Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 Mar;51(3):1027-36.
doi: 10.1002/hep.23368.

Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice

Kojiro Taura  1 , Kouichi Miura, Keiko Iwaisako, Christoph H Osterreicher, Yuzo Kodama, Melitta Penz-Osterreicher, David A Brenner
Affiliations

Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice

Kojiro Taura et al. Hepatology. 2010 Mar.

Abstract

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 beta-galactosidase (beta-gal), albumin Cre, and collagen alpha1(I) green fluorescent protein (GFP), in which hepatocyte-derived cells are permanently labeled by beta-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 beta-gal as well as expression of alpha-smooth muscle actin (alpha-SMA) and fibroblast-specific protein 1 (FSP-1). Upon stimulation with transforming growth factor beta-1, cultured hepatocytes isolated from untreated liver expressed both GFP and beta-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 beta-gal. All beta-gal-positive cells exhibited abundant cytoplasm, a typical morphology of hepatocytes, and expressed none of the mesenchymal markers including alpha-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.

PubMed Disclaimer

Conflict of interest statement

No conflicts of interest exist.

Figures

Figure 1
Figure 1
Figure 2
Figure 2
Figure 3
Figure 3
Figure 4
Figure 4
Figure 5
Figure 5
Figure 6
Figure 6
See this image and copyright information in PMC

Comment in

References

    1. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology. 2008;134:1655–1669. - PMC - PubMed
    1. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209–218. - PMC - PubMed
    1. Friedman SL, Roll FJ, Boyles J, Bissell DM. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci U S A. 1985;82:8681–8685. - PMC - PubMed
    1. Beaussier M, Wendum D, Schiffer E, Dumont S, Rey C, Lienhart A, Housset C. Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. Lab Invest. 2007;87:292–303. - PubMed
    1. Kisseleva T, Uchinami H, Feirt N, Quintana-Bustamante O, Segovia JC, Schwabe RF, Brenner DA. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis. J Hepatol. 2006;45:429–438. - PubMed

Publication types

Substances