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Identifying signals from the skeletal muscle niche that regulate satellite cell function

ABSTRACT: Skeletal muscle is the most common tissue in the body. Its continued maintenance and regeneration throughout life is essential to the function of the organism. Satellite cells are critical to regeneration of the skeletal muscle and strategies to improve function of satellite cells are of great importance. Muscle-resident Fibro-Adipogenic Precursors (FAPs) cells are a critical component of the satellite cell niche and help orchestrate efficient muscle regeneration and potentiate satellite cell differentiation via soluble or secreted factors. Populations with similar phenotype and function to muscle FAPs have been isolated from the skin and white adipose tissue. Interactions between tissue-specific FAP cells and resident stem cells in those tissues might be conserved. Therefore, defining specific factors that mediate the relationship between muscle FAPs and satellite cells would have implications for other organs.

ORGANISM(S): Mus musculus

PROVIDER: GSE67117 | GEO | 2019/06/30

REPOSITORIES: GEO

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Fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH regulation of adipogenesis

Project description:Fibro adipogenic progenitors (FAPs) promote satellite cell differentiation in adult skeletal muscle regeneration. However, in pathological conditions, FAPs are responsible for fibrosis and fatty infiltrations. Here we show that the NOTCH pathway negatively modulates FAP differentiation both in vitro and in vivo. However, FAPs isolated from young dystrophin- deficient mdx mice are insensitive to this control mechanism. An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild type and mdx mice, suggest that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. Remarkably, we demonstrated that factors released by hematopoietic cells restore the sensitivity to NOTCH adipogenic inhibition in mdx FAPs. These results offer a basis for rationalizing pathological ectopic fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fat depositions in muscles of dystrophic patients.

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Project description:During aging, the number and functionality of muscle stem cells (MuSCs) decreases leading to impaired regeneration of aged skeletal muscle. In addition to intrinsic changes in aged MuSCs, extracellular matrix (ECM) proteins deriving from other cell types, e.g., fibrogenic-adipogenic progenitor cells (FAPs), contribute to the aging phenotype of MuSCs and impaired regeneration in the elderly. So far, no comprehensive analysis on how age-dependent changes in the whole skeletal muscle proteome affect MuSC function have been conducted. Here, we investigated age-dependent changes in the proteome of different skeletal muscle types by applying deep quantitative mass spectrometry. We identified 183 extracellular matrix proteins that show different abundances in skeletal muscles of old mice. By integrating single cell sequencing data, we reveal that transcripts of those ECM proteins are mainly expressed in FAPs, suggesting that FAPs are the main contributors to ECM remodelling during aging. We functionally investigated one of those ECM molecules, namely Smoc2, which is aberrantly expressed during aging. We show that Smoc2 levels are elevated during regeneration and that its accumulation in the aged MuSC niche causes impairment of MuSCs function through constant activation of integrin/MAPK signaling. In vivo, supplementation of exogenous Smoc2 hampers the regeneration of young muscles following serial injuries, leading to a phenotype reminiscent of regenerating aged skeletal muscle. Taken together, we provide a comprehensive resource of changes in the composition of the ECM of aged skeletal muscles, we pinpoint the cell types driving these changes, and we identify a new niche protein causing functional impairment of MuSCs thereby hampering the regeneration capacity of skeletal muscles.

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