M1-Polarized Macrophages Promote Self-Renewing Phenotype of Hepatic Progenitor Cells with Jagged1-Notch Signalling Involved: Relevance in Primary Sclerosing Cholangitis

The immunologic interaction between parenchyma cells and encircling inflammatory cells is thought to be the most important mechanism of biliary damage and repair in primary sclerosing cholangitis (PSC). Monocytes/macrophages as master regulators of hepatic inflammation have been demonstrated to contribute to PSC pathogenesis. Macrophages coordinate with liver regeneration, and multiple phenotypes have been identified with diverse expressions of surface proteins and cytokine productions. We analyzed the expression of Notch ligand Jagged1 in polarized macrophages and investigated the relevance of Notch signalling activation in liver regeneration. M1 or M2 macrophages were generated from mouse bone marrow-derived macrophages (BMDMs) by classical or alternative activation, respectively. Then, the expression levels of Jagged1 (Jag1) of each phenotype were measured. The effects of polarized BMDMs on the expression of hepatic progenitor cell- (HPC-) specific markers and hairy and enhancer of split-1 (HES1) in HPCs in coculture were also analyzed. Monocyte-macrophage and Notch signalling-associated gene signatures were evaluated in the GEO database (access ID: GSE61260) by gene set enrichment analysis (GSEA). M1 macrophages were found associated with elevated Jag1 expression, which increased the fraction of HPC with self-renewing phenotypes (CD326