Muscle Satellite Cell Cross-Talk with a Vascular Niche Maintains Quiescence via VEGF and Notch Signaling

Mayank Verma; Yoko Asakura; Bhavani Sai Rohit Murakonda; Thomas Pengo; Claire Latroche; Benedicte Chazaud; Linda K McLoon; Atsushi Asakura

doi:10.1016/j.stem.2018.09.007

Muscle Satellite Cell Cross-Talk with a Vascular Niche Maintains Quiescence via VEGF and Notch Signaling

Mayank Verma, Yoko Asakura, Bhavani Sai Rohit Murakonda, Thomas Pengo, Claire Latroche, Benedicte Chazaud, Linda K McLoon, Atsushi Asakura

Research output: Contribution to journal › Article › peer-review

215 Scopus citations

Abstract

Skeletal muscle is a complex tissue containing tissue resident muscle stem cells (satellite cells) (MuSCs) important for postnatal muscle growth and regeneration. Quantitative analysis of the biological function of MuSCs and the molecular pathways responsible for a potential juxtavascular niche for MuSCs is currently lacking. We utilized fluorescent reporter mice and muscle tissue clearing to investigate the proximity of MuSCs to capillaries in 3 dimensions. We show that MuSCs express abundant VEGFA, which recruits endothelial cells (ECs) in vitro, whereas blocking VEGFA using both a vascular endothelial growth factor (VEGF) inhibitor and MuSC-specific VEGFA gene deletion reduces the proximity of MuSCs to capillaries. Importantly, this proximity to the blood vessels was associated with MuSC self-renewal in which the EC-derived Notch ligand Dll4 induces quiescence in MuSCs. We hypothesize that MuSCs recruit capillary ECs via VEGFA, and in return, ECs maintain MuSC quiescence though Dll4. Verma et al. performed skeletal muscle tissue clearing and unbiased fluorescent image analysis to show that muscle stem cells (satellite cells) pattern the microvasculature to be in close proximity to them via VEGFA. In turn, this juxtavascular niche keeps the satellite cells in a more quiescent state, suggesting a beneficial cross-talk.

Original language	English (US)
Pages (from-to)	530-543.e9
Journal	Cell Stem Cell
Volume	23
Issue number	4
DOIs	https://doi.org/10.1016/j.stem.2018.09.007
State	Published - Oct 4 2018

Bibliographical note

Funding Information:
We thank the Minnesota Supercomputing Institute, University of Minnesota Imaging Center, University of Minnesota FACS Facility, and University of Minnesota Genomics Center for providing data for this paper. We also thank Jake Trask and Drs. Norio Motohashi and Mathew Angelos for critical reading of this paper. We thank Drs. Brian Fife and Jason Mitchell for use of Imaris. We thank Dr. Napoleone Ferrara and Masatsugu Ema for providing VEGFALoxP/LoxP and Flk1-GFP mice. This work was supported by the Greg Marzolf Jr. Foundation (B.S.R.M.), Association Fran?aise contre les Myopathies (grant 18003 to B.C.), the NIH (grants NIHT32-GM008244 and NIHF30AR066454 to M.V. and grants NIHR01AR062142 and NIHR21AR070319 to A.A.), and a Muscular Dystrophy Association (MDA) Research Grant (MDA 241600 to A.A.).

Funding Information:
We thank the Minnesota Supercomputing Institute, University of Minnesota Imaging Center, University of Minnesota FACS Facility, and University of Minnesota Genomics Center for providing data for this paper. We also thank Jake Trask and Drs. Norio Motohashi and Mathew Angelos for critical reading of this paper. We thank Drs. Brian Fife and Jason Mitchell for use of Imaris. We thank Dr. Napoleone Ferrara and Masatsugu Ema for providing VEGFA LoxP/LoxP and Flk1-GFP mice. This work was supported by the Greg Marzolf Jr. Foundation (B.S.R.M.), Association Française contre les Myopathies (grant 18003 to B.C.), the NIH (grants NIHT32-GM008244 and NIHF30AR066454 to M.V. and grants NIHR01AR062142 and NIHR21AR070319 to A.A.), and a Muscular Dystrophy Association ( MDA) Research Grant ( MDA 241600 to A.A.).

Publisher Copyright:
© 2018 Elsevier Inc.

Keywords

Dll4
Notch
VEGF
endothelial cell
niche
satellite cell
skeletal muscle
stem cell
tissue clearing
vasculature

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10.1016/j.stem.2018.09.007

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@article{2820493215894fecb4a0cfbf39922314,

title = "Muscle Satellite Cell Cross-Talk with a Vascular Niche Maintains Quiescence via VEGF and Notch Signaling",

abstract = "Skeletal muscle is a complex tissue containing tissue resident muscle stem cells (satellite cells) (MuSCs) important for postnatal muscle growth and regeneration. Quantitative analysis of the biological function of MuSCs and the molecular pathways responsible for a potential juxtavascular niche for MuSCs is currently lacking. We utilized fluorescent reporter mice and muscle tissue clearing to investigate the proximity of MuSCs to capillaries in 3 dimensions. We show that MuSCs express abundant VEGFA, which recruits endothelial cells (ECs) in vitro, whereas blocking VEGFA using both a vascular endothelial growth factor (VEGF) inhibitor and MuSC-specific VEGFA gene deletion reduces the proximity of MuSCs to capillaries. Importantly, this proximity to the blood vessels was associated with MuSC self-renewal in which the EC-derived Notch ligand Dll4 induces quiescence in MuSCs. We hypothesize that MuSCs recruit capillary ECs via VEGFA, and in return, ECs maintain MuSC quiescence though Dll4. Verma et al. performed skeletal muscle tissue clearing and unbiased fluorescent image analysis to show that muscle stem cells (satellite cells) pattern the microvasculature to be in close proximity to them via VEGFA. In turn, this juxtavascular niche keeps the satellite cells in a more quiescent state, suggesting a beneficial cross-talk.",

keywords = "Dll4, Notch, VEGF, endothelial cell, niche, satellite cell, skeletal muscle, stem cell, tissue clearing, vasculature",

author = "Mayank Verma and Yoko Asakura and Murakonda, {Bhavani Sai Rohit} and Thomas Pengo and Claire Latroche and Benedicte Chazaud and McLoon, {Linda K} and Atsushi Asakura",

note = "Funding Information: We thank the Minnesota Supercomputing Institute, University of Minnesota Imaging Center, University of Minnesota FACS Facility, and University of Minnesota Genomics Center for providing data for this paper. We also thank Jake Trask and Drs. Norio Motohashi and Mathew Angelos for critical reading of this paper. We thank Drs. Brian Fife and Jason Mitchell for use of Imaris. We thank Dr. Napoleone Ferrara and Masatsugu Ema for providing VEGFALoxP/LoxP and Flk1-GFP mice. This work was supported by the Greg Marzolf Jr. Foundation (B.S.R.M.), Association Fran?aise contre les Myopathies (grant 18003 to B.C.), the NIH (grants NIHT32-GM008244 and NIHF30AR066454 to M.V. and grants NIHR01AR062142 and NIHR21AR070319 to A.A.), and a Muscular Dystrophy Association (MDA) Research Grant (MDA 241600 to A.A.). Funding Information: We thank the Minnesota Supercomputing Institute, University of Minnesota Imaging Center, University of Minnesota FACS Facility, and University of Minnesota Genomics Center for providing data for this paper. We also thank Jake Trask and Drs. Norio Motohashi and Mathew Angelos for critical reading of this paper. We thank Drs. Brian Fife and Jason Mitchell for use of Imaris. We thank Dr. Napoleone Ferrara and Masatsugu Ema for providing VEGFA LoxP/LoxP and Flk1-GFP mice. This work was supported by the Greg Marzolf Jr. Foundation (B.S.R.M.), Association Fran{\c c}aise contre les Myopathies (grant 18003 to B.C.), the NIH (grants NIHT32-GM008244 and NIHF30AR066454 to M.V. and grants NIHR01AR062142 and NIHR21AR070319 to A.A.), and a Muscular Dystrophy Association ( MDA) Research Grant ( MDA 241600 to A.A.). Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

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doi = "10.1016/j.stem.2018.09.007",

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AU - Asakura, Yoko

AU - Murakonda, Bhavani Sai Rohit

AU - Pengo, Thomas

AU - Latroche, Claire

AU - Chazaud, Benedicte

AU - McLoon, Linda K

AU - Asakura, Atsushi

N1 - Funding Information: We thank the Minnesota Supercomputing Institute, University of Minnesota Imaging Center, University of Minnesota FACS Facility, and University of Minnesota Genomics Center for providing data for this paper. We also thank Jake Trask and Drs. Norio Motohashi and Mathew Angelos for critical reading of this paper. We thank Drs. Brian Fife and Jason Mitchell for use of Imaris. We thank Dr. Napoleone Ferrara and Masatsugu Ema for providing VEGFALoxP/LoxP and Flk1-GFP mice. This work was supported by the Greg Marzolf Jr. Foundation (B.S.R.M.), Association Fran?aise contre les Myopathies (grant 18003 to B.C.), the NIH (grants NIHT32-GM008244 and NIHF30AR066454 to M.V. and grants NIHR01AR062142 and NIHR21AR070319 to A.A.), and a Muscular Dystrophy Association (MDA) Research Grant (MDA 241600 to A.A.). Funding Information: We thank the Minnesota Supercomputing Institute, University of Minnesota Imaging Center, University of Minnesota FACS Facility, and University of Minnesota Genomics Center for providing data for this paper. We also thank Jake Trask and Drs. Norio Motohashi and Mathew Angelos for critical reading of this paper. We thank Drs. Brian Fife and Jason Mitchell for use of Imaris. We thank Dr. Napoleone Ferrara and Masatsugu Ema for providing VEGFA LoxP/LoxP and Flk1-GFP mice. This work was supported by the Greg Marzolf Jr. Foundation (B.S.R.M.), Association Française contre les Myopathies (grant 18003 to B.C.), the NIH (grants NIHT32-GM008244 and NIHF30AR066454 to M.V. and grants NIHR01AR062142 and NIHR21AR070319 to A.A.), and a Muscular Dystrophy Association ( MDA) Research Grant ( MDA 241600 to A.A.). Publisher Copyright: © 2018 Elsevier Inc.

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N2 - Skeletal muscle is a complex tissue containing tissue resident muscle stem cells (satellite cells) (MuSCs) important for postnatal muscle growth and regeneration. Quantitative analysis of the biological function of MuSCs and the molecular pathways responsible for a potential juxtavascular niche for MuSCs is currently lacking. We utilized fluorescent reporter mice and muscle tissue clearing to investigate the proximity of MuSCs to capillaries in 3 dimensions. We show that MuSCs express abundant VEGFA, which recruits endothelial cells (ECs) in vitro, whereas blocking VEGFA using both a vascular endothelial growth factor (VEGF) inhibitor and MuSC-specific VEGFA gene deletion reduces the proximity of MuSCs to capillaries. Importantly, this proximity to the blood vessels was associated with MuSC self-renewal in which the EC-derived Notch ligand Dll4 induces quiescence in MuSCs. We hypothesize that MuSCs recruit capillary ECs via VEGFA, and in return, ECs maintain MuSC quiescence though Dll4. Verma et al. performed skeletal muscle tissue clearing and unbiased fluorescent image analysis to show that muscle stem cells (satellite cells) pattern the microvasculature to be in close proximity to them via VEGFA. In turn, this juxtavascular niche keeps the satellite cells in a more quiescent state, suggesting a beneficial cross-talk.

AB - Skeletal muscle is a complex tissue containing tissue resident muscle stem cells (satellite cells) (MuSCs) important for postnatal muscle growth and regeneration. Quantitative analysis of the biological function of MuSCs and the molecular pathways responsible for a potential juxtavascular niche for MuSCs is currently lacking. We utilized fluorescent reporter mice and muscle tissue clearing to investigate the proximity of MuSCs to capillaries in 3 dimensions. We show that MuSCs express abundant VEGFA, which recruits endothelial cells (ECs) in vitro, whereas blocking VEGFA using both a vascular endothelial growth factor (VEGF) inhibitor and MuSC-specific VEGFA gene deletion reduces the proximity of MuSCs to capillaries. Importantly, this proximity to the blood vessels was associated with MuSC self-renewal in which the EC-derived Notch ligand Dll4 induces quiescence in MuSCs. We hypothesize that MuSCs recruit capillary ECs via VEGFA, and in return, ECs maintain MuSC quiescence though Dll4. Verma et al. performed skeletal muscle tissue clearing and unbiased fluorescent image analysis to show that muscle stem cells (satellite cells) pattern the microvasculature to be in close proximity to them via VEGFA. In turn, this juxtavascular niche keeps the satellite cells in a more quiescent state, suggesting a beneficial cross-talk.

KW - Dll4

KW - Notch

KW - VEGF

KW - endothelial cell

KW - niche

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KW - stem cell

KW - tissue clearing

KW - vasculature

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Muscle Satellite Cell Cross-Talk with a Vascular Niche Maintains Quiescence via VEGF and Notch Signaling

Abstract

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Muscle Satellite Cell Cross-Talk with a Vascular Niche Maintains Quiescence via VEGF and Notch Signaling

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