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

TitleMacrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease.
Publication TypeJournal Article
Year of Publication2012
AuthorsBoulter L, Govaere O, Bird TG, Radulescu S, Ramachandran P, Pellicoro A, Ridgway RA, Seo SSoo, Spee B, van Rooijen N, Sansom OJ, Iredale JP, Lowell S, Roskams T, Forbes SJ
JournalNat Med
Date Published2012 Apr
KeywordsAdult, Aged, Animals, Antigens, Differentiation, beta Catenin, Biliary Tract, Calcium-Binding Proteins, Cell Communication, Cell Differentiation, Cells, Cultured, Chronic Disease, Creatine Kinase, Ethionine, Female, gamma-Glutamyltransferase, Gene Expression Regulation, Hepatocytes, Humans, Intercellular Signaling Peptides and Proteins, Keratins, Hair-Specific, Liver Diseases, Liver Regeneration, Macrophages, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Nerve Tissue Proteins, Receptors, Notch, RNA, Messenger, Signal Transduction, Stem Cell Niche, Stem Cells, Wnt3A Protein, Young Adult

During chronic injury a population of bipotent hepatic progenitor cells (HPCs) become activated to regenerate both cholangiocytes and hepatocytes. Here we show in human diseased liver and mouse models of the ductular reaction that Notch and Wnt signaling direct specification of HPCs via their interactions with activated myofibroblasts or macrophages. In particular, we found that during biliary regeneration, expression of Jagged 1 (a Notch ligand) by myofibroblasts promoted Notch signaling in HPCs and thus their biliary specification to cholangiocytes. Alternatively, during hepatocyte regeneration, macrophage engulfment of hepatocyte debris induced Wnt3a expression. This resulted in canonical Wnt signaling in nearby HPCs, thus maintaining expression of Numb (a cell fate determinant) within these cells and the promotion of their specification to hepatocytes. By these two pathways adult parenchymal regeneration during chronic liver injury is promoted.

Alternate JournalNat. Med.
PubMed ID22388089
PubMed Central IDPMC3364717
Grant ListG0600033 / / Medical Research Council / United Kingdom
G1000868 / / Medical Research Council / United Kingdom
G1000868(97900) / / Medical Research Council / United Kingdom
MR/J010766/1 / / Medical Research Council / United Kingdom
/ / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom