title: Origin of myofibroblasts in the fibrotic liver in mice.
abstract: Hepatic myofibroblasts are activated in response to chronic liver injury of any etiology to produce a fibrous scar. Despite extensive studies, the origin of myofibroblasts in different types of fibrotic liver diseases is unresolved. To identify distinct populations of myofibroblasts and quantify their contribution to hepatic fibrosis of two different etiologies, collagen-α1(I)-GFP mice were subjected to hepatotoxic (carbon tetrachloride; CCl4) or cholestatic (bile duct ligation; BDL) liver injury. All myofibroblasts were purified by flow cytometry of GFP(+) cells and then different subsets identified by phenotyping. Liver resident activated hepatic stellate cells (aHSCs) and activated portal fibroblasts (aPFs) are the major source (>95%) of fibrogenic myofibroblasts in these models of liver fibrosis in mice. As previously reported using other methodologies, hepatic stellate cells (HSCs) are the major source of myofibroblasts (>87%) in CCl4 liver injury. However, aPFs are a major source of myofibroblasts in cholestatic liver injury, contributing >70% of myofibroblasts at the onset of injury (5 d BDL). The relative contribution of aPFs decreases with progressive injury, as HSCs become activated and contribute to the myofibroblast population (14 and 20 d BDL). Unlike aHSCs, aPFs respond to stimulation with taurocholic acid and IL-25 by induction of collagen-α1(I) and IL-13, respectively. Furthermore, BDL-activated PFs express high levels of collagen type I and provide stimulatory signals to HSCs. Gene expression analysis identified several novel markers of aPFs, including a mesothelial-specific marker mesothelin. PFs may play a critical role in the pathogenesis of cholestatic liver fibrosis and, therefore, serve as an attractive target for antifibrotic therapy.
authors: Departments of Medicine,Department of Target Therapy Oncology, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;Surgery, and.
authors: Keiko
authors: K
authors: Iwaisako
authors: Departments of Medicine,Surgery, andBeijing Friendship Hospital, Capital Medical University, Beijing 100050, China;
authors: Chunyan
authors: C
authors: Jiang
authors: Departments of Medicine.
authors: Mingjun
authors: M
authors: Zhang
authors: Departments of Medicine,Surgery, andBeijing Friendship Hospital, Capital Medical University, Beijing 100050, China;
authors: Min
authors: M
authors: Cong
authors: School of Pharmacy, University of California, San Diego, La Jolla, CA 92093;
authors: Thomas Joseph
authors: TJ
authors: Moore-Morris
authors: Departments of Medicine.
authors: Tae Jun
authors: TJ
authors: Park
authors: Departments of Medicine,Surgery, and.
authors: Xiao
authors: X
authors: Liu
authors: Departments of Medicine,Surgery, and.
authors: Jun
authors: J
authors: Xu
authors: Departments of Medicine,Surgery, andBeijing Friendship Hospital, Capital Medical University, Beijing 100050, China;
authors: Ping
authors: P
authors: Wang
authors: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 135-710, Korea;
authors: Yong-Han
authors: YH
authors: Paik
authors: Departments of Medicine,Department of Hepatology, Qilu Hospital Shandong University, Shandong 250012, China;
authors: Fanli
authors: F
authors: Meng
authors: Innovation Center for Immunoregulation and Therapeutics, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan;
authors: Masataka
authors: M
authors: Asagiri
authors: MedImmune Ltd., Cambridge CB21 6GH, United Kingdom; and.
authors: Lynne A
authors: LA
authors: Murray
authors: Departments of Medicine.
authors: Alan F
authors: AF
authors: Hofmann
authors: Department of Chemistry, College of Humanities and Sciences, Nihon University, Sakurajousui, Setagaya, Tokyo 156-8550, Japan.
authors: Takashi
authors: T
authors: Iida
authors: Cellular and Molecular Medicine, and.
authors: Christopher K
authors: CK
authors: Glass
authors: Departments of Medicine.
authors: David A
authors: DA
authors: Brenner
authors: Surgery, and tkisseleva@ucsd.edu.
authors: Tatiana
authors: T
authors: Kisseleva
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002779:Cholestasis / Q000150:complications; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D000090204:Mesothelin; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D011994:Recombinant Proteins; D014801:Vitamin A; D049452:Green Fluorescent Proteins; D002251:Carbon Tetrachloride; D000090204:Mesothelin
keywords: ECM deposition; markers of fibrogenic myofibroblasts