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J. Biol. Chem., Vol. 282, Issue 32, 23337-23347, August 10, 2007

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Fibroblasts Derive from Hepatocytes in Liver Fibrosis via Epithelial to Mesenchymal Transition^*

Michael Zeisberg¹², Changqing Yang¹³, Margot Martino, Michael B. Duncan⁴, Florian Rieder, Harikrishna Tanjore, and Raghu Kalluri^¶5

From the Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachussetts 02215, the Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, and the ^¶Harvard-MIT Division of Health Sciences and Technology, Boston, Massachusetts 02215

Activated fibroblasts are key contributors to the fibrotic extracellular matrix accumulation during liver fibrosis. The origin of such fibroblasts is still debated, although several studies point to stellate cells as the principal source. The role of adult hepatocytes as contributors to the accumulation of fibroblasts in the fibrotic liver is yet undetermined. Here, we provide evidence that the pro-fibrotic growth factor, TGF-1, induces adult mouse hepatocytes to undergo phenotypic and functional changes typical of epithelial to mesenchymal transition (EMT). We perform lineage-tracing experiments using AlbCre. R26RstoplacZ double transgenic mice to demonstrate that hepatocytes which undergo EMT contribute substantially to the population of FSP1-positive fibroblasts in CCL₄-induced liver fibrosis. Furthermore, we demonstrate that bone morphogenic protein-7 (BMP7), a member of the TGF superfamily, which is known to antagonize TGF signaling, significantly inhibits progression of liver fibrosis in these mice. BMP7 treatment abolishes EMT-derived fibroblasts, suggesting that the therapeutic effect of BMP7 was at least partially due to the inhibition of EMT. These results provide direct evidence for the functional involvement of adult hepatocytes in the accumulation of activated fibroblasts in the fibrotic liver. Furthermore, our findings suggest that EMT is a promising therapeutic target for the attenuation of liver fibrosis.

Received for publication, January 8, 2007 , and in revised form, June 6, 2007.

^* This study was funded in part by the Espinosa Fibrosis Fund, a research grant from the Johnson & Johnson Companies, Research Grants DK62987, DK55001, DK61688, and AI53194 (to R. K.) from the National Institutes of Health, and a research fund from the Beth Israel Deaconess Medical Center for the Division of Matrix Biology. The first evidence for EMT involving adult primary hepatocytes was first reported by our laboratory at the 2003 Digestive Disease Week (DDW) meeting in Orlando, Florida. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this report.

² Funded by Grant 5K08DK074558-01 from the National Institutes of Health and the ASN Carl W. Gottschalk Award 2006.

³ Funded by a postdoctoral fellowship derived from the Espinosa Fibrosis Fund and BIDMC Liver Center.

⁴ Funded by National Institutes of Health Grant DK055001-07S1.

⁵ To whom correspondence should be addressed: Dept. of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave., RW514, Boston, MA 02215. Tel.: 617-667-0445; Fax: 617-975-5663; E-mail: rkalluri{at}bidmc.harvard.edu.

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