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Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia.

ABSTRACT: 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. PROM1positive (pos) cells express Collagen-1?1. Subsets of PROM1pos cells coexpress progenitor cell marker CD49f, epithelial marker E-CADHERIN, biliary marker CYTOKERATIN-19, and mesenchymal markers VIMENTIN and alpha-SMOOTH MUSCLE ACTIN (?SMA). Expansion of the PROM1pos cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor-beta (TGF?) signaling. In vitro cotreatment of PROM1-expressing Mat1a-/- hepatic progenitor cells with recombinant human FGF10 and TGF?1 promotes morphologic transformation toward a myofibroblastic cell phenotype with increased expression of myofibroblastic genes Collagen-1?1, Fibronectin, and ?-Sma. Infants with BA demonstrate similar expansion of periportal PROM1pos 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.Expansion of collagen-producing PROM1pos cells within regions of periportal fibrosis is associated with activated FGF and TGF? pathways in both experimental and human BA. PROM1pos cells may therefore play an important role in the biliary fibrosis of BA.

SUBMITTER: Mavila N

PROVIDER: S-EPMC4146699 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia.

Mavila Nirmala N James David D Shivakumar Pranavkumar P Nguyen Marie V MV Utley Sarah S Mak Katrina K Wu Allison A Zhou Shengmei S Wang Larry L Vendyres Christopher C Groff Megan M Asahina Kinji K Wang Kasper S KS

Hepatology (Baltimore, Md.) 20140717 3

<h4>Unlabelled</h4>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 ...[more]

PMID: 24798639

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Project description:BackgroundIntrahepatic biliary fibrosis, as seen with cholestatic liver injuries such as biliary atresia, is mechanistically distinct from fibrosis caused by hepatocyte toxicity. We previously demonstrated the expansion of cells expressing the stem/progenitor cell marker Prominin-1, within regions of developing fibrosis in biliary atresia. Thus, we hypothesized that Prominin-1 expression is biliary fibrosis-specific.MethodsGene expression of Prominin-1 was analyzed in adult mice undergoing either cholestatic bile duct ligation or hepatotoxic carbon tetrachloride administration by quantitative polymerase chair reaction. Lineage tracing of Prominin-1-expressing cells and Collagen-1α-expressing cells was performed after bile duct ligation in Prominin-1cre-ert2-lacz;Gfplsl and Collagen-1αGfp transgenic mice, respectively.ResultsProminin-1 expression increased significantly after bile duct ligation compared with sham (6.6 ± 0.9-fold change at 2 weeks, P < .05) but not with carbon tetrachloride (-0.7 ± 0.5-fold change, not significant). Upregulation of Prominin-1 was observed histologically throughout the liver as early as 5 days after bile duct ligation in Prominin-1cre-ert2-lacz mice by LacZ staining in nonhepatocyte cells. Lineage tracing of Prominin-1-expressing cells labeled prior to bile duct ligation in Prominin-1cre-ert2-lacz;Gfplsl mice, demonstrated increasing colocalization of GREEN FLUORESCENT PROTEIN with biliary marker CYTOKERATIN-19 within ductular reactions up to 5 weeks after bile duct ligation consistent with biliary transdifferentiation. In contrast, rare colocalization of GREEN FLUORESCENT PROTEIN with mesenchymal marker α-SMOOTH MUSCLE ACTIN in Prominin-1cre-ert2-lacz;Gfplsl mice and some colocalization of GREEN FLUORESCENT PROTEIN with PROMININ-1 in Collagen-1αGfp mice, indicate minimal contribution of Prominin-1 progenitor cells to the pool of collagen-producing myofibroblasts.ConclusionDuring biliary fibrosis Prominin-1-expressing progenitor cells transdifferentiate into cells within ductular reactions. This transdifferentiation may promote fibrosis.

Project description:We investigated noninvasive follow-up markers for histologic liver fibrosis and portal hypertension (PH) in patients with biliary atresia after successful portoenterostomy (PE). Among children with bilirubin <20 µmol/L after PE (n = 39), Metavir fibrosis stage was evaluated at PE and in follow-up protocol liver biopsies (n = 83). PH was defined as endoscopically confirmed esophageal varices or thrombocytopenia associated with splenomegaly. The accuracy of liver biochemistry and stiffness in detecting liver fibrosis and PH was analyzed by the area under the receiving operating characteristic curve (AUROC) and multiple regression models. During a median native liver survival of 8.3 years (interquartile range 2.5-10.8 years), cirrhosis (Metavir F4) had developed in 51% of patients and PH in 54% of patients. Cirrhosis was equally common in all age tertiles of 1.2-2.1 years (n = 10/27), 3.9-5.8 years (n = 12/28), and 9.0-14 years (n = 12/28). In the two oldest age tertiles, histologic liver fibrosis had progressed further in patients with PH than without PH (P < 0.001). PH was accurately predicted by the aspartate aminotransferase-to-platelet ratio index (APRI) (cutoff, 0.70; AUROC, 0.92), bile acids (cutoff, 49 µmol/L; AUROC, 0.91), and liver stiffness (cutoff, 16.9 kPa; AUROC, 0.89; P < 0.001 each) across all age tertiles. Liver stiffness was the most accurate predictor of cirrhosis overall (AUROC, 0.82; P < 0.001), whereas bilirubin was >11 µmol/L in the youngest tertile (AUROC, 0.91; P < 0.001), bile acids was >80 µmol/L in the middle tertile (AUROC, 0.81; P = 0.009), and liver stiffness was >24 kPa in the oldest age tertile (AUROC, 0.96; P = 0.002). Conclusion: After successful PE, development of PH associates with progression of liver fibrosis and can be accurately detected by APRI and stiffness. Liver stiffness most accurately identified cirrhosis in older children, whereas biochemical markers of cholestasis closely reflected histologic cirrhosis in younger children.

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Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia.

Publications

Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia.

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