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-beta and PDGFR alpha signaling pathways in the fate of FAPs. Here, we show that the number of FAPs correlates with TGF-beta levels and with extracellular matrix deposition during regeneration and repair. Interestingly, the expression of PDGFR alpha changed dynamically in the fibroblast lineage after injury. Furthermore, PDGFR alpha-dependent immediate early gene expression changed during regeneration and repair. We also found that TGF-beta signaling reduces PDGFR alpha expression in FAPs, mouse dermal fibroblasts and in two related mesenchymal cell lines. Moreover, TGF-beta promotes myofibroblast differentiation of FAPs but inhibits their adipogenicity. Accordingly, TGF-beta impairs the expression of PDGFR alpha-dependent immediate early genes in a TGFBR1-dependent manner. Finally, pharmacological inhibition of PDGFR alpha activity with AG1296 impaired TGF-beta-induced extracellular matrix remodeling, Smad2 signaling, myofibroblast differentiation and migration of MSCs. Thus, our work establishes a functional cross-talk between TGF-beta and PDGFR alpha signaling pathways that is involved in regulating the biology of FAPs and/or MSCs.