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Cell Stem Cell. 2019 Jul 3;25(1):39-53.e10. doi: 10.1016/j.stem.2019.04.005. Epub 2019 May 9.

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

Author information

1
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland.
2
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Cambridge, MA, USA.
3
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland; Hospital Aleman, Buenos Aires, Argentina.
4
Institute for Pathology, University Hospital Basel, Basel, Switzerland.
5
Novartis Institutes for Biomedical Research, Novartis Pharma AG, East Hanover, NJ, USA.
6
Novartis Institutes for BioMedical Research, Novartis Pharma AG, Basel, Switzerland. Electronic address: jan.tchorz@novartis.com.

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/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.

KEYWORDS:

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

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

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