Genetic lineage tracing defines myofibroblast origin and function in the injured heart

Nat Commun. 2016 Jul 22;7:12260. doi: 10.1038/ncomms12260.

Abstract

Cardiac fibroblasts convert to myofibroblasts with injury to mediate healing after acute myocardial infarction (MI) and to mediate long-standing fibrosis with chronic disease. Myofibroblasts remain a poorly defined cell type in terms of their origins and functional effects in vivo. Here we generate Postn (periostin) gene-targeted mice containing a tamoxifen-inducible Cre for cellular lineage-tracing analysis. This Postn allele identifies essentially all myofibroblasts within the heart and multiple other tissues. Lineage tracing with four additional Cre-expressing mouse lines shows that periostin-expressing myofibroblasts in the heart derive from tissue-resident fibroblasts of the Tcf21 lineage, but not endothelial, immune/myeloid or smooth muscle cells. Deletion of periostin(+) myofibroblasts reduces collagen production and scar formation after MI. Periostin-traced myofibroblasts also revert back to a less-activated state upon injury resolution. Our results define the myofibroblast as a periostin-expressing cell type necessary for adaptive healing and fibrosis in the heart, which arises from Tcf21(+) tissue-resident fibroblasts.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biomarkers / metabolism
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Female
  • Integrases
  • Male
  • Mice
  • Mice, Transgenic
  • Myocardial Infarction / pathology*
  • Myocardium / metabolism
  • Myocardium / pathology*
  • Myofibroblasts / metabolism*
  • Tamoxifen

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers
  • Cell Adhesion Molecules
  • Postn protein, mouse
  • Tcf21 protein, mouse
  • Tamoxifen
  • Cre recombinase
  • Integrases