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

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

Author information

1
Departamento de Biología Celular y Molecular and Center for Aging and Regeneration (CARE-ChileUC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile oicontre@uc.cl ebrandan@bio.puc.cl.
2
Biomedical Research Centre, Department of Medical Genetics and School of Biomedical Engineering, University of British Columbia, V6T 1Z3 Vancouver, BC, Canada.
3
Departamento de Biología Celular y Molecular and Center for Aging and Regeneration (CARE-ChileUC), Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8331150 Santiago, Chile.
4
Faculty of Pharmacy, Minia University, 61519 Minia, Egypt.

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

PMID:
31434718
DOI:
10.1242/jcs.232157

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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