The FibromiR miR-214-3p Is Upregulated in Duchenne Muscular Dystrophy and Promotes Differentiation of Human Fibro-Adipogenic Muscle Progenitors.
Adipocytes
/ metabolism
Adipogenesis
/ genetics
Adolescent
Adult
Base Sequence
Cell Differentiation
Child
Female
Fibroblast Growth Factor 2
/ genetics
Fibrosis
Gene Expression Profiling
Gene Expression Regulation
Humans
Male
MicroRNAs
/ genetics
Middle Aged
Muscle Development
/ genetics
Muscle, Skeletal
/ metabolism
Muscular Dystrophy, Duchenne
/ genetics
Myofibroblasts
/ metabolism
Receptor, Fibroblast Growth Factor, Type 1
/ genetics
Signal Transduction
Stem Cells
/ metabolism
Transforming Growth Factor beta1
/ genetics
Duchenne muscular dystrophy (DMD)
FGFR1
fibro-adipogenic progenitor (FAP)
fibrosis
microRNA (miRNA)
transforming growth factor beta (TGFβ)
Journal
Cells
ISSN: 2073-4409
Titre abrégé: Cells
Pays: Switzerland
ID NLM: 101600052
Informations de publication
Date de publication:
20 07 2021
20 07 2021
Historique:
received:
01
06
2021
revised:
06
07
2021
accepted:
15
07
2021
entrez:
7
8
2021
pubmed:
8
8
2021
medline:
28
10
2021
Statut:
epublish
Résumé
Fibrosis is a deleterious invasion of tissues associated with many pathological conditions, such as Duchenne muscular dystrophy (DMD) for which no cure is at present available for its prevention or its treatment. Fibro-adipogenic progenitors (FAPs) are resident cells in the human skeletal muscle and can differentiate into myofibroblasts, which represent the key cell population responsible for fibrosis. In this study, we delineated the pool of microRNAs (miRNAs) that are specifically modulated by TGFβ1 in FAPs versus myogenic progenitors (MPs) by a global miRNome analysis. A subset of candidates, including several "FibromiRs", was found differentially expressed between FAPs and MPs and was also deregulated in DMD versus healthy biopsies. Among them, the expression of the TGFβ1-induced miR-199a~214 cluster was strongly correlated with the fibrotic score in DMD biopsies. Loss-of-function experiments in FAPs indicated that a miR-214-3p inhibitor efficiently blocked expression of fibrogenic markers in both basal conditions and following TGFβ1 stimulation. We found that FGFR1 is a functional target of miR-214-3p, preventing the signaling of the anti-fibrotic FGF2 pathway during FAP fibrogenesis. Overall, our work demonstrates that the « FibromiR » miR-214-3p is a key activator of FAP fibrogenesis by modulating the FGF2/FGFR1/TGFβ axis, opening new avenues for the treatment of DMD.
Identifiants
pubmed: 34360002
pii: cells10071832
doi: 10.3390/cells10071832
pmc: PMC8303294
pii:
doi:
Substances chimiques
MIRN214 microRNA, human
0
MicroRNAs
0
TGFB1 protein, human
0
Transforming Growth Factor beta1
0
Fibroblast Growth Factor 2
103107-01-3
FGFR1 protein, human
EC 2.7.10.1
Receptor, Fibroblast Growth Factor, Type 1
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 : Association Française contre les Myopathies
ID : 17708
Organisme : Agence Nationale de la Recherche
ID : ANR-PRCI-18-CE92-0009-01
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