Origin and function of myofibroblasts in kidney fibrosis

Nat Med. 2013 Aug;19(8):1047-53. doi: 10.1038/nm.3218. Epub 2013 Jun 30.

Abstract

Myofibroblasts are associated with organ fibrosis, but their precise origin and functional role remain unknown. We used multiple genetically engineered mice to track, fate map and ablate cells to determine the source and function of myofibroblasts in kidney fibrosis. Through this comprehensive analysis, we identified that the total pool of myofibroblasts is split, with 50% arising from local resident fibroblasts through proliferation. The nonproliferating myofibroblasts derive through differentiation from bone marrow (35%), the endothelial-to-mesenchymal transition program (10%) and the epithelial-to-mesenchymal transition program (5%). Specific deletion of Tgfbr2 in α-smooth muscle actin (αSMA)(+) cells revealed the importance of this pathway in the recruitment of myofibroblasts through differentiation. Using genetic mouse models and a fate-mapping strategy, we determined that vascular pericytes probably do not contribute to the emergence of myofibroblasts or fibrosis. Our data suggest that targeting diverse pathways is required to substantially inhibit the composite accumulation of myofibroblasts in kidney fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actins / metabolism
  • Animals
  • Antigens / metabolism
  • Bone Marrow Cells / pathology
  • Cell Differentiation
  • Cell Proliferation
  • Epithelial-Mesenchymal Transition
  • Female
  • Fibrosis
  • Kidney / metabolism*
  • Kidney / pathology*
  • Kidney Diseases / metabolism*
  • Kidney Diseases / pathology*
  • Male
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Myofibroblasts / metabolism*
  • Myofibroblasts / pathology*
  • Pericytes / metabolism
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteoglycans / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Receptor, Transforming Growth Factor-beta Type II
  • Receptors, Transforming Growth Factor beta / metabolism
  • Signal Transduction

Substances

  • Actins
  • Antigens
  • Proteoglycans
  • Receptors, Transforming Growth Factor beta
  • alpha-smooth muscle actin, mouse
  • chondroitin sulfate proteoglycan 4
  • Receptor, Platelet-Derived Growth Factor beta
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type II