Department of Pediatrics & Neurology, Division of Pediatric Neurology, The University of Texas Southwestern Medical Center, Dallas, United States; Stem Cell Institute, University of Minnesota Medical School, Minneapolis, United States; Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, United States; Department of Neurology, University of Minnesota Medical School, Minneapolis, United States
Stem Cell Institute, University of Minnesota Medical School, Minneapolis, United States; Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, United States; Department of Neurology, University of Minnesota Medical School, Minneapolis, United States
Xuerui Wang
Stem Cell Institute, University of Minnesota Medical School, Minneapolis, United States; Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, United States; Department of Neurology, University of Minnesota Medical School, Minneapolis, United States
Kasey Zhou
Stem Cell Institute, University of Minnesota Medical School, Minneapolis, United States; Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, United States; Department of Neurology, University of Minnesota Medical School, Minneapolis, United States
Mahmut Ünverdi
Stem Cell Institute, University of Minnesota Medical School, Minneapolis, United States; Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, United States; Department of Neurology, University of Minnesota Medical School, Minneapolis, United States
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States; Graduate School of Biomedical Sciencesf, Icahn School of Medicine at Mount Sinai, New York, United States
Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States; Graduate School of Biomedical Sciencesf, Icahn School of Medicine at Mount Sinai, New York, United States
Stem Cell Institute, University of Minnesota Medical School, Minneapolis, United States; Greg Marzolf Jr. Muscular Dystrophy Center, University of Minnesota Medical School, Minneapolis, United States; Department of Neurology, University of Minnesota Medical School, Minneapolis, United States
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.
