Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia.
Expansion of prominin-1-expressing cells in association with fibrosis of biliary atresia.
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DOI：
10.1002/hep.27203
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发表时间：
2014-09
期刊：
影响因子：
13.5
通讯作者：
Wang, Kasper S.
中科院分区：
文献类型：
--
作者：
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.
胆道闭锁（BA）是终末期肝病的最常见原因，也是儿科肝移植的主要适应症，与快速扩张的门静脉周围胆道纤维化区域内的肝内胆管反应相关。虽然这种胆道纤维化的程度是长期无移植存活的负面预测因素，但纤维化中涉及的细胞表型尚未得到很好的确定。使用恒河猴轮状病毒（RRV）诱导的BA小鼠模型，我们证明了显著扩增的细胞群表达推定的干/祖细胞标志物PROMININ-1（PROM 1）附近的小管反应区域内的门静脉周围纤维化。PROM 1阳性（阳性）细胞表达胶原蛋白-1 α1。PROM 1 pos细胞亚群共表达祖细胞标志物CD 49 f、上皮标志物E-CADHERIN、胆汁标志物CYTOKERATIN-19和间充质标志物波形蛋白和α-平滑肌肌动蛋白。PROM 1 pos细胞群的扩增与成纤维细胞生长因子（FGF）和转化生长因子-β（TGFβ）信号传导的激活相关。在体外用重组人FGF 10和TGFβ1共处理表达PROM 1的Mat 1a −/−肝祖细胞可促进向肌纤维母细胞表型的形态转化，并增加肌纤维母细胞基因胶原蛋白-1 α1、纤连蛋白和α-平滑肌肌动蛋白的表达。患有BA的婴儿表现出门静脉周围PROM 1 pos细胞的类似扩增，其具有激活的SMAD 3信号传导，与FGF 10、FGFR 1和FGFR 2以及间充质基因SLUG和SNAIL的肝表达增加相关。具有围产期BA亚型的婴儿比具有胚胎亚型的婴儿具有更高的组织水平的PROM 1表达。在实验和人类BA中，门静脉周围纤维化区域内产生胶原的PROM 1 pos细胞的扩增与激活的FGF和TGFβ途径相关。因此，PROM 1 pos细胞可能在BA的胆管纤维化中起重要作用。
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. While 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 (RRV)-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 co-express progenitor cell marker CD49f, epithelial marker E-CADHERIN, biliary marker CYTOKERATIN-19, and mesenchymal markers VIMENTIN and α-SMOOTH MUSCLE ACTIN. Expansion of the PROM1pos cell population is associated with activation of Fibroblast Growth Factor (FGF) and Transforming Growth Factor-β (TGFβ) signaling. In vitro co-treatment 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–Smooth muscle actin. Infants with BA demonstrate similar expansion of periportal PROM1pos cells with activated 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 the 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.
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