Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell

Elife. 2024 Jun 6:13:e73592. doi: 10.7554/eLife.73592.

Abstract

Endothelial and skeletal muscle lineages arise from common embryonic progenitors. Despite their shared developmental origin, adult endothelial cells (ECs) and muscle stem cells (MuSCs; satellite cells) have been thought to possess distinct gene signatures and signaling pathways. Here, we shift this paradigm by uncovering how adult MuSC behavior is affected by the expression of a subset of EC transcripts. We used several computational analyses including single-cell RNA-seq (scRNA-seq) to show that MuSCs express low levels of canonical EC markers in mice. We demonstrate that MuSC survival is regulated by one such prototypic endothelial signaling pathway (VEGFA-FLT1). Using pharmacological and genetic gain- and loss-of-function studies, we identify the FLT1-AKT1 axis as the key effector underlying VEGFA-mediated regulation of MuSC survival. All together, our data support that the VEGFA-FLT1-AKT1 pathway promotes MuSC survival during muscle regeneration, and highlights how the minor expression of select transcripts is sufficient for affecting cell behavior.

Keywords: Flt1; VEGF; developmental biology; endothelial cell; mouse; muscle stem cell; regenerative medicine; satellite cell; skeletal muscle; stem cells.

MeSH terms

  • Animals
  • Cell Survival*
  • Endothelial Cells* / metabolism
  • Endothelial Cells* / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism
  • Proto-Oncogene Proteins c-akt* / metabolism
  • Satellite Cells, Skeletal Muscle / metabolism
  • Satellite Cells, Skeletal Muscle / physiology
  • Signal Transduction*
  • Vascular Endothelial Growth Factor A* / genetics
  • Vascular Endothelial Growth Factor A* / metabolism
  • Vascular Endothelial Growth Factor Receptor-1* / genetics
  • Vascular Endothelial Growth Factor Receptor-1* / metabolism

Substances

  • Vascular Endothelial Growth Factor Receptor-1
  • Proto-Oncogene Proteins c-akt
  • Vascular Endothelial Growth Factor A
  • Flt1 protein, mouse
  • vascular endothelial growth factor A, mouse
  • Akt1 protein, mouse

Associated data

  • GEO/GSE129057
  • GEO/GSE143437
  • GEO/GSE108739
  • GEO/GSE64379
  • GEO/GSE97399
  • GEO/GSE113631
  • GEO/GSE3483
  • GEO/GSE3307
  • GEO/GSE465
  • GEO/GSE466
  • GEO/GSE69040
  • GEO/GSE15155