Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease

Abstract

During chronic injury, regeneration of the adult liver becomes impaired. In this context bipotent Hepatic Progenitor Cells (HPCs) become activated and can regenerate both cholangiocytes and hepatocytes. Notch and Wnt signalling during hepatic ontogeny are described, but their roles in HPC mediated liver regeneration are unclear. Here we show in human diseased liver and murine models of the ductular reaction with biliary and hepatocyte regeneration that Notch and Wnt signalling direct HPC specification within the activated myofibroblasts and macrophages HPC niche. During biliary regeneration, Numb is downregulated in HPCs, Jagged1 promotes biliary specification within HPCs. During hepatocyte regeneration, macrophage derived canonical Wnt signalling maintains Numb within HPCs, and Notch signalling is reduced promoting hepatocyte specification. This dominant Wnt state is stimulated through engulfment of hepatocyte debris by niche macrophages and can directly influence the HPCs. Macrophage Wnt3a expression in turn facilitates hepatocyte regeneration – thus exemplifying a novel positive feedback mechanism in adult parenchymal regeneration.

Identification of a novel alpha‐fetoprotein‐expressing cell population induced by the Jagged1/Notch2 signal in murine fibrotic liver

“…Consistently, mutations in Jagged1 or its major receptor gene Notch2 lead to Alagille syndrome in humans, which is characterized by abnormal formation of the ductal network, causing jaundice 35. In addition to such a fundamental role in fetal liver development, several recent studies have indicated another functional role of Notch signaling in ductular hyperplasia (so‐called pseudoductal reaction) induced by feeding of a DDC diet and the biliary type of liver injury 36, 37. In contrast to those studies, the results of the present study showed that the extent of ductular cell proliferation was not altered by Jagged1 deletion in CCl 4 ‐induced fibrotic liver tissue (Fig.…”

“…In the previous studies, the contribution of Notch signaling to the pseudoductal reaction was suggested by using gamma secretase inhibitors and mice either overexpressing NICD1 or lacking the Notch target molecule Hes1 36, 37, 38. Therefore, it is unknown which Notch ligand(s) plays a central role in DDC diet‐induced ductular hyperplasia.…”

Cellular and molecular mechanisms in liver fibrogenesis

“…Experimental studies from ethanol-induced chronic injury in rodents and clinical data from patients affected by alcoholic liver disease (ALD), chronic HCV infection or NAFLD indicate that oxidative stress-mediated injury can result in the development of circulating IgG antibodies directed against epitopes derived from protein modified by ROS or other intermediates. Titre of these antibodies correlate with disease severity and, as proposed for either ALD or NAFLD patients, may serve as a prognostic predictor of progression of CLD to advanced fibrosis [22].…”

Identifying Molecular Factors That Contribute to Resolution of Liver Fibrosis

“…5 In the longer term and associated with functional recovery architectural restoration is required with a normal organ structure and repopulation with non-pathologic cell lineages (and phenotypes). 6 A crucial finding in rodent models of advanced fibrosis is that the persistent scar tissue contains not only fibrillar collagen, but is also rich in elastin (a matrix protein only susceptible to degradation by specific elastases such as MMP12). Additionally, scar tissue contains monocyte-derived macrophages, which are associated with fibrogenesis.…”

“…9,10 Associated with the onset of fibrosis resolution, this same macrophage population undergoes a phenotypic switch in situ, expressing markers that define a distinct phenotype and up-regulate the expression of matrix-degrading enzymes (and survival and proliferative signals for hepatocytes and hepatic progenitor cells) after ingestion of debris. 6,10 Against this background, the work by Yang et al 4 provides another crucial insight to the molecular regulators of fibrosis resolution. As identified by the authors, vascular endothelial growth factor (VEGF) has previously been found to play a role in fibrogenesis via a proinflammatory effect acting primarily on endothelial cells.…”