Cross-talk between TGF-β and PDGFRα signaling pathways regulates the fate of stromal fibro-adipogenic progenitors

J Cell Sci. 2019 Oct 9;132(19):jcs232157. doi: 10.1242/jcs.232157.

Abstract

Fibro-adipogenic progenitors (FAPs) are tissue-resident mesenchymal stromal cells (MSCs) required for proper skeletal muscle development, regeneration and maintenance. However, FAPs are also responsible for fibro-fatty scar deposition following chronic damage. We aimed to investigate the role of functional cross-talk between TGF-β and PDGFRα signaling pathways in the fate of FAPs. Here, we show that the number of FAPs correlates with TGF-β levels and with extracellular matrix deposition during regeneration and repair. Interestingly, the expression of PDGFRα changed dynamically in the fibroblast lineage after injury. Furthermore, PDGFRα-dependent immediate early gene expression changed during regeneration and repair. We also found that TGF-β signaling reduces PDGFRα expression in FAPs, mouse dermal fibroblasts and in two related mesenchymal cell lines. Moreover, TGF-β promotes myofibroblast differentiation of FAPs but inhibits their adipogenicity. Accordingly, TGF-β impairs the expression of PDGFRα-dependent immediate early genes in a TGFBR1-dependent manner. Finally, pharmacological inhibition of PDGFRα activity with AG1296 impaired TGF-β-induced extracellular matrix remodeling, Smad2 signaling, myofibroblast differentiation and migration of MSCs. Thus, our work establishes a functional cross-talk between TGF-β and PDGFRα signaling pathways that is involved in regulating the biology of FAPs and/or MSCs.This article has an associated First Person interview with the first author of the paper.

Keywords: Fibroblast; Fibrosis; Mesenchymal progenitors; Myofibroblast; Regeneration; Skeletal muscle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Movement / physiology
  • Enzyme Activation / drug effects
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique, Indirect
  • Male
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / metabolism
  • Real-Time Polymerase Chain Reaction
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Stem Cells / metabolism
  • Transforming Growth Factor beta / metabolism*
  • Tyrphostins / pharmacology

Substances

  • Transforming Growth Factor beta
  • Tyrphostins
  • 6,7-dimethoxy-3-phenylquinoxaline
  • Receptor, Platelet-Derived Growth Factor alpha