YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury.
Cell Stem Cell
; 25(1): 39-53.e10, 2019 07 03.
Article
em En
| MEDLINE
| ID: mdl-31080135
ABSTRACT
Biliary epithelial cells (BECs) form bile ducts in the liver and are facultative liver stem cells that establish a ductular reaction (DR) to support liver regeneration following injury. Liver damage induces periportal LGR5+ putative liver stem cells that can form BEC-like organoids, suggesting that RSPO-LGR4/5-mediated WNT/ß-catenin activity is important for a DR. We addressed the roles of this and other signaling pathways in a DR by performing a focused CRISPR-based loss-of-function screen in BEC-like organoids, followed by in vivo validation and single-cell RNA sequencing. We found that BECs lack and do not require LGR4/5-mediated WNT/ß-catenin signaling during a DR, whereas YAP and mTORC1 signaling are required for this process. Upregulation of AXIN2 and LGR5 is required in hepatocytes to enable their regenerative capacity in response to injury. Together, these data highlight heterogeneity within the BEC pool, delineate signaling pathways involved in a DR, and clarify the identity and roles of injury-induced periportal LGR5+ cells.
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Bases de dados:
MEDLINE
Assunto principal:
Ductos Biliares
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Proteínas de Ciclo Celular
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Proteínas Adaptadoras de Transdução de Sinal
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Células Epiteliais
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Lesão Pulmonar Aguda
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Células-Tronco Pluripotentes Induzidas
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Cell Stem Cell
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
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