Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell
- The University of Texas Southwestern Medical Center, United States
- University of Minnesota, United States
- Icahn School of Medicine at Mount Sinai, United States
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 RNAseq 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.
Data availability
All data availability was described in Supplementary Table S1, Source Code, Source Data file, and Transparent Reporting File.
Article and author information
Author details
Funding
National Institutes of Health (NIHT32-GM008244)
- Mayank Verma
National Institutes of Health (NIHF30AR066454)
- Mayank Verma
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR070231)
- Robert S Krauss
New York State Stem Cell Science (NYSTEM-C32561GG)
- Allison P Kann
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIHR01AR062142)
- Atsushi Asakura
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIHR21AR070319)
- Atsushi Asakura
Muscular Dystrophy Association (MDA241600)
- Atsushi Asakura
Regenerative Medicine Minnesota (RMM 092319 TR 010)
- Atsushi Asakura
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Tom H Cheung, The Hong Kong University of Science and Technology, Hong Kong
Ethics
Animal experimentation: The animals were housed in an SPF environment and were monitored by the Research Animal Resources (RAR) of the University of Minnesota. All protocols (2204-39969A) were approved by the Institutional Animal Care and Usage Committee (IACUC) of the University of Minnesota and complied with the NIH guidelines for the use of animals in research.
Version history
- Received: September 2, 2021
- Accepted: June 5, 2024
- Accepted Manuscript published: June 6, 2024 (version 1)
Copyright
© 2024, Verma et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Endothelial cell signature in muscle stem cells validated by VEGFA-FLT1-AKT1 axis promoting survival of muscle stem cell
eLife 13:e73592.
https://doi.org/10.7554/eLife.73592
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