Nature. 2021 Mar;591(7849):281-287. doi: 10.1038/s41586-021-03199-7. | PubMed

Dhanushika Ratnayake^1,2, Phong D Nguyen^3,4, Fernando J Rossello^1,5, Verena C Wimmer^6,7, Jean L Tan^1,2, Laura A Galvis^1,8, Ziad Julier^1,2, Alasdair J Wood^1,2, Thomas Boudier^6,7, Abdulsalam I Isiaku¹, Silke Berger^1,2, Viola Oorschot^9,10, Carmen Sonntag^1,2, Kelly L Rogers^6,7, Christophe Marcelle^1,8, Graham J Lieschke¹, Mikaël M Martino^1,2, Jeroen Bakkers^3,4, Peter D Currie^11,12

1. Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia.
2. EMBL Australia, Monash University, Clayton, Victoria, Australia.
3. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, Utrecht, The Netherlands.
4. Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
5. University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia.
6. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
7. Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
8. Institut NeuroMyoGène (INMG), University Claude Bernard Lyon 1, CNRS UMR 5310, INSERM U1217, Lyon, France.
9. Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Melbourne, Victoria, Australia.
10. European Molecular Biology Laboratory, Electron Microscopy Core Facility, Heidelberg, Germany.
11. Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia. peter.currie@monash.edu.
12. EMBL Australia, Monash University, Clayton, Victoria, Australia. peter.currie@monash.edu.

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.

Presented By Dhanushika Ratnayake | ORCID iD