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Hepatocytes do not undergo epithelial‐mesenchymal transition in liver fibrosis in mice
Author(s) -
Taura Kojiro,
Miura Kouichi,
Iwaisako Keiko,
Österreicher Christoph H.,
Kodama Yuzo,
PenzÖsterreicher Melitta,
Brenner David A.
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23368
Subject(s) - mesenchymal stem cell , vimentin , epithelial–mesenchymal transition , desmin , hepatocyte , green fluorescent protein , hepatic stellate cell , microbiology and biotechnology , biology , fibroblast , chemistry , pathology , immunology , downregulation and upregulation , in vitro , endocrinology , immunohistochemistry , medicine , gene , biochemistry
The origin of fibrogenic cells in liver fibrosis remains controversial. We assessed the emerging concept that hepatocytes contribute to production of extracellular matrix (ECM) in liver fibrosis through epithelial‐mesenchymal transition (EMT). We bred triple transgenic mice expressing ROSA26 stop β‐galactosidase (β‐gal), albumin Cre, and collagen α1(I) green fluorescent protein (GFP), in which hepatocyte‐derived cells are permanently labeled by β‐gal and type I collagen‐expressing cells are labeled by GFP. We induced liver fibrosis by repetitive carbon tetrachloride (CCl 4 ) injections. Liver sections and isolated cells were evaluated for GFP and β‐gal as well as expression of α‐smooth muscle actin (α‐SMA) and fibroblast‐specific protein 1 (FSP‐1). Upon stimulation with transforming growth factor β‐1, cultured hepatocytes isolated from untreated liver expressed both GFP and β‐gal with a fibroblast‐like morphological change but lacked expression of other mesenchymal markers. Cells from CCl 4 ‐treated livers never showed double‐positivity for GFP and β‐gal. All β‐gal‐positive cells exhibited abundant cytoplasm, a typical morphology of hepatocytes, and expressed none of the mesenchymal markers including α‐SMA, FSP‐1, desmin, and vimentin. In liver sections of CCl 4 ‐treated mice, GFP‐positive areas were coincident with fibrotic septa and never overlapped X‐gal‐positive areas. Conclusion: Type I collagen‐producing cells do not originate from hepatocytes. Hepatocytes in vivo neither acquire mesenchymal marker expression nor exhibit a morphological change clearly distinguishable from normal hepatocytes. Our results strongly challenge the concept that hepatocytes in vivo acquire a mesenchymal phenotype through EMT to produce the ECM in liver fibrosis. (H EPATOLOGY 2009.)