Cross-talk between TGF-β and PDGFRα signaling pathways regulates the fate of stromal fibro-adipogenic progenitors.
Animals
Cell Differentiation
/ physiology
Cell Movement
/ physiology
Enzyme Activation
/ drug effects
Fibroblasts
/ cytology
Flow Cytometry
Fluorescent Antibody Technique, Indirect
Male
Mesenchymal Stem Cells
/ cytology
Mice
Mice, Inbred C57BL
Muscle, Skeletal
/ cytology
Real-Time Polymerase Chain Reaction
Receptor, Platelet-Derived Growth Factor alpha
/ metabolism
Signal Transduction
/ drug effects
Stem Cells
/ metabolism
Transforming Growth Factor beta
/ metabolism
Tyrphostins
/ pharmacology
Fibroblast
Fibrosis
Mesenchymal progenitors
Myofibroblast
Regeneration
Skeletal muscle
Journal
Journal of cell science
ISSN: 1477-9137
Titre abrégé: J Cell Sci
Pays: England
ID NLM: 0052457
Informations de publication
Date de publication:
09 10 2019
09 10 2019
Historique:
received:
21
03
2019
accepted:
12
08
2019
pubmed:
23
8
2019
medline:
21
7
2020
entrez:
23
8
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31434718
pii: jcs.232157
doi: 10.1242/jcs.232157
pii:
doi:
Substances chimiques
Transforming Growth Factor beta
0
Tyrphostins
0
6,7-dimethoxy-3-phenylquinoxaline
146535-11-7
Receptor, Platelet-Derived Growth Factor alpha
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : CIHR
ID : FDN-159908
Pays : Canada
Informations de copyright
© 2019. Published by The Company of Biologists Ltd.
Déclaration de conflit d'intérêts
Competing interestsThe authors declare no competing or financial interests.