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Expansion of prominin‐1‐expressing cells in association with fibrosis of biliary atresia
Author(s) -
Mavila Nirmala,
James David,
Shivakumar Pranavkumar,
Nguyen Marie V.,
Utley Sarah,
Mak Katrina,
Wu Allison,
Zhou Shengmei,
Wang Larry,
Vendyres Christopher,
Groff Megan,
Asahina Kinji,
Wang Kasper S.
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27203
Subject(s) - biology , biliary atresia , progenitor cell , population , pathology , fibrosis , cancer research , immunology , transplantation , stem cell , liver transplantation , microbiology and biotechnology , medicine , environmental health
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‐1α1 . 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 (αSMA). Expansion of the PROM1 pos cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor‐beta (TGFβ) signaling. In vitro cotreatment of PROM1‐expressing Mat1a −/− hepatic progenitor cells with recombinant human FGF10 and TGFβ1 promotes morphologic transformation toward a myofibroblastic cell phenotype with increased expression of myofibroblastic genes Collagen‐1α1 , Fibronectin , and α‐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 collagen‐producing PROM1 pos cells within regions of periportal fibrosis is associated with activated FGF and TGFβ pathways in both experimental and human BA. PROM1 pos cells may therefore play an important role in the biliary fibrosis of BA. (H epatology 2014;60:941–953)