Expansion of Prominin-1-Expressing Cells in Association With Fibrosis of Biliary Atresia

Biliary atresia (BA), the most common cause of end-stage liver disease and the leading indication for pediatric liver transplantation, is associated with intrahepatic ductular reactions within regions of rapidly expanding periportal biliary fibrosis. Whereas the extent of such biliary fibrosis is a negative predictor of long-term transplant-free survival, the cellular phenotypes involved in the fibrosis are not well established. Using a rhesus rotavirus-induced mouse model of BA, we demonstrate significant expansion of a cell population expressing the putative stem/progenitor cell marker, PROMININ-1 (PROM1), adjacent to ductular reactions within regions of periportal fibrosis. PROM1(positive) ((pos)) cells express Collagen-1 alpha 1. Subsets of PROM1(pos) cells coexpress progenitor cell marker CD49f, epithelial marker E-CADHERIN, biliary marker CYTOKERATIN-19, and mesenchymal markers VIMENTIN and alpha-SMOOTH MUSCLE ACTIN (alpha SMA). Expansion of the PROM1(pos) cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor-beta (TGF beta) signaling. In vitro cotreatment of PROM1-expressing Mat1a(-/-) hepatic progenitor cells with recombinant human FGF10 and TGF beta 1 promotes morphologic transformation toward a myofibroblastic cell phenotype with increased expression of myofibroblastic genes Collagen-1 alpha 1, Fibronectin, and alpha-Sma. Infants with BA demonstrate similar expansion of periportal PROM1(pos) cells with activated Mothers Against Decapentaplegic Homolog 3 (SMAD3) signaling in association with increased hepatic expression of FGF10, FGFR1, and FGFR2 as well as mesenchymal genes SLUG and SNAIL. Infants with perinatal subtype of BA have higher tissue levels of PROM1 expression than those with embryonic subtype. Conclusion: Expansion of collagenproducing PROM1(pos) cells within regions of periportal fibrosis is associated with activated FGF and TGFb pathways in both experimental and human BA. PROM1(pos) cells may therefore play an important role in the biliary fibrosis of BA.