Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration
Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration
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DOI：
10.1016/j.stem.2019.04.004
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发表时间：
2019-07-03
期刊：
影响因子：
23.9
通讯作者：
Camargo, Fernando D.
中科院分区：
文献类型：
--
作者：
Pepe-Mooney, Brian J.;Dill, Michael T.;Camargo, Fernando D.
肝脏损伤后可以大量再生，主要的上皮细胞类型，肝细胞和胆管上皮细胞（BEC），在实质再生中发挥着重要作用。除了代谢功能外，BEC 还表现出巨大的可塑性，在某些情况下可以驱动肝脏再生。在这里，我们进行了单细胞 RNA 测序，以检查稳态期间和损伤后的 BEC 和肝细胞异质性。我们没有发现转录定义的类祖细胞 BEC 细胞的证据，而是发现了显着的稳态 BEC 异质性，反映了 YAP 依赖性程序的波动激活。这种转录特征定义了稳态期间的动态细胞状态，并且对损伤高度敏感。 YAP 信号传导由生理胆汁酸 (BA) 诱导，是 BEC 暴露于 BA 后存活所必需的，也是肝细胞在损伤后重编程为胆汁祖细胞所必需的。总之，这些发现揭示了导管上皮内的分子异质性，并揭示了 YAP 作为哺乳动物肝脏中的保护性变阻器和再生调节器。
The liver can substantially regenerate after injury, with both main epithelial cell types, hepatocytes and biliary epithelial cells (BECs), playing important roles in parenchymal regeneration. Beyond metabolic functions, BECs exhibit substantial plasticity and in some contexts can drive hepatic repopulation. Here, we performed single-cell RNA sequencing to examine BEC and hepatocyte heterogeneity during homeostasis and after injury. Instead of evidence for a transcriptionally defined progenitor-like BEC cell, we found significant homeostatic BEC heterogeneity that reflects fluctuating activation of a YAP-dependent program. This transcriptional signature defines a dynamic cellular state during homeostasis and is highly responsive to injury. YAP signaling is induced by physiological bile acids (BAs), required for BEC survival in response to BA exposure, and is necessary for hepatocyte reprogramming into biliary progenitors upon injury. Together, these findings uncover molecular heterogeneity within the ductal epithelium and reveal YAP as a protective rheostat and regenerative regulator in the mammalian liver.