Hic1 Defines Quiescent Mesenchymal Progenitor Subpopulations with Distinct Functions and Fates in Skeletal Muscle Regeneration

Cell Stem Cell. 2019 Dec 5;25(6):797-813.e9. doi: 10.1016/j.stem.2019.11.004.


Many adult tissues contain resident stem cells, such as the Pax7+ satellite cells within skeletal muscle, that regenerate parenchymal elements following damage. Tissue-resident mesenchymal progenitors (MPs) also participate in regeneration, although their function and fate in this process are unclear. Here, we identify Hypermethylated in cancer 1 (Hic1) as a marker of MPs in skeletal muscle and further show that Hic1 deletion leads to MP hyperplasia. Single-cell RNA-seq and ATAC-seq analysis of Hic1+ MPs in skeletal muscle shows multiple subpopulations, which we further show have distinct functions and lineage potential. Hic1+ MPs orchestrate multiple aspects of skeletal muscle regeneration by providing stage-specific immunomodulation and trophic and mechanical support. During muscle regeneration, Hic1+ derivatives directly contribute to several mesenchymal compartments including Col22a1-expressing cells within the myotendinous junction. Collectively, these findings demonstrate that HIC1 regulates MP quiescence and identifies MP subpopulations with transient and enduring roles in muscle regeneration.

Keywords: lineage tracing; mesenchymal progenitors; myotendinous junction; pericytes; quiescence; scATAC-seq; scRNA-seq; skeletal muscle; tendon; tissue regeneration.

MeSH terms

  • Animals
  • Cell Cycle / genetics
  • Cell Cycle / physiology
  • Cell Differentiation / genetics
  • Cell Differentiation / physiology
  • Cell Proliferation / genetics
  • Cell Proliferation / physiology
  • Cells, Cultured
  • Female
  • Fluorescent Antibody Technique
  • Kruppel-Like Transcription Factors / genetics
  • Kruppel-Like Transcription Factors / metabolism*
  • Male
  • Mice
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / physiology*
  • Regeneration / genetics
  • Regeneration / physiology*
  • Satellite Cells, Skeletal Muscle / metabolism*
  • Wound Healing / genetics
  • Wound Healing / physiology


  • Hic1 protein, mouse
  • Kruppel-Like Transcription Factors