Macrophages provide a transient muscle stem cell niche via NAMPT secretion

Dhanushika Ratnayake; Phong D Nguyen; Fernando J Rossello; Verena C Wimmer; Jean L Tan; Laura A Galvis; Ziad Julier; Alasdair J Wood; Thomas Boudier; Abdulsalam I Isiaku; Silke Berger; Viola Oorschot; Carmen Sonntag; Kelly L Rogers; Christophe Marcelle; Graham J Lieschke; Mikaël M Martino; Jeroen Bakkers; Peter D Currie

doi:10.1038/s41586-021-03199-7

Macrophages provide a transient muscle stem cell niche via NAMPT secretion

Dhanushika Ratnayake, Phong D Nguyen, Fernando J Rossello, Verena C Wimmer, Jean L Tan, Laura A Galvis, Ziad Julier, Alasdair J Wood, Thomas Boudier, Abdulsalam I Isiaku, Silke Berger, Viola Oorschot, Carmen Sonntag, Kelly L Rogers, Christophe Marcelle, Graham J Lieschke, Mikaël M Martino, Jeroen Bakkers, Peter D Currie

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

135 Citations (Scopus)

Abstract

Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals1. Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound. Here we use muscle injury models in zebrafish to systematically capture the interactions between satellite cells and the innate immune system after injury, in real time, throughout the repair process. This analysis revealed that a specific subset of macrophages 'dwell' within the injury, establishing a transient but obligate niche for stem cell proliferation. Single-cell profiling identified proliferative signals that are secreted by dwelling macrophages, which include the cytokine nicotinamide phosphoribosyltransferase (Nampt, which is also known as visfatin or PBEF in humans). Nampt secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (Ccr5), which is expressed on muscle stem cells. This analysis shows that in addition to their ability to modulate the immune response, specific macrophage populations also provide a transient stem-cell-activating niche, directly supplying proliferation-inducing cues that govern the repair process that is mediated by muscle stem cells. This study demonstrates that macrophage-derived niche signals for muscle stem cells, such as NAMPT, can be applied as new therapeutic modalities for skeletal muscle injury and disease.

Original language	English
Pages (from-to)	281-287
Number of pages	7
Journal	Nature
Volume	591
Issue number	7849
DOIs	https://doi.org/10.1038/s41586-021-03199-7
Publication status	Published - Mar 2021

Keywords

Animals
Cell Proliferation
Disease Models, Animal
Humans
Macrophages/cytology
Male
Matrix Metalloproteinase 9/genetics
Mice
Mice, Inbred C57BL
Muscle, Skeletal/cytology
Myoblasts/cytology
Nicotinamide Phosphoribosyltransferase/genetics
PAX7 Transcription Factor/metabolism
RNA-Seq
Receptors, CCR5/genetics
Regeneration/physiology
Single-Cell Analysis
Stem Cell Niche
Zebrafish/immunology

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10.1038/s41586-021-03199-7

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Ratnayake, D., Nguyen, P. D., Rossello, F. J., Wimmer, V. C., Tan, J. L., Galvis, L. A., Julier, Z., Wood, A. J., Boudier, T., Isiaku, A. I., Berger, S., Oorschot, V., Sonntag, C., Rogers, K. L., Marcelle, C., Lieschke, G. J., Martino, M. M., Bakkers, J., & Currie, P. D. (2021). Macrophages provide a transient muscle stem cell niche via NAMPT secretion. Nature, 591(7849), 281-287. https://doi.org/10.1038/s41586-021-03199-7

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title = "Macrophages provide a transient muscle stem cell niche via NAMPT secretion",

abstract = "Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals1. Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound. Here we use muscle injury models in zebrafish to systematically capture the interactions between satellite cells and the innate immune system after injury, in real time, throughout the repair process. This analysis revealed that a specific subset of macrophages 'dwell' within the injury, establishing a transient but obligate niche for stem cell proliferation. Single-cell profiling identified proliferative signals that are secreted by dwelling macrophages, which include the cytokine nicotinamide phosphoribosyltransferase (Nampt, which is also known as visfatin or PBEF in humans). Nampt secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (Ccr5), which is expressed on muscle stem cells. This analysis shows that in addition to their ability to modulate the immune response, specific macrophage populations also provide a transient stem-cell-activating niche, directly supplying proliferation-inducing cues that govern the repair process that is mediated by muscle stem cells. This study demonstrates that macrophage-derived niche signals for muscle stem cells, such as NAMPT, can be applied as new therapeutic modalities for skeletal muscle injury and disease.",

keywords = "Animals, Cell Proliferation, Disease Models, Animal, Humans, Macrophages/cytology, Male, Matrix Metalloproteinase 9/genetics, Mice, Mice, Inbred C57BL, Muscle, Skeletal/cytology, Myoblasts/cytology, Nicotinamide Phosphoribosyltransferase/genetics, PAX7 Transcription Factor/metabolism, RNA-Seq, Receptors, CCR5/genetics, Regeneration/physiology, Single-Cell Analysis, Stem Cell Niche, Zebrafish/immunology",

author = "Dhanushika Ratnayake and Nguyen, {Phong D} and Rossello, {Fernando J} and Wimmer, {Verena C} and Tan, {Jean L} and Galvis, {Laura A} and Ziad Julier and Wood, {Alasdair J} and Thomas Boudier and Isiaku, {Abdulsalam I} and Silke Berger and Viola Oorschot and Carmen Sonntag and Rogers, {Kelly L} and Christophe Marcelle and Lieschke, {Graham J} and Martino, {Mika{\"e}l M} and Jeroen Bakkers and Currie, {Peter D}",

year = "2021",

month = mar,

doi = "10.1038/s41586-021-03199-7",

language = "English",

volume = "591",

pages = "281--287",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group",

number = "7849",

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Ratnayake, D, Nguyen, PD, Rossello, FJ, Wimmer, VC, Tan, JL, Galvis, LA, Julier, Z, Wood, AJ, Boudier, T, Isiaku, AI, Berger, S, Oorschot, V, Sonntag, C, Rogers, KL, Marcelle, C, Lieschke, GJ, Martino, MM, Bakkers, J & Currie, PD 2021, 'Macrophages provide a transient muscle stem cell niche via NAMPT secretion', Nature, vol. 591, no. 7849, pp. 281-287. https://doi.org/10.1038/s41586-021-03199-7

TY - JOUR

T1 - Macrophages provide a transient muscle stem cell niche via NAMPT secretion

AU - Ratnayake, Dhanushika

AU - Nguyen, Phong D

AU - Rossello, Fernando J

AU - Wimmer, Verena C

AU - Tan, Jean L

AU - Galvis, Laura A

AU - Julier, Ziad

AU - Wood, Alasdair J

AU - Boudier, Thomas

AU - Isiaku, Abdulsalam I

AU - Berger, Silke

AU - Oorschot, Viola

AU - Sonntag, Carmen

AU - Rogers, Kelly L

AU - Marcelle, Christophe

AU - Lieschke, Graham J

AU - Martino, Mikaël M

AU - Bakkers, Jeroen

AU - Currie, Peter D

PY - 2021/3

Y1 - 2021/3

N2 - Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals1. Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound. Here we use muscle injury models in zebrafish to systematically capture the interactions between satellite cells and the innate immune system after injury, in real time, throughout the repair process. This analysis revealed that a specific subset of macrophages 'dwell' within the injury, establishing a transient but obligate niche for stem cell proliferation. Single-cell profiling identified proliferative signals that are secreted by dwelling macrophages, which include the cytokine nicotinamide phosphoribosyltransferase (Nampt, which is also known as visfatin or PBEF in humans). Nampt secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (Ccr5), which is expressed on muscle stem cells. This analysis shows that in addition to their ability to modulate the immune response, specific macrophage populations also provide a transient stem-cell-activating niche, directly supplying proliferation-inducing cues that govern the repair process that is mediated by muscle stem cells. This study demonstrates that macrophage-derived niche signals for muscle stem cells, such as NAMPT, can be applied as new therapeutic modalities for skeletal muscle injury and disease.

AB - Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals1. Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound. Here we use muscle injury models in zebrafish to systematically capture the interactions between satellite cells and the innate immune system after injury, in real time, throughout the repair process. This analysis revealed that a specific subset of macrophages 'dwell' within the injury, establishing a transient but obligate niche for stem cell proliferation. Single-cell profiling identified proliferative signals that are secreted by dwelling macrophages, which include the cytokine nicotinamide phosphoribosyltransferase (Nampt, which is also known as visfatin or PBEF in humans). Nampt secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (Ccr5), which is expressed on muscle stem cells. This analysis shows that in addition to their ability to modulate the immune response, specific macrophage populations also provide a transient stem-cell-activating niche, directly supplying proliferation-inducing cues that govern the repair process that is mediated by muscle stem cells. This study demonstrates that macrophage-derived niche signals for muscle stem cells, such as NAMPT, can be applied as new therapeutic modalities for skeletal muscle injury and disease.

KW - Animals

KW - Cell Proliferation

KW - Disease Models, Animal

KW - Humans

KW - Macrophages/cytology

KW - Male

KW - Matrix Metalloproteinase 9/genetics

KW - Mice

KW - Mice, Inbred C57BL

KW - Muscle, Skeletal/cytology

KW - Myoblasts/cytology

KW - Nicotinamide Phosphoribosyltransferase/genetics

KW - PAX7 Transcription Factor/metabolism

KW - RNA-Seq

KW - Receptors, CCR5/genetics

KW - Regeneration/physiology

KW - Single-Cell Analysis

KW - Stem Cell Niche

KW - Zebrafish/immunology

U2 - 10.1038/s41586-021-03199-7

DO - 10.1038/s41586-021-03199-7

M3 - Article

C2 - 33568815

SN - 0028-0836

VL - 591

SP - 281

EP - 287

JO - Nature

JF - Nature

IS - 7849

ER -

Macrophages provide a transient muscle stem cell niche via NAMPT secretion

Abstract

Keywords

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