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

Nat Med. 2012 Mar 4;18(4):572-9. doi: 10.1038/nm.2667.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Antigens, Differentiation / metabolism
  • Biliary Tract / metabolism
  • Biliary Tract / pathology
  • Biliary Tract / physiopathology
  • Calcium-Binding Proteins / metabolism
  • Cell Communication / genetics
  • Cell Communication / physiology
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cells, Cultured
  • Chronic Disease
  • Creatine Kinase / metabolism
  • Ethionine / administration & dosage
  • Female
  • Gene Expression Regulation / physiology
  • Hepatocytes / physiology
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Jagged-1 Protein
  • Keratin-1
  • Keratins, Hair-Specific / genetics
  • Liver Diseases / pathology*
  • Liver Regeneration / genetics
  • Liver Regeneration / physiology
  • Macrophages / metabolism*
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Nerve Tissue Proteins / metabolism
  • RNA, Messenger / metabolism
  • Receptors, Notch / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction / physiology*
  • Stem Cell Niche / physiology
  • Stem Cells / physiology*
  • Wnt3A Protein / metabolism*
  • Young Adult
  • beta Catenin / genetics
  • gamma-Glutamyltransferase / metabolism

Substances

  • Antigens, Differentiation
  • CTNNB1 protein, mouse
  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Keratin-1
  • Keratins, Hair-Specific
  • Krt1 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Numb protein, human
  • RNA, Messenger
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • Wnt3A Protein
  • Wnt3a protein, mouse
  • beta Catenin
  • monocyte-macrophage differentiation antigen
  • gamma-Glutamyltransferase
  • Creatine Kinase
  • Ethionine