Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis.
Lineage tracing demonstrates no evidence of cholangiocyte epithelial-to-mesenchymal transition in murine models of hepatic fibrosis.
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DOI：
10.1002/hep.24206
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发表时间：
2011-05
期刊：
影响因子：
13.5
通讯作者：
Wells, Rebecca G.
中科院分区：
文献类型：
--
作者：
Chu, Andrew S.;Diaz, Rosalyn;Hui, Jia-Ji;Yanger, Kilangsungla;Zong, Yiwei;Alpini, Gianfranco;Stanger, Ben Z.;Wells, Rebecca G.
胆管细胞或其肝祖细胞是否在胆道纤维化过程中经历上皮-间质转化（EMT）成为基质生成肌成纤维细胞是一个重要的持续争议。为了评估EMT在胆道纤维化期间是否活跃，我们使用了Alfp-Cre x Rosa 26-YFP小鼠，其中肝脏的上皮细胞（肝细胞、胆管细胞及其双能祖细胞）被黄色荧光蛋白（YFP）高效遗传标记。从我们的报告菌株分离的原代胆管细胞能够在单独的转化生长因子-β1或与肿瘤坏死因子-α联合处理时进行体外EMT，如采用成纤维细胞形态，E-cadherin的细胞内再定位和α-平滑肌肌动蛋白（α-SMA）的表达所示。为了确定EMT是否在体内发生，我们使用胆管结扎（BDL; 2、4和8周）、四氯化碳（CCl 4，3周）和3，5-二乙氧羰基-1，4-二氢可力丁（DDC; 2和3周）模型在Alfp-Cre x Rosa 26-YFP小鼠中诱导肝纤维化。在任何情况下，我们都没有发现YFP与间充质标志物S100 A4、波形蛋白、α-SMA或前胶原1α2共定位的证据，尽管这些蛋白质在胆管周围区域丰富。在小鼠肝纤维化模型中，肝细胞和胆管细胞不经历EMT。
Whether or not cholangiocytes or their hepatic progenitors undergo an epithelial-to-mesenchymal transition (EMT) to become matrix-producing myofibroblasts during biliary fibrosis is a significant ongoing controversy. To assess whether EMT is active during biliary fibrosis, we used Alfp-Cre x Rosa26-YFP mice, in which the epithelial cells of the liver (hepatocytes, cholangiocytes, and their bipotential progenitors) are heritably labeled at high efficiency with yellow fluorescent protein (YFP). Primary cholangiocytes isolated from our reporter strain were able to undergo EMT in vitro when treated with transforming growth factor-β1 alone or in combination with tumor necrosis factor-α, as indicated by adoption of fibroblastoid morphology, intracellular relocalization of E-cadherin, and expression of α-smooth muscle actin (α-SMA). To determine whether EMT occurs in vivo, we induced liver fibrosis in Alfp-Cre x Rosa26-YFP mice using the bile duct ligation (BDL; 2, 4, and 8 weeks), carbon tetrachloride (CCl4, 3 weeks), and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC; 2 and 3 weeks) models. In no case did we find evidence of co-localization of YFP with the mesenchymal markers S100A4, vimentin, α-SMA, or pro-collagen 1α2, although these proteins were abundant in the peribiliary regions. Hepatocytes and cholangiocytes do not undergo EMT in murine models of hepatic fibrosis.
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