YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury
YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury
复制标题
DOI：
10.1016/j.stem.2019.04.005
复制
发表时间：
2019-07-03
期刊：
影响因子：
23.9
通讯作者：
Tchorz, Jan S.
中科院分区：
文献类型：
--
作者：
Planas-Paz, Lara;Sun, Tianliang;Tchorz, Jan S.
胆管上皮细胞（BEC）在肝脏中形成胆管，并且是建立小管反应（DR）以支持损伤后的肝脏再生的兼性肝干细胞。肝损伤诱导门静脉周围LGR 5+推定的肝干细胞，可以形成BEC样类器官，这表明RSPO-LGR 4/5介导的WNT/β-连环蛋白活性对DR很重要。我们通过在BEC样类器官中进行集中的基于CRISPR的功能丧失筛选，然后进行体内验证和单细胞RNA测序，解决了这一信号通路和其他信号通路在DR中的作用。我们发现BEC在DR过程中缺乏并且不需要LGR 4/5介导的WNT/β-连环蛋白信号传导，而雅普和mTORC 1信号传导是这个过程所必需的。在肝细胞中需要上调AXIN 2和LGR 5以使其响应损伤的再生能力成为可能。总之，这些数据突出了BEC池内的异质性，描绘了DR中涉及的信号传导途径，并阐明了损伤诱导的门脉周围LGR 5+细胞的身份和作用。
Biliary epithelial cells (BECs) form bile ducts in the liver and are facultative liver stem cells that establish a ductular reaction (DR) to support liver regeneration following injury. Liver damage induces periportal LGR5+ putative liver stem cells that can form BEC-like organoids, suggesting that RSPO-LGR4/5-mediated WNT/beta-catenin activity is important for a DR. We addressed the roles of this and other signaling pathways in a DR by performing a focused CRISPR-based loss-of-function screen in BEC-like organoids, followed by in vivo validation and single-cell RNA sequencing. We found that BECs lack and do not require LGR4/5-mediated WNT/beta-catenin signaling during a DR, whereas YAP and mTORC1 signaling are required for this process. Upregulation of AXIN2 and LGR5 is required in hepatocytes to enable their regenerative capacity in response to injury. Together, these data highlight heterogeneity within the BEC pool, delineate signaling pathways involved in a DR, and clarify the identity and roles of injury-induced periportal LGR5+ cells.