The Hedgehog Pathway Regulates Remodeling Responses to Biliary Obstruction in Rats

¹ Duke University Medical Center, Durham, NC, United States
² Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, United States

^* To whom correspondence should be addressed. E-mail: annamae.diehl{at}duke.edu.

Accepted 5 March 2008

	Abstract

Aims and Objectives: Chronic biliary obstruction provokes fibrosis and accumulation of immature ductular cells. This fibroductular reaction resolves following biliary decompression, suggesting that it may be also involved in repair of biliary damage. The Hedgehog (Hh) pathway becomes activated in liver after bile duct ligation (BDL), and might modulate hepatic remodeling because Hh ligands are potent morphogens. Our aims were to study Hh pathway induction during progression and resolution of biliary fibrosis, and to clarify if Hh signaling regulates accumulation of bile duct progenitor cells.

Design & Main Outcome Measures: Livers from BDL rats were examined by QRT-PCR analysis and immunohistochemistry to identify factors that might stimulate Hh signaling. BDL rats were subjected to Roux-en-Y hepaticojejunostomy (R-Y) to relieve biliary obstruction in order to determine if these factors and Hh signaling declined as ductular populations and concomitant fibrosis regressed. Cultures of immature ductular cells were treated with putative Hh-inducers and Hh ligands to confirm their functional relevance.

Results: BDL increased expression of platelet derived growth factor (PDGF)-BB and Sonic hedgehog (Shh), down-regulated hedgehog-interacting protein (Hip), activated Hh-signaling, and expanded populations of Hh-responsive ductular cells that expressed pancyotkeratin, a liver progenitor cell marker. After R-Y, Hip remained suppressed, expression of PDGF-BB and Shh gradually declined, and populations of Hedgehog-responsive ductular cells regressed. In cultured ductular cells, PDGF-BB treatment induced Shh expression, and incubation with Shh inhibited apoptotic activity.

Conclusions: These results identify a mechanism for Hh pathway activation during cholestasis and suggest that Hh signaling regulates ductular cell accumulation after biliary injury.