Elimination of Wnt secretion from hepatic stellate cells impairs hepatocyte proliferation after partial hepatectomy

Abstract

Wnt‐dependent β‐catenin activation contributes to hepatocyte proliferation following 2/3 partial hepatectomy (PH) through regulation of Cyclin‐D1 (Ccnd1) expression, as we have previously shown using β‐catenin or Wnt coreceptors low‐density lipoprotein receptor‐related protein 5/6 conditional knockouts (KO). However, given the redundancy between the 19 mammalian Wnt proteins and various cell sources for Wnt secretion, the precise mechanisms of Wnt signaling in liver regeneration (LR) are not completely understood. Recently, using endothelial cell (EC)‐specific deletion of Wntless (Wls), a cargo receptor required for Wnt secretion, we have reported that sinusoidal ECs secrete Wnts (Wnt2 and Wnt9b) to activate β‐catenin in hepatocytes and enhance Ccnd1 expression, which is indispensable for proliferation of hepatocytes during LR after PH. Alternatively, conditional deletion of Wls in hepatocytes or cholangiocytes did not impact LR, whereas Wls deletion in macrophages only marginally affected LR post‐PH. Here, to investigate the roles for hepatic stellate cell (HSC)‐secreted Wnts in LR, we have characterized HSC‐Wls‐KO, generated by interbreeding Wls‐floxed and Lecithin Retinol Acyl Transferase (LRAT)‐driven Cre (Lrat‐cre) transgenic mice. HSC‐Wls‐KO mice showed no effect on liver weight or β‐catenin‐dependent pericentral gene expression at baseline. However, hepatocyte‐specific Cyclin‐D1 expression was abolished in baseline KO liver, whereas Cyclin‐D1 expression in non‐parenchymal cells was intact in KO liver. After PH, HSC‐Wls‐KO showed diminished protein and mRNA expression of Ccnd1, Ccnb1 and Ccna2 at 24–40 hour (h) post‐PH, but displayed slight increases at 72h, which led to a lower number of BrdU+ hepatocytes at 24 and 40h but a rebound increase by 72h. Interestingly, among several Wnts, HSC‐Wls‐KO livers at 24h post‐PH showed decrease of Wnt3 and Wnt9b mRNA compared to controls, although expression became comparable at 40–72h post‐PH.ConclusionAt baseline, HSCs secrete Wnt ligands essential for Cyclin‐D1 expression in midzonal hepatocytes but not for β‐catenin‐dependent hepatic zonation. Following PH, HSCs‐derived Wnts also contribute to Cyclin‐D1‐dependent hepatocyte proliferation during LR.Support or Funding InformationThe work was supported by NIH grants to S.P.M. (DK62277, DK100287, CA204586). S.P.M. is an Endowed Chair for Experimental Pathology.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.