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, Yang, Yi, Heim, Markus, Terracciano, Luigi, Bouwmeester, Antonius, Cong, Feng, Mcallister, Gregory, Hoffman, Gregory, Roma, Guglielmo, Tchorz, Jan, Sigoillot, Frederic and Roska, Botond (2020) YAP, but Not RSPO-LGR4/5, Signaling in Biliary Epithelial Cells Promotes a Ductular Reaction in Response to Liver Injury. Cell Stem Cell, x (x). x-x. ISSN x

Abstract

The liver has an intrinsically high capacity to regenerate, involving several discrete cellular niches. Oval cells in a ductular reaction (DR) transiently expand around the portal vein following damage to support liver regeneration. However, the regulatory mechanisms controlling a DR are poorly understood. Here, we performed a CRISPR loss-of-function (LOF) oval cell expansion screen in liver organoids, hit validation in a DR in vivo model, and oval cell single-cell RNA sequencing (scRNA-Seq) combined with histological analyses rendering a detailed picture of regulatory pathways controlling the DR. Our scRNA-Seq analysis further revealed two distinct clusters of EPCAM+ oval cells and the signalling networks determining their cellular identity. We clarified the role of LGR4/5-mediated Wnt/β-Catenin signaling during a DR, show that AXIN2/LGR5 are essential for hepatocyte dedifferentiation enabling their regenerative potential, and linked hepatocyte-mediated liver regeneration to DR resolution. Our data highlight a spatio-temporal requirement of signalling pathways in controlling regulatory mechanisms of a DR and liver regeneration.

Item Type:	Article
Date Deposited:	14 Aug 2025 00:45
Last Modified:	14 Aug 2025 00:45
URI:	https://oak.novartis.com/id/eprint/35982