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

  1. Mayank Verma
  2. Yoko Asakura
  3. Xuerui Wang
  4. Kasey Zhou
  5. Mahmut Ünverdi
  6. Allison P Kann
  7. Robert S Krauss
  8. Atsushi Asakura  Is a corresponding author
  1. The University of Texas Southwestern Medical Center, United States
  2. University of Minnesota, United States
  3. 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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Mayank Verma

    Department of Pediatrics and Neurology, The University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0167-0842
  2. Yoko Asakura

    Department of Neurology, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4107-4236
  3. Xuerui Wang

    Department of Neurology, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Kasey Zhou

    Department of Neurology, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mahmut Ünverdi

    Department of Neurology, University of Minnesota, Minneapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Allison P Kann

    Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0111-9081
  7. Robert S Krauss

    Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7661-3335
  8. Atsushi Asakura

    Department of Neurology, University of Minnesota, Minneapolis, United States
    For correspondence
    asakura@umn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8078-1027

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

  1. 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

  1. Received: September 2, 2021
  2. Accepted: June 5, 2024
  3. 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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  1. Mayank Verma
  2. Yoko Asakura
  3. Xuerui Wang
  4. Kasey Zhou
  5. Mahmut Ünverdi
  6. Allison P Kann
  7. Robert S Krauss
  8. Atsushi Asakura
(2024)
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

Share this article

https://doi.org/10.7554/eLife.73592

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