YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury.

Acute Lung Injury / metabolism Adaptor Proteins, Signal Transducing / genetics Animals Axin Protein / genetics Bile Ducts / pathology Cell Cycle Proteins / genetics Cells, Cultured Clustered Regularly Interspaced Short Palindromic Repeats Disease Models, Animal Epithelial Cells / physiology Humans Induced Pluripotent Stem Cells / physiology Liver Regeneration Male Mice Mice, Inbred C57BL Pyridines / toxicity Receptors, G-Protein-Coupled / genetics Thrombospondins / genetics Wnt Signaling Pathway YAP-Signaling Proteins

CRISPR screen LGR5 YAP ductular reaction hepatic progenitor cell liver organoids liver stem cells oval cell regeneration single-cell RNA sequencing

Journal

Cell stem cell

ISSN: 1875-9777

Titre abrégé: Cell Stem Cell

Pays: United States

ID NLM: 101311472

Informations de publication

Date de publication:
03 07 2019

Historique:

received: 01 06 2018

revised: 29 01 2019

accepted: 04 04 2019

pubmed: 14 5 2019

medline: 22 8 2020

entrez: 14 5 2019

Statut: ppublish

Résumé

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/β-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/β-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.

Identifiants

DOI: 10.1016/j.stem.2019.04.005 PMID: 31080135

pubmed: 31080135

pii: S1934-5909(19)30154-7

doi: 10.1016/j.stem.2019.04.005

pii:

doi:

Substances chimiques

3,5-diethoxycarbonyl-1,4-dihydrocollidine 0

Adaptor Proteins, Signal Transducing 0

Axin Protein 0

Axin2 protein, mouse 0

Cell Cycle Proteins 0

LGR4 protein, mouse 0

Lgr5 protein, mouse 0

Pyridines 0

RSPO1 protein, mouse 0

Receptors, G-Protein-Coupled 0

Thrombospondins 0

YAP-Signaling Proteins 0

Yap1 protein, mouse 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

39-53.e10

Commentaires et corrections

Type : CommentIn