title: Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease.
abstract: 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.
authors.affiliation: Medical Research Council Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Boulter
authors.forename: Olivier
authors.initials: O
authors.lastname: Govaere
authors.forename: Tom G
authors.initials: TG
authors.lastname: Bird
authors.forename: Sorina
authors.initials: S
authors.lastname: Radulescu
authors.forename: Prakash
authors.initials: P
authors.lastname: Ramachandran
authors.forename: Antonella
authors.initials: A
authors.lastname: Pellicoro
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Ridgway
authors.forename: Sang Soo
authors.initials: SS
authors.lastname: Seo
authors.forename: Bart
authors.initials: B
authors.lastname: Spee
authors.forename: Nico
authors.initials: N
authors.lastname: Van Rooijen
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: John P
authors.initials: JP
authors.lastname: Iredale
authors.forename: Sally
authors.initials: S
authors.lastname: Lowell
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Forbes
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002450:Cell Communication / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D002908:Chronic Disease; D003402:Creatine Kinase / Q000378:metabolism; D005001:Ethionine / Q000008:administration & dosage; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D022781:Hepatocytes / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D000072100:Jagged-1 Protein; D053556:Keratin-1; D053564:Keratins, Hair-Specific / Q000235:genetics; D008107:Liver Diseases / Q000473:pathology*; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction / Q000502:physiology*; D055153:Stem Cell Niche / Q000502:physiology; D013234:Stem Cells / Q000502:physiology*; D060509:Wnt3A Protein / Q000378:metabolism*; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics; D005723:gamma-Glutamyltransferase / Q000378:metabolism
chemical_list: D000943:Antigens, Differentiation; C495267:CTNNB1 protein, mouse; D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D053556:Keratin-1; D053564:Keratins, Hair-Specific; C507530:Krt1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C113026:NUMB protein, human; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072099:Serrate-Jagged Proteins; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin; C036763:monocyte-macrophage differentiation antigen; D005723:gamma-Glutamyltransferase; D003402:Creatine Kinase; D005001:Ethionine