Prominin-1 Promotes Biliary Fibrosis Associated With Biliary Atresia.

Abstract

In patients with biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical bypass of the congenital cholangiopathy as well as subsequent transplant-free survival. We recently linked the expansion of a population of prominin-1 (Prom1)-expressing hepatic progenitor cells to biliary fibrogenesis. Herein, we hypothesized that Prom1-expressing progenitor cells play a role in BA-associated fibrosis. Rhesus rotavirus (RRV)-mediated experimental BA was induced in newborn mice homozygous for the transgene Prom1cre-ert2-nlacz , which was knocked in to the Prom1 gene locus, thus creating functional Prom1 knockout (KO) mice, and their wildtype (WT) littermates. Clinical data and tissue samples from BA infants from the Childhood Liver Disease Research Consortium were analyzed. Extrahepatic biliary obliteration was present in both WT and KO mice; there was no difference in serum total bilirubin (TBili) levels. The intrahepatic periportal expansion of the PROM1pos cell population, typically observed in RRV-induced BA, was absent in KO mice. RRV-treated KO mice demonstrated significantly fewer cytokeratin-19 (CK19)-positive ductular reactions (P = 0.0004) and significantly less periportal collagen deposition (P = 0.0001) compared with WT. RRV-treated KO mice expressed significantly less integrin-β6, which encodes a key biliary-specific subunit of a transforming growth factor (TGF) β activator (P = 0.0004). Infants with successful biliary drainage (Tbili ≤1.5 mg/dL within 3 months postoperatively), which is highly predictive of increased transplant-free survival, expressed significantly less hepatic PROM1, CK19, and COLLAGEN-1α compared with those with TBili >1.5 (P < 0.05). Conclusion: Prom1 plays an important role in biliary fibrogenesis, in part through integrin-mediated TGF pathway activation.