Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration
Name
nihms-1528538.pdf
Description
Accepted version
Size
5.8 MB
Format
Adobe PDF
Checksum (MD5)
3bd963fec9fbb014b7f69ac19949eec8
Author(s)
Pepe-Mooney, Brian J
Dill, Michael T
Alemany, Anna
Ordovas-Montanes, Jose
Matsushita, Yuki
Rao, Anuradha
Sen, Anushna
Miyazaki, Makoto
Anakk, Sayeepriyadarshini
Dawson, Paul A
Date Issued
2019
Journal
Cell Stem Cell
Publisher
Elsevier BV
Version
Author's final manuscript
Abstract
© 2019 Elsevier Inc. 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. The transcriptional landscape of the epithelium in healthy and regenerating murine livers was investigated, revealing a dynamically fluctuating and heterogeneous YAP transcriptional program. Further analysis uncovered YAP signaling dualism: it is essential in biliary epithelial cells for homeostatic maintenance and in hepatocytes for the regenerative response to injury.
MIT Department
Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
Ragon Institute of MGH, MIT and Harvard
Harvard University--MIT Division of Health Sciences and Technology
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
Persistent DSpace Link
DOI of Published Version
10.1016/J.STEM.2019.04.004
https://doi.org/10.1016/J.STEM.2019.04.004
