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

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

doi:10.1016/j.stem.2019.04.004

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

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

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

164 Citaten (Scopus)

Samenvatting

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.

Originele taal-2	Engels
Pagina's (van-tot)	23-38.e8
Tijdschrift	Cell Stem Cell
Volume	25
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1016/j.stem.2019.04.004
Status	Gepubliceerd - 03 jul. 2019

Toegang tot document

10.1016/j.stem.2019.04.004

Citeer dit

Pepe-Mooney, B. J., Dill, M. T., Alemany, A., Ordovas-Montanes, J., Matsushita, Y., Rao, A., Sen, A., Miyazaki, M., Anakk, S., Dawson, P. A., Ono, N., Shalek, A. K., van Oudenaarden, A., & Camargo, F. D. (2019). Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration. Cell Stem Cell, 25(1), 23-38.e8. https://doi.org/10.1016/j.stem.2019.04.004

@article{693f33e04182406bafa4773187a91a11,

title = "Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration",

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.",

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

year = "2019",

month = jul,

day = "3",

doi = "10.1016/j.stem.2019.04.004",

language = "English",

volume = "25",

pages = "23--38.e8",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "1",

}

Pepe-Mooney, BJ, Dill, MT, Alemany, A, Ordovas-Montanes, J, Matsushita, Y, Rao, A, Sen, A, Miyazaki, M, Anakk, S, Dawson, PA, Ono, N, Shalek, AK, van Oudenaarden, A & Camargo, FD 2019, 'Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration', Cell Stem Cell, vol. 25, nr. 1, blz. 23-38.e8. https://doi.org/10.1016/j.stem.2019.04.004

Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration. / Pepe-Mooney, Brian J; Dill, Michael T; Alemany, Anna et al.
In: Cell Stem Cell, Vol. 25, Nr. 1, 03.07.2019, blz. 23-38.e8.

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

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

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.

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.

U2 - 10.1016/j.stem.2019.04.004

DO - 10.1016/j.stem.2019.04.004

M3 - Article

C2 - 31080134

SN - 1934-5909

VL - 25

SP - 23-38.e8

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 1

ER -

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

Samenvatting

Toegang tot document

Vingerafdruk

Citeer dit