Notch Signaling Coordinates Progenitor Cell-Mediated Biliary Regeneration Following Partial Hepatectomy.
Notch Signaling Coordinates Progenitor Cell-Mediated Biliary Regeneration Following Partial Hepatectomy.
复制标题
缺口信号传导部分肝切除术后祖细胞介导的胆汁再生。
DOI：
10.1038/srep22754
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发表时间：
2016-03-08
影响因子：
4.6
通讯作者：
Guo C
中科院分区：
文献类型：
--
作者：
Lu J;Zhou Y;Hu T;Zhang H;Shen M;Cheng P;Dai W;Wang F;Chen K;Zhang Y;Wang C;Li J;Zheng Y;Yang J;Zhu R;Wang J;Lu W;Zhang H;Wang J;Xia Y;De Assuncao TM;Jalan-Sakrikar N;Huebert RC;Bin Zhou;Guo C
异常的转录调控有助于先天性和成人形式的肝病的发病机制。虽然转录因子RBPJ是必不可少的肝脏形态发生和胆管发育，其在肝祖细胞（HPC）的分化的具体功能尚未调查，并很少有人知道它在成人肝再生的作用。HPC是双能肝干细胞，其可以在体外自我复制并分化为肝细胞或胆管细胞。HPC被认为在肝再生和修复反应中起重要作用。虽然肝细胞和胆管细胞隔室的协调再增殖对再生后肝脏的结构和功能至关重要，但协调胆道再生的机制仍有待深入研究。在这里，我们利用复杂的遗传操作，以驱动肝脏特异性删除的Rbpj基因与谱系追踪技术，以描绘精确的功能RBPJ在胆道发展和肝切除术后的HPC相关的胆道再生。此外，我们证明，RBPJ促进HPC分化向胆管细胞在体外和阻断肝细胞分化的机制，涉及Hippo-Notch串扰。总之，这项研究表明，Notch-RBPJ信号轴通过协调HPC的命运决定来严格调节胆汁再生，并阐明了所涉及的分子机制。
Aberrant transcriptional regulation contributes to the pathogenesis of both congenital and adult forms of liver disease. Although the transcription factor RBPJ is essential for liver morphogenesis and biliary development, its specific function in the differentiation of hepatic progenitor cells (HPC) has not been investigated, and little is known about its role in adult liver regeneration. HPCs are bipotent liver stem cells that can self-replicate and differentiate into hepatocytes or cholangiocytes in vitro. HPCs are thought to play an important role in liver regeneration and repair responses. While the coordinated repopulation of both hepatocyte and cholangiocyte compartment is pivotal to the structure and function of the liver after regeneration, the mechanisms coordinating biliary regeneration remain vastly understudied. Here, we utilized complex genetic manipulations to drive liver-specific deletion of the Rbpj gene in conjunction with lineage tracing techniques to delineate the precise functions of RBPJ during biliary development and HPC-associated biliary regeneration after hepatectomy. Furthermore, we demonstrate that RBPJ promotes HPC differentiation toward cholangiocytes in vitro and blocks hepatocyte differentiation through mechanisms involving Hippo-Notch crosstalk. Overall, this study demonstrates that the Notch-RBPJ signaling axis critically regulates biliary regeneration by coordinating the fate decision of HPC and clarifies the molecular mechanisms involved.