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 Prom1CreERT2‐nLacZ/+;Rosa26Lsl‐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 Prom1CreERT‐nLacZ/+;Rosa26DTA/+ 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.
Highlights
Progression of liver fibrosis toward cirrhosis is the final common pathway for cholestatic liver injuries, such as biliary atresia (BA), progressive sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC) (Fabris, Spirli, Cadamuro, Fiorotto, & Strazzabosco, 2017)
We previously reported that expression of stem/progenitor cell marker Prominin-1 (Prom1), or CD133, by hepatic progenitor cells (HPCs) is upregulated in BA in regions of evolving intrahepatic biliary fibrosis (Mavila et al, 2014; Nguyen et al, 2017)
We demonstrated that Prom1-expressing HPCs in neonatal mouse livers possess bipotential capacity to give rise to biliary epithelial cells and hepatocytes, whereas in adult livers undergoing cholestatic liver injury, they produce only biliary epithelial cells
Summary
Progression of liver fibrosis toward cirrhosis is the final common pathway for cholestatic liver injuries, such as biliary atresia (BA), progressive sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC) (Fabris, Spirli, Cadamuro, Fiorotto, & Strazzabosco, 2017). Cell lineage tracing studies indicate that hepatic progenitor cells (HPCs) residing in or adjacent to bile ductules within portal triads contribute the majority of newly differentiated cholangiocytes to ductular reactions (Miyajima, Tanaka, & Itoh, 2014; Sato et al, 2019). During early cholestatic injury, activated portal fibroblasts comprise the majority of myofibroblasts responsible for production of type I Collagen (Iwaisako et al, 2014) Associated with these myofibroblasts are HPCs and ductular reactions, which promote liver fibrosis in part via the conversion of latent pro-fibrogenic Transforming Growth Factor-β (TGF-β) through cholangiocyte expression of Integrins, a large family of transmembrane heterodimers (Iwaisako et al, 2014; Peng et al, 2016). Using transgenic mice for lineage tracing, transcriptomic, and loss-of-function analyses, we provide further evidence that PROM1 is integral to liver fibrogenesis during cholestatic liver injury
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