TY - JOUR
T1 - Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration
AU - Pepe-Mooney, Brian J.
AU - Dill, Michael T.
AU - Alemany, Anna
AU - Ordovas-Montanes, Jose
AU - Matsushita, Yuki
AU - Rao, Anuradha
AU - Sen, Anushna
AU - Miyazaki, Makoto
AU - Anakk, Sayeepriyadarshini
AU - Dawson, Paul A.
AU - Ono, Noriaki
AU - Shalek, Alex K.
AU - van Oudenaarden, Alexander
AU - Camargo, Fernando D.
N1 - Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/7/3
Y1 - 2019/7/3
N2 - 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.
AB - 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.
KW - YAP signaling
KW - bile acids
KW - biliary epithelial cells
KW - cellular plasticity
KW - cholangiocytes
KW - hepatocytes
KW - liver biology
KW - liver progenitor cells
KW - regeneration
KW - single-cell RNA sequencing
UR - http://www.scopus.com/inward/record.url?scp=85067229796&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067229796&partnerID=8YFLogxK
U2 - 10.1016/j.stem.2019.04.004
DO - 10.1016/j.stem.2019.04.004
M3 - Article
C2 - 31080134
AN - SCOPUS:85067229796
SN - 1934-5909
VL - 25
SP - 23-38.e8
JO - Cell Stem Cell
JF - Cell Stem Cell
IS - 1
ER -