title: Beneficial effect of mechanical stimulation on the regenerative potential of muscle-derived stem cells is lost by inhibiting vascular endothelial growth factor.
abstract: OBJECTIVE
  We previously reported that mechanical stimulation increased the effectiveness of muscle-derived stem cells (MDSCs) for tissue repair. The objective of this study was to determine the importance of vascular endothelial growth factor (VEGF) on mechanically stimulated MDSCs in a murine model of muscle regeneration.
  
  
  RESULTS
  MDSCs were transduced with retroviral vectors encoding the LacZ reporter gene (lacZ-MDSCs), the soluble VEGF receptor Flt1 (sFlt1-MDSCs), or a short hairpin RNA (shRNA) targeting messenger RNA of VEGF (shRNA_VEGF MDSCs). Cells were subjected to 24 hours of mechanical cyclic strain and immediately transplanted into the gastrocnemius muscles of mdx/scid mice. Two weeks after transplantation, angiogenesis, fibrosis, and regeneration were analyzed. There was an increase in angiogenesis in the muscles transplanted with mechanically stimulated lacZ-MDSCs compared with nonstimulated lacZ-MDSCs, sFlt1-MDSCs, and shRNA _VEGF MDSCs. Dystrophin-positive myofiber regeneration was significantly lower in the shRNA_VEGF-MDSC group compared with the lacZ-MDSC and sFlt1-MDSC groups. In vitro proliferation of MDSCs was not decreased by inhibition of VEGF; however, differentiation into myotubes and adhesion to collagen were significantly lower in the shRNA_VEGF-MDSC group compared with the lacZ-MDSC and sFlt1-MDSC groups.
  
  
  CONCLUSIONS
  The beneficial effects of mechanical stimulation on MDSC-mediated muscle repair are lost by inhibiting VEGF.
authors.affiliation: Departments of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, PA 15219, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Beckman
authors.forename: William C W
authors.initials: WC
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Tang
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Proto
authors.forename: Logan
authors.initials: L
authors.lastname: Mlakar
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.forename: Johnny
authors.initials: J
authors.lastname: Huard
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics / Q000502:physiology; D006085:Graft Survival / Q000502:physiology; D007763:Lac Operon; D051379:Mice; D018101:Mice, Inbred mdx; D016513:Mice, SCID; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology* / Q000502:physiology*; D009137:Muscular Dystrophy, Animal / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D018919:Neovascularization, Physiologic / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D012038:Regeneration / Q000502:physiology; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D013314:Stress, Mechanical; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics
chemical_list: D016189:Dystrophin; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: angiogenesis; muscular dystrophies; stem cells; vascular endothelial growth factor