Planas Paz, Lara, Pikiolek, Monika, Cochran, Nadire, Orsini, Vanessa, Bergling, Sebastian, Neri, Marilisa, Schuierer, Sven, Yang, Zinger, Cobos, Carlos Manuel, Muhic, Jasna, Hoppe, Philipp, Alford, John, Russ, Carsten, Reece-Hoyes, John, Calabrese, Diego, Cuttat-Theurillat, Rachel, Waldt, Annick, Nigsch, Florian, Gubser Keller, Caroline, Nicholson, Thomas, Mao, Xiaohong, Heim, Markus, Terracciano, Luigi, Bouwmeester, Antonius, Mcallister, Gregory, Hoffman, Gregory, Roma, Guglielmo and Tchorz, Jan (2019) 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. ISSN 1875-9777

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.

Item Type:	Article
Keywords:	Acute Lung Injury Adaptor Proteins, Signal Transducing Animals Axin Protein Bile Ducts Cell Cycle Proteins Cells, Cultured Clustered Regularly Interspaced Short Palindromic Repeats Disease Models, Animal Epithelial Cells Humans Induced Pluripotent Stem Cells Liver Regeneration Male Mice Mice, Inbred C57BL Pyridines Receptors, G-Protein-Coupled Thrombospondins Wnt Signaling Pathway YAP-Signaling Proteins
Date Deposited:	14 Aug 2025 00:45
Last Modified:	14 Aug 2025 00:45
URI:	https://oak.novartis.com/id/eprint/32982