GSE157674
Fibro-Adipogenic muscle Progenitors (FAP) and myogenic progenitors (MPs) display a distinct miRNA expression profile that is modulated in response to TGFß1
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 TGFß1 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 TGFß1-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 TGFß1 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/TGFß axis, opening new avenues for the treatment of DMD. Overall design: Small RNA-seq of FAPs and MPs from three muscle biopsies treated or not by TGFß1 was performed and showed that FAPs and MPs expressed very different subsets of miRNAs. A subset of 59 miRNAs efficiently discriminated FAPs- and MPs-derived samples. Moreover, additional miRNAs were differentially regulated by TGFß1, pointing out a specific miRNome modulation in the 2 muscle cell progenitors during differentiation. FAPs and MPs from three healthy skeletal muscles were treated or not with 5 ng/mL TGFß1 for 48h, total RNA was purified and subjected to Small RNA-seq, for a total of 12 distinct samples