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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia
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Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia

机译：与胆道闭锁纤维化相关的表达prominin-1的细胞的扩增

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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-1α1. 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 (αSMA). Expansion of the PROM1pos 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 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. Conclusion: Expansion of collagen-producing PROM1pos cells within regions of periportal fibrosis is associated with activated FGF and TGFβ pathways in both experimental and human BA. PROM1pos cells may therefore play an important role in the biliary fibrosis of BA.
机译：胆道闭锁（BA）是终末期肝病的最常见原因，也是小儿肝移植的主要指征，它与迅速扩大的门静脉周围胆纤维化区域内的肝内导管反应有关。尽管这种胆汁纤维化的程度是长期无移植存活的负面预测因素，但涉及纤维化的细胞表型尚不十分清楚。使用恒河猴轮状病毒诱导的BA小鼠模型，我们证明了表达推定的干/祖细胞标记物PROMININ-1（PROM1）的细胞群显着扩展，与门静脉周围纤维化区域内的导管反应相邻。 PROM1阳性（阳性）细胞表达胶原1α1。 PROM1pos细胞亚群共表达祖细胞标记CD49f，上皮标记E-CADHERIN，胆汁标记CYTOKERATIN-19和间充质标记VIMENTIN和α-平滑肌肌动蛋白（αSMA）。 PROM1pos细胞群体的扩张与成纤维细胞生长因子（FGF）和转化生长因子-β（TGFβ）信号转导有关。用重组人FGF10和TGFβ1在体外共表达PROM1的Mat1a-/-肝祖细胞可促进向成肌纤维细胞表型的形态转化，并增加成肌纤维蛋白基因Collagen-1α1，纤连蛋白和α-Sma的表达。 BA婴儿在激活的抗十足瘫痪同系物3（SMAD3）信号激活的母亲中表现出与门静脉PROM1pos细胞类似的扩增，并伴随着肝FGF10，FGFR1和FGFR2以及间充质基因SLUG和SNAIL表达的增加。围产期BA型亚型的婴儿比胚胎型亚型的婴儿具有更高的PROM1表达组织水平。结论：在实验性BA和人BA中，在门静脉周围纤维化区域内产生胶原的PROM1pos细胞的扩增与活化的FGF和TGFβ途径有关。因此，PROM1pos细胞可能在BA的胆汁纤维化中起重要作用。

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