Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration
© 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 c...
| Main Authors: | , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Elsevier BV
2021
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| Online Access: | https://hdl.handle.net/1721.1/136180 |
| _version_ | 1811088459500093440 |
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| author | 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 Ono, Noriaki Shalek, Alex K van Oudenaarden, Alexander Camargo, Fernando D |
| author2 | Massachusetts Institute of Technology. Institute for Medical Engineering & Science |
| author_facet | Massachusetts Institute of Technology. Institute for Medical Engineering & Science 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 Ono, Noriaki Shalek, Alex K van Oudenaarden, Alexander Camargo, Fernando D |
| author_sort | Pepe-Mooney, Brian J |
| collection | MIT |
| description | © 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. |
| first_indexed | 2024-09-23T14:02:32Z |
| format | Article |
| id | mit-1721.1/136180 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:02:32Z |
| publishDate | 2021 |
| publisher | Elsevier BV |
| record_format | dspace |
| spelling | mit-1721.1/1361802024-03-20T19:09:35Z 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 Ordovas-Montanes, Jose Matsushita, Yuki Rao, Anuradha Sen, Anushna Miyazaki, Makoto Anakk, Sayeepriyadarshini Dawson, Paul A Ono, Noriaki Shalek, Alex K van Oudenaarden, Alexander Camargo, Fernando D 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 © 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. 2021-10-27T20:34:08Z 2021-10-27T20:34:08Z 2019 2020-07-20T15:42:29Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/136180 en 10.1016/J.STEM.2019.04.004 Cell Stem Cell Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier BV PMC |
| spellingShingle | 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 Ono, Noriaki Shalek, Alex K van Oudenaarden, Alexander Camargo, Fernando D Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration |
| title | Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration |
| title_full | Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration |
| title_fullStr | Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration |
| title_full_unstemmed | Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration |
| title_short | Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration |
| title_sort | single cell analysis of the liver epithelium reveals dynamic heterogeneity and an essential role for yap in homeostasis and regeneration |
| url | https://hdl.handle.net/1721.1/136180 |
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