PROMININ-1 Promotes Biliary Fibrosis Associated with Biliary Atresia

Objective: In biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical drainage of the congenital cholangiopathy and with subsequent transplant-free survival. We recently... [ view full abstract ]

Objective: In biliary atresia (BA), the extent of intrahepatic biliary fibrosis negatively correlates with successful surgical drainage of the congenital cholangiopathy and with subsequent transplant-free survival. We recently observed the expansion of a population of Prominin-1 (Prom1)-expressing hepatic progenitor cells within regions of emerging biliary fibrosis. Thus, we hypothesized that Prom1-expressing progenitor cells play a role in BA-associated biliary fibrosis.

Methods: Rhesus rotavirus (RRV)-mediated experimental BA was induced in wildtype (WT) and Prom1-cre^+/+ transgenic mice, which are functionally Prom1 knockout (KO) mice. After 2 weeks, serum and whole liver were analyzed for bilirubin level, gene expression and histology. Clinical data and tissue samples from BA infants from the Childhood Liver Disease Research Consortium were analyzed.

Results: No difference in serum total bilirubin levels was observed between WT and KO mice and extrahepatic biliary obliteration was present in both. Lineage tracing of Prom1-expressing cells demonstrated transdifferentiation to CYTOKERATIN-19^+ive ductular reactions. RRV-treated KO mice demonstrated significantly fewer CK19^+ive ductular reactions (104.3±8.2 vs. 33.63±3.9 cells, p=0.0004) and significantly less periportal collagen deposition (3.6±0.2 vs. 5.2±0.03, p=0.0001) compared WT. Infants with successful biliary drainage (Tbili <1.5 mg/dL within 3 months postoperatively), expressed significantly less hepatic PROM1, CK19, and COLLAGEN-1α compared to those with TBili >1.5 (p<0.05).

Conclusions: As compared to WT mice, functional Prom1 KO leads to decreased ductular reactions and fibrogenesis after RRV injury. In human BA, decreased PROM1 is associated with improved liver function, as evidenced by lower total bilirubin levels. Therefore, Prom1 plays an important and evolving role in biliary fibrogenesis.