Open AccessThe cross-talk between TGF-β and PDGFRα signaling pathways regulates stromal fibro/adipogenic progenitors’ fate
Author(s) -
Osvaldo Contreras,
Meilyn Cruz-Soca,
Marine Théret,
H. S. Soliman,
Lin Tung,
Elena Groppa,
Fábio Rossi,
Enrique Brandan
Publication year - 2019
Publication title -
journal of cell science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.384
H-Index - 278
eISSN - 1477-9137
pISSN - 0021-9533
DOI - 10.1242/jcs.232157
Subject(s) - biology , adipogenesis , myofibroblast , microbiology and biotechnology , mesenchymal stem cell , stromal cell , extracellular matrix , progenitor cell , signal transduction , platelet derived growth factor receptor , regeneration (biology) , cancer research , growth factor , stem cell , fibrosis , receptor , medicine , genetics
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 study a functional cross-talk between TGF-β and PDGFRα signaling pathways in FAPs’ fate. 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 stromal/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/fibroblast 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 TGF-BR1-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/MSCs.