Cell Reports
Volume 30, Issue 10, 10 March 2020, Pages 3583-3595.e5
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Single-Cell Analysis of the Muscle Stem Cell Hierarchy Identifies Heterotypic Communication Signals Involved in Skeletal Muscle Regeneration

https://doi.org/10.1016/j.celrep.2020.02.067Get rights and content
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Highlights

  • Single-cell RNA-sequencing identifies cell populations involved in muscle regeneration

  • Muscle stem/progenitor cells form a hierarchy with stage-specific regulatory programs

  • Bioinformatic analysis identified paracrine factors influencing muscle stem cells

  • Syndecan-1/2/4 coordinate paracrine ligand-specific muscle progenitor proliferation

Summary

Muscle regeneration relies on the regulation of muscle stem cells (MuSCs) through paracrine signaling interactions. We analyzed muscle regeneration in mice using single-cell RNA sequencing (scRNA-seq) and generated over 34,000 single-cell transcriptomes spanning four time-points. We identified 15 distinct cell types including heterogenous populations of muscle stem and progenitor cells. We resolved a hierarchical map of these myogenic cells by trajectory inference and observed stage-specific regulatory programs within this continuum. Through ligand-receptor interaction analysis, we identified over 100 candidate regeneration-associated paracrine communication pairs between MuSCs and non-myogenic cells. We show that myogenic stem/progenitor cells exhibit heterogeneous expression of multiple Syndecan proteins in cycling myogenic cells, suggesting that Syndecans may coordinate myogenic fate regulation. We performed ligand stimulation in vitro and confirmed that three paracrine factors (FGF2, TGFβ1, and RSPO3) regulate myogenic cell proliferation in a Syndecan-dependent manner. Our study provides a scRNA-seq reference resource to investigate cell communication interactions in muscle regeneration.

Keywords

muscle stem cells
single-cell RNA-sequencing
skeletal muscle regeneration
myogenic differentiation
ligand receptor interaction
syndecans

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