近日，美国波士顿儿童医院 的Fernando D. Camargo研究组，报道了肝上皮细胞的单细胞测序分析结果，揭示了细胞的动态异质性以及YAP信号通路在肝脏内稳态和再生中的关键性作用。2019年7月3日出版的国际知名学术期刊《细胞—干细胞》发表了这一成果。

研究人员进行了单细胞RNA测序，以检测稳态中和损伤后的BEC与肝细胞的异质性。研究人员没有找到由转录组定义的、与前体细胞类似的BEC细胞存在，而是发现了明显的BEC稳态异质性，这反映了YAP信号通路的波动性激活。这一转录组特征揭示了稳态中细胞状态的异质性并且这种状态对损伤能够高度响应。YAP信号是由生理胆汁酸(BA)引起的，这对BEC暴露在BA后的存活是所需的，也是肝细胞在损伤后重新编程为胆管前体细胞所必需的。总之，这些发现揭示了胆管上皮细胞的分子异质性，并揭示了YAP信号在哺乳动物肝脏中扮演的保护性和再生性调节者的作用。

据介绍，肝损伤后可大量再生，作为两类主要的上皮细胞类型，肝细胞和胆管上皮细胞(BEC)在肝实质再生中起到重要作用。除了代谢功能外，BEC还表现出明显的可塑性，在某些情况下能促进肝脏的再生。

附：英文原文

Title: Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration

Author: Brian J. Pepe-Mooney, Michael T. Dill, Anna Alemany, Jose Ordovas-Montanes, Yuki Matsushita, Anuradha Rao, Anushna Sen, Makoto Miyazaki, Sayeepriyadarshini Anakk, Paul A. Dawson, Noriaki Ono, Alex K. Shalek, Alexander van Oudenaarden, Fernando D. Camargo

Issue&Volume: May 09, 2019

Abstract: 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.

DOI: https://doi.org/10.1016/j.stem.2019.04.004

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(19)30153-5