Macrophages provide a transient muscle stem cell niche via NAMPT secretion

Nature. 2021 Mar;591(7849):281-287. doi: 10.1038/s41586-021-03199-7. Epub 2021 Feb 10.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • PAX7 Transcription Factor
  • Receptors, CCR5
  • Nicotinamide Phosphoribosyltransferase
  • Matrix Metalloproteinase 9