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Crosstalk between macrophages and fibro-adipogenic progenitors during muscle regeneration

ABSTRACT: The purpose of this study is to investigate how immune cells (macrophages) are closely linked with fibro-adipogenic progenitors (FAPs) during recovery processe. We report that the depletion of Mrc1+ (gene encoding CD206) M2-like macrophages promoted the recovery of muscle after injury. A total RNA sequence analysis of whole muscle or isolated FAPs revealed that the depletion of Mrc1+ M2-like macrophages resulted in the activation of FAPs. Activated FAPs secrete follistatin (Fst), a promyogenic factor, boosting the recovery process. We further determined that the knockdown of FAPs-derived Fst delayed the recovery process. Mechanistically, Mrc1+ M2-like macrophages-specific TGF-b1 inhibited the activation of FAPs, and the FAPs failed to secrete Fst.

ORGANISM(S): Mus musculus

PROVIDER: GSE173555 | GEO | 2022/09/12

REPOSITORIES: GEO

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Project description:Fibro-adipogenic progenitors (FAPs) are emerging cellular components of the skeletal muscle regenerative environment. The alternative functional phenotype of FAPs - either supportive of muscle regeneration or promoting fibro-adipogenic degeneration - is a key determinant in the pathogenesis of muscular diseases, including Duchenne Muscular Dystrophy (DMD). However, the molecular regulation of FAPs is still unknown. We show here that an "HDAC-myomiR-BAF60 variant network" regulates the functional phenotype of FAPs in dystrophic muscles of mdx mice. Combinatorial analysis of gene expression microarray and genome-wide chromatin remodeling by Nuclease accessibility (NA)-seq revealed that HDAC inhibitors de-repress a "latent" myogenic program in FAPs from dystrophic muscles at early stages of disease progression. In these cells HDAC inhibition promoted the expression of two core components of the myogenic transcriptional machinery, MyoD and BAF60C, and upregulated the myomiRs (miRs) miR-1.2, miR-133 and miR-206, which target two alternative BAF60 variants (BAF60A and B) ultimately leading to the activation of a pro-myogenic program at the expense of the fibro-adipogenic phenotype. By contrast, FAPs from dystrophic muscles at late stages of disease progression displayed resistance to HDACi-induced chromatin remodeling at myogenic loci and fail to activate the pro-myogenic phenotype. These results reveal a previously unappreciated disease stage-specific bipotency of mesenchimal cells within the regenerative environment of dystrophic muscles. Resolution of such bi-potency by epigenetic interventions, such as HDACi, provides the molecular rationale for the in situ reprogramming of target cells to promote therapeutic regeneration of dystrophic muscles. miRNA modulation upon Histone Deacetylase inhibition in Fibro-Adipogenic Progenitors (FAPs) derived from young mdx mice was evaluated by small RNA-sequencing in 2 controls and 2 treated samples

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Crosstalk between macrophages and fibro-adipogenic progenitors during muscle regeneration

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