Defective angiogenesis in CXCL12 mutant mice impairs skeletal muscle regeneration

Skelet Muscle. 2019 Sep 18;9(1):25. doi: 10.1186/s13395-019-0210-5.

Abstract

Background: During muscle regeneration, the chemokine CXCL12 (SDF-1) and the synthesis of some specific heparan sulfates (HS) have been shown to be critical. CXCL12 activity has been shown to be heavily influenced by its binding to extracellular glycosaminoglycans (GAG) by modulating its presentation to its receptors and by generating haptotactic gradients. Although CXCL12 has been implicated in several phases of tissue repair, the influence of GAG binding under HS influencing conditions such as acute tissue destruction remains understudied.

Methods: To investigate the role of the CXCL12/HS proteoglycan interactions in the pathophysiology of muscle regeneration, we performed two models of muscle injuries (notexin and freeze injury) in mutant CXCL12Gagtm/Gagtm mice, where the CXCL12 gene having been selectively mutated in critical binding sites of CXCL12 to interact with HS. Histological, cytometric, functional transcriptomic, and ultrastructure analysis focusing on the satellite cell behavior and the vessels were conducted on muscles before and after injuries. Unless specified, statistical analysis was performed with the Mann-Whitney test.

Results: We showed that despite normal histology of the resting muscle and normal muscle stem cell behavior in the mutant mice, endothelial cells displayed an increase in the angiogenic response in resting muscle despite the downregulated transcriptomic changes induced by the CXCL12 mutation. The regenerative capacity of the CXCL12-mutated mice was only delayed after a notexin injury, but a severe damage by freeze injury revealed a persistent defect in the muscle regeneration of CXCL12 mutant mice associated with vascular defect and fibroadipose deposition with persistent immune cell infiltration.

Conclusion: The present study shows that CXCL12 is crucial for proper muscle regeneration. We highlight that this homing molecule could play an important role in drastic muscle injuries and that the regeneration defect could be due to an impairment of angiogenesis, associated with a long-lasting fibro-adipogenic scar.

Keywords: Angiogenesis; CXCL12; Endothelial cells; Fibrosis; Heparan sulfates; Muscle stem cells; Regeneration; Skeletal muscle; Vasculogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CXCL12 / genetics*
  • Chemokine CXCL12 / physiology*
  • Elapid Venoms / toxicity
  • Endothelial Cells / pathology
  • Endothelial Cells / physiology
  • Freezing / adverse effects
  • Gene Expression Profiling
  • Heparan Sulfate Proteoglycans / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Muscle, Skeletal / blood supply*
  • Muscle, Skeletal / injuries
  • Muscle, Skeletal / physiopathology*
  • Neovascularization, Physiologic / genetics*
  • Regeneration / drug effects
  • Regeneration / genetics*
  • Regeneration / physiology*
  • Satellite Cells, Skeletal Muscle / pathology
  • Satellite Cells, Skeletal Muscle / physiology

Substances

  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Elapid Venoms
  • Heparan Sulfate Proteoglycans
  • notexin