhosis, liver failure, and portal hypertension. Liver transplantation is the only treatment available for patients with advanced stage of fibrosis. Therefore, alternative methods are required to develop new strategies for anti-fibrotic therapy. Available treatments are designed to substitute for liver transplantation or bridge the patients, they include inhibitors of fibrogenic cytokines such as TGF-β1 and EGF, inhibitors of rennin angiotensin system, and blockers of TLR4 signalling. Development of liver fibrosis is orchestrated by many cell types. However, activated myofibroblasts remain the primary target for anti-fibrotic therapy. Hepatic stellate cells and portal fibroblasts are considered to play a major role in development of liver fibrosis. Here we discuss the origin of activated myofibroblasts and different aspects of their activation, differentiation and potential inactivation during regression of liver fibrosis.
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Affiliation(s)
| | - David A. Brenner
- Dept. of Medicine, University of California, San Diego, CA, USA,Corresponding author, Contact information: David Brenner, M.D., 1318 Biomedical Sciences Building, 9500 Gilman Drive, La Jolla, CA 92093-0602, T: 858-534-1501 / F: 858-822-0084,
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26
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Tanaka M, Itoh T, Tanimizu N, Miyajima A. Liver stem/progenitor cells: their characteristics and regulatory mechanisms. J Biochem 2011; 149:231-9. [PMID: 21217146 DOI: 10.1093/jb/mvr001] [Citation(s) in RCA: 94] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Liver stem cells give rise to both hepatocytes and bile duct epithelial cells also known as cholangiocytes. During liver development hepatoblasts emerge from the foregut endoderm and give rise to both cell types. Colony-forming cells are present in the liver primordium and clonally expanded cells differentiate into either hepatocytes or cholangiocytes depending on culture conditions, showing stem cell characteristics. The growth and differentiation of hepatoblasts are regulated by various extrinsic signals. For example, periportal mesenchymal cells provide a cue for bipotential hepatoblasts to become cholangiocytes, and mesothelial cells covering the parenchyma support the expansion of foetal hepatocytes by producing growth factors. The adult liver has an extraordinary capacity to regenerate, and after 70% hepatectomy the liver recovers its original mass by replication of the remaining hepatocytes without the activation of liver stem cells. However, in certain types of liver injury models, liver stem/progenitor-like cells, known as oval cells in rodents, proliferate around the portal vein, while the roles of such cells in liver regeneration remain a matter of debate. Clonogenic and bipotential cells are also present in the normal adult liver. In this minireview we describe recent studies on liver stem/progenitor cells by focusing on extracellular signals.
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Affiliation(s)
- Minoru Tanaka
- Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan
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Liver Stem Cells. Regen Med 2011. [DOI: 10.1007/978-90-481-9075-1_14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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Abstract
PURPOSE OF REVIEW Patients with liver cirrhosis often require liver transplantation, which remains the only effective treatment of the end-stage cirrhosis. Here we briefly summarize the current concepts in treatment of liver diseases based on the transplantation of intrahepatic liver cells, capable of repopulating the injured liver. These cells include hepatocytes, oval cells (bipotential intrahepatic progenitor cells), bone marrow hematopoietic and mesenchymal stem cells, and induced pluripotent stem (iPS) cells. RECENT FINDINGS Although liver transplantation remains the only conventional treatment, liver cell transplantation is an experimental procedure which has been successfully used in clinical trials in patients with acute liver failure, chronic liver disease with end-stage cirrhosis. Extraordinary progress has been made in the field of hepatic progenitors and iPS. Liver precursor cells (oval cells) are recognized as bipotential precursor cells in the damaged liver. They can rapidly proliferate, change their cellular composition, and differentiate into hepatocytes and cholangiocytes to compensate for the cellular loss and maintain liver homeostasis in animal models of liver injury. Similarly, iPS are somatic cells obtained from patients and differentiated into hepatocytes in vitro. Future studies of iPS are designed to develop of specific conditions to expand and in vitro differentiate somatic cells into functionally mature liver cells. SUMMARY The current review defines and discusses different populations of hepatic cells which can be potentially used for liver cell transplantation to advance the therapy of hepatic cirrhosis.
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Conigliaro A, Brenner DA, Kisseleva T. Hepatic progenitors for liver disease: current position. STEM CELLS AND CLONING-ADVANCES AND APPLICATIONS 2010; 3:39-47. [PMID: 24198509 PMCID: PMC3781731 DOI: 10.2147/sccaa.s6035] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Liver regeneration restores the original functionality of hepatocytes and cholangiocytes in response to injury. It is regulated on several levels, with different cellular populations contributing to this process, eg, hepatocytes, liver precursor cells, intrahepatic stem cells. In response to injury, mature hepatocytes have the capability to proliferate and give rise to new hepatocytes and cholangiocytes. Meanwhile, liver precursor cells (oval cells) have become the most recognized bipotential precursor cells in the damaged liver. They rapidly proliferate, change their cellular composition, and differentiate into hepatocytes and cholangiocytes to compensate for the cellular loss and maintain liver homeostasis. There is a growing body of evidence that oval cells originate from the intrahepatic stem cell(s), which in turn give(s) rise to epithelial, including oval cells, and/or other hepatic cells of nonepithelial origin. Since there is a close relationship between the liver and hematopoiesis, bone marrow derived cells can also contribute to liver regeneration by the fusion of myeloid cells with damaged hepatocytes, or differentiation of mesenchymal stem cells into hepatocyte-like cells. The current review discusses the contribution of different cells to liver regeneration and their characteristics.
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Affiliation(s)
- Alice Conigliaro
- University "La Sapienza", Dipartimento di Biotecnologie Cellulari ed Ematologia Policlinico Umberto I, V Clinica Medica, Rome, Italy
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The role of stem cells in liver repair and fibrosis. Int J Biochem Cell Biol 2009; 43:222-9. [PMID: 19914396 DOI: 10.1016/j.biocel.2009.11.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2009] [Revised: 10/20/2009] [Accepted: 11/06/2009] [Indexed: 11/21/2022]
Abstract
In response to liver injury or loss of liver mass, proliferation of mature liver cells is the first-line defense to restore liver homeostasis. In the setting of chronic liver disease, however, the ability of hepatocytes and cholangiocytes to proliferate is blocked and small bipotential progenitor cells are activated. Recent studies have established the role of these facultative progenitor cells in injury repair and fibrosis in patients with chronic liver disease and in experimental models. Several signaling pathways linking progenitor cell activation and fibrosis have been identified, and there is increasing evidence that cross-talk (both physical and via soluble factors) between progenitor cells and myofibroblasts is essential for both fibrosis and parenchymal regeneration. Even more exciting are new data examining the cellular components of the progenitor cell niche, demonstrating that both resident liver cells and circulating cells from the bone marrow can function as stem cells, suggesting that there is a surprising degree of phenotypic plasticity such that progenitor cells can contribute to the myofibroblast population and vice versa. We highlight here recent findings from the literature demonstrating the cellular and functional complexity of the progenitor cell niche, and emphasize some of the important questions that remain to drive future research.
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