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Research Article

Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis

¹Duke University ²DUke University ³Duke University Medical Center ⁴Memorial Sloan-Kettering Cancer Center ⁵GHeorge Washington University Medical Center

Submitted 17 July 2009 ; revision received 24 September 2009 ; accepted in final form 25 September 2009

ABSTRACT

Myofibroblastic hepatic stellate cells (MF-HSC) are derived from quiescent HSC (Q-HSC). Q-HSC express certain epithelial cell markers, and reportedly form junctional complexes like epithelial cells. We have shown that Hedgehog (Hh) signaling plays a key role in HSC growth. Because Hh ligands regulate epithelial-to-mesenchymal transition (EMT), we determined whether Q-HSC expressed EMT markers, and then assessed if these markers changed as Q-HSC transition into MF-HSC and whether the process was modulated by Hh signaling. Q-HSC were isolated from healthy livers and cultured to promote myofibroblastic transition. Changes in mRNA and protein expression of epithelial and mesenchymal markers, Hh ligands and target genes were monitored in HSC treated with and without cyclopamine (Hh inhibitor). Studies were repeated in primary human HSC and clonally-derived HSC from a cirrhotic rat. Q-HSC activation in vitro (culture) and in vivo (CCl₄-induced cirrhosis) resulted in decreased expression of Hhip (Hh antagonist), the EMT inhibitors bone morphogenic protein (BMP-7) and Inhibitor of differentiation (Id2), the adherens junction component E-cadherin, and epithelial keratins 7 and 19, while increasing expression of Gli2 (Hh target gene) and mesenchymal markers, including the mesenchyme-associated transcription factors, Lhx2 and Msx2, the myofibroblast marker, alpha-smooth muscle actin, and matrix molecules such as collagen. Cyclopamine reverted myofibroblastic trans-differentiation, reducing mesenchymal gene expression while increasing epithelial markers in both rodent and human HSC. Conclusion: Hh signaling plays a key role in Q-HSC transition into MF-HSC. Our findings suggest that Q-HSC are capable of transitioning between epithelial and mesenchymal fates.

bone morphogenic protein 7; cyclopamine; fibrosis