Prominin‐1‐expressing hepatic progenitor cells induce fibrogenesis in murine cholestatic liver injury. Issue 14 (20th July 2020)

• Record Type: Journal Article
• Authors: Fenlon, Michael; Short, Celia; Xu, Jiabo; Malkoff, Nicolas; Mahdi, Elaa; Hough, Michelle; Glazier, Alison; Lee, Calvin; Asahina, Kinji; Wang, Kasper S.
• Is Part Of: Physiological reports. Volume 8:Issue 14(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-07-20
• Subjects: Biliary atresia -- cell lineage tracing -- cholangiocyte -- cholestasis -- liver fibrosis -- RNA‐seq; Physiology -- Periodicals; 571
• DOI: 10.14814/phy2.14508
• Languages: English
• ISSNs: 2051-817X

Abstract

Abstract: Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin‐1 (Prom1 or CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1 ‐expressing HPCs promote fibrogenesis in cholestatic liver injury. Using Prom1 CreERT2‐nLacZ/+ ;Rosa26 Lsl‐GFP/+ mice, we traced the fate of Prom1 ‐expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Prom1 ‐expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential toward both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1 ‐expressing HPCs gave rise to both PROM1(+) and PROM1(‐) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA‐sequencing analysis of GFP(+) Prom1 ‐expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor‐β pathway activation. When Prom1 ‐expressing cells were ablated with induced Diphtheria toxin in Prom1 CreERT‐nLacZ/+ ;Rosa26 DTA/+ mice, we observed a decrease in ductular reactions and biliary fibrosis typically present in BDL as well as decreased expression of numerous fibrogenic gene markers. Our data indicate that Prom1 ‐expressing HPCs promote biliary fibrosis associated with activation of myofibroblasts in cholestatic liver injury. Abstract : In this study, we demonstrate that during cholestatic liver injury following bile duct ligation that cholangiocytes derived from Prominin‐1‐expressing hepatic progenitor cells promote biliary fibrosis; ablation of Prom1‐expressing cells decreases fibrosis.