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Identification of underexplored mesenchymal and vascular-related cell populations in human skeletal muscle

ABSTRACT: Skeletal muscle repair and maintenance are directly and indirectly supported by stromal populations such as vascular cells and fibro-adiopgenic progenitors (FAPs), a subset of which express Twist2 and possess direct myogenic potential in rodents. However, less is understood of the complexity and heterogeneity of human skeletal muscle stromal cells. To this end, we performed single-cell RNA-sequencing on ~2000 cells isolated from the human semitendinosus muscle of young individuals. This demonstrated the presence of two poorly described cell populations. First, we detected a vascular-related cell type that expressed pericyte and pan-endothelial genes that we localized to large blood vessels within skeletal muscle cross-sections and termed endothelial-like pericytes (ELPCs). RNA velocity analysis demonstrated that ELPCs may represent a "transition state" between endothelial cells and pericytes. Analysis of published single-cell RNA-seq datasets revealed evidence for ELPCs in trunk and heart musculature, which showed transcriptional similarity. Additionally, we identified a subset of FAPs expressing TWIST2 mRNA and protein. Human TWIST2-expressing cells were anatomically and transcriptionally comparable to mouse Twist2 cells as they were restricted to the myofiber interstitium, expressed fibrogenic genes but lacked satellite cell markers and colocalized with the FAPs marker PDGFRα in human muscle cross-sections. Taken together, these results highlight the complexity of stromal cells residing in human skeletal muscle and support the utility of single-cell RNA-sequencing for discovery and characterization of poorly described cell populations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216544 | GEO | 2022/11/01

REPOSITORIES: GEO

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Project description:Skeletal muscle regeneration is primarily accomplished through the concerted action of the myoblasts as well as the supporting stromal cells. Following accomplishment of injury repair, activated stromal cells disappear via apoptosis. In the case of muscle dystrophies where in a chronic inflammatory environment is present, activated stromal cells are transformed into a myofibroblastic state with the deposition of extracellular matrix components. Excessive accumulation of ECM leads to irreversible fibrosis and tissue deterioration. A distinct stromal cell population named fibro-adipogenic precursors (FAPs) are known to be responsible for contribution to fibrosis and fatty infiltration. Fibrosis is also evident in disuse atrophy and sarcopenia without any significant inflammation. This study aims to analyze the heterogeneous population of FAPs comparatively in the course of acute damage and immobilization models. We isolated and analyzed the mononuclear cell population of skeletal muscles following tenotomy and denervation models in mice. Immunophenotyping of the FAPs was conducted based on exclusion of CD45, CD31 and CD11b and a comparative analysis was accomplished on three different subpopulations of i) CD140a(+), Sca1(+) ii) CD140a(+), Sca1(-) iii) CD140a(-), Sca1(+). High-throughput transcriptome analysis was employed to further characterize the transcriptome of these three cell populations and compare their quiescent and activated states. Results: Investigated sub-populations exhibited diverse activation properties and kinetics for each studied model. While CD140a(+), Sca1(+) was the predominating activated population along with tenotomy, denervation majorly stimulated the proliferation of CD140a(+), Sca1(+) cells. Both immobilization models lacked myofiber damage and exhibited a minute inflammatory response compared to the acute damage. Transcriptome analysis supports commonalities in upregulation of ECM components in diverse subpopulation of cells as well as discriminating candidate cell surface markers. Skeletal muscle regeneration is primarily accomplished through the concerted action of the myoblasts as well as the supporting stromal cells. Following accomplishment of injury repair, activated stromal cells disappear via apoptosis. In the case of muscle dystrophies where in a chronic inflammatory environment is present, activated stromal cells are transformed into a myofibroblastic state with the deposition of extracellular matrix components. Excessive accumulation of ECM leads to irreversible fibrosis and tissue deterioration. A distinct stromal cell population named fibro-adipogenic precursors (FAPs) are known to be responsible for contribution to fibrosis and fatty infiltration. Fibrosis is also evident in disuse atrophy and sarcopenia without any significant inflammation. This study aims to analyze the heterogeneous population of FAPs comparatively in the course of acute damage and immobilization models. We isolated and analyzed the mononuclear cell population of skeletal muscles following tenotomy and denervation models in mice. Immunophenotyping of the FAPs was conducted based on exclusion of CD45, CD31 and CD11b and a comparative analysis was accomplished on three different subpopulations of i) CD140a(+), Sca1(+) ii) CD140a(+), Sca1(-) iii) CD140a(-), Sca1(+). High-throughput transcriptome analysis was employed to further characterize the transcriptome of these three cell populations and compare their quiescent and activated states. Results: Investigated sub-populations exhibited diverse activation properties and kinetics for each studied model. While CD140a(+), Sca1(+) was the predominating activated population along with tenotomy, denervation majorly stimulated the proliferation of CD140a(+), Sca1(+) cells. Both immobilization models lacked myofiber damage and exhibited a minute inflammatory response compared to the acute damage. Transcriptome analysis supports commonalities in upregulation of ECM components in diverse subpopulation of cells as well as discriminating candidate cell surface markers.

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Identification of underexplored mesenchymal and vascular-related cell populations in human skeletal muscle

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