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.
Footnotes
Competing interests
The authors declare no competing or financial interests.
Author contributions
Conceptualization: O.C., E.B.; Methodology: O.C., M.C.-S., M.T., H.S., L.W.T.; Software: O.C., H.S., L.W.T., E.G.; Validation: O.C., M.C.-S., M.T., H.S., L.W.T., E.G., F.M.R., E.B.; Formal analysis: O.C., M.C.-S., E.B.; Investigation: O.C., M.C.-S., M.T., H.S., L.W.T., F.M.R.; Resources: O.C., F.M.R., E.B.; Data curation: O.C., M.C.-S., E.B.; Writing - original draft: O.C.; Writing - review & editing: O.C., M.T., H.S., E.G., F.M.R., E.B.; Visualization: O.C., M.C.-S., M.T., H.S., L.W.T., F.M.R., E.B.; Supervision: O.C., F.M.R., E.B.; Project administration: O.C., E.B.; Funding acquisition: O.C., E.B., F.M.R.
Funding
Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grant 1190144 and Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) grant AFB170005 to E.B.; CONICYT Beca de Doctorado Nacional Folio 21140378 to O.C.; CONICYT Beca de Doctorado Nacional Folio 21170735 to M.C.-S.; and Canadian Institutes of Health Research (CIHR) grant FDN-159908 to F.M.R. supported this work. The funding agencies had no role in the design of the study, data collection, analysis, the decision to publish or preparation of the manuscript.
Supplementary information
Supplementary information available online at http://jcs.biologists.org/lookup/doi/10.1242/jcs.232157.supplemental
- Received March 21, 2019.
- Accepted August 12, 2019.
- © 2019. Published by The Company of Biologists Ltd