Origin of myofibroblasts in the fibrotic liver in mice

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 32; pp. E3297 - E3305
• Main Authors: Iwaisako, Keiko, Jiang, Chunyan, Zhang, Mingjun, Cong, Min, Moore-Morris, Thomas Joseph, Park, Tae Jun, Liu, Xiao, Xu, Jun, Wang, Ping, Paik, Yong-Han, Meng, Fanli, Asagiri, Masataka, Murray, Lynne A, Hofmann, Alan F, Iida, Takashi, Glass, Christopher K, Brenner, David A, Kisseleva, Tatiana
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 12.08.2014; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; Biological Sciences; Carbon Tetrachloride - toxicity; Chemical and Drug Induced Liver Injury - genetics; Chemical and Drug Induced Liver Injury - metabolism; Chemical and Drug Induced Liver Injury - pathology; Cholestasis - complications; Collagen; Collagen Type I - genetics; Collagen Type I - metabolism; Disease Models, Animal; Flow cytometry; Genotype & phenotype; GPI-Linked Proteins - metabolism; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Hepatology; Liver - metabolism; Liver - pathology; Liver Cirrhosis - etiology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myofibroblasts - metabolism; Myofibroblasts - pathology; Pathogenesis; Pathology; PNAS Plus; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Rodents; Vitamin A - metabolism; markers of fibrogenic myofibroblasts; ECM deposition
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1400062111

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; CCl ₄) 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 CCl ₄ 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.