Macrophages provide a transient muscle stem cell niche via NAMPT secretion

• Published in: Nature (London) Vol. 591; no. 7849; pp. 281 - 287
• Main Authors: Ratnayake, Dhanushika, Nguyen, Phong D., Rossello, Fernando J., Wimmer, Verena C., Tan, Jean L., Galvis, Laura A., Julier, Ziad, Wood, Alasdair J., Boudier, Thomas, Isiaku, Abdulsalam I., Berger, Silke, Oorschot, Viola, Sonntag, Carmen, Rogers, Kelly L., Marcelle, Christophe, Lieschke, Graham J., Martino, Mikaël M., Bakkers, Jeroen, Currie, Peter D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 11-03-2021; Nature Publishing Group
• Subjects: 13; 13/100; 14; 14/63; 631/250/2504/342; 631/532/2439; 64; 64/116; Ablation; Animals; CCR5 protein; Cell activation; Cell division; Cell interactions; Cell Proliferation; Chemokine receptors; Cytokines; Disease Models, Animal; Gene expression; Humanities and Social Sciences; Humans; Immune response; Immune system; Injuries; Injury analysis; Innate immunity; Macrophages; Macrophages - cytology; Macrophages - metabolism; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Mice; Mice, Inbred C57BL; Microscopy; multidisciplinary; Muscle, Skeletal - cytology; Muscle, Skeletal - injuries; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscles; Musculoskeletal system; Myoblasts - cytology; Myoblasts - metabolism; Nicotinamide; Nicotinamide phosphoribosyltransferase; Nicotinamide Phosphoribosyltransferase - genetics; Nicotinamide Phosphoribosyltransferase - metabolism; PAX7 Transcription Factor - metabolism; Phosphoribosyltransferase; Physiological aspects; Receptors, CCR5 - genetics; Receptors, CCR5 - metabolism; Regeneration - physiology; RNA-Seq; Satellite cells; Science; Science (multidisciplinary); Single-Cell Analysis; Skeletal muscle; Stem Cell Niche; Stem cells; Transferases; Wounds; Zebrafish; Zebrafish - immunology; Zebrafish - metabolism; Australia
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-021-03199-7

Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals
1
. 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.
Specific macrophage populations provide a transient niche that activates muscle stem cells after muscle injury and supply proliferation-inducing cues that govern the repair process mediated by these cells in both zebrafish and mouse injury models.