title: Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium.
abstract: BACKGROUND
  Although mesenchymal stem cell (MSC) transplantation has been shown to promote cardiac repair in acute myocardial injury in vivo, its overall restorative capacity appears to be restricted mainly because of poor cell viability and low engraftment in the ischemic myocardium. Specific chemokines are upregulated in the infarcted myocardium. However the expression levels of the corresponding chemokine receptors (eg, CCR1, CXCR2) in MSCs are very low. We hypothesized that this discordance may account for the poor MSC engraftment and survival.
  
  
  OBJECTIVE
  To determine whether overexpression of CCR1 or CXCR2 chemokine receptors in MSCs augments their cell survival, migration and engraftment after injection in the infarcted myocardium.
  
  
  RESULTS
  Overexpression of CCR1, but not CXCR2, dramatically increased chemokine-induced murine MSC migration and protected MSC from apoptosis in vitro. Moreover, when MSCs were injected intramyocardially one hour after coronary artery ligation, CCR1-MSCs accumulated in the infarcted myocardium at significantly higher levels than control-MSCs or CXCR2-MSCs 3 days postmyocardial infarction (MI). CCR1-MSC-injected hearts exhibited a significant reduction in infarct size, reduced cardiomyocytes apoptosis and increased capillary density in injured myocardium 3 days after MI. Furthermore, intramyocardial injection of CCR1-MSCs prevented cardiac remodeling and restored cardiac function 4 weeks after MI.
  
  
  CONCLUSIONS
  Our results demonstrate the in vitro and in vivo salutary effects of genetic modification of stem cells. Specifically, overexpression of chemokine receptor enhances the migration, survival and engraftment of MSCs, and may provide a new therapeutic strategy for the injured myocardium.
authors.affiliation: Duke University Medical Center & Health System, DUMC 3701, Durham, NC 27701, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Guo
authors.forename: Aiguo
authors.initials: A
authors.lastname: Ni
authors.forename: Arjun
authors.initials: A
authors.lastname: Deb
authors.forename: Lunan
authors.initials: L
authors.lastname: Zhang
authors.forename: Maria
authors.initials: M
authors.lastname: Mirotsou
authors.forename: Richard E
authors.initials: RE
authors.lastname: Pratt
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Dzau
mesh_terms: D000818:Animals; D017209:Apoptosis; D002196:Capillaries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement; D002470:Cell Survival; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D005260:Female; D005355:Fibrosis; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D054389:Receptors, CCR1 / Q000096:biosynthesis* / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis / Q000235:genetics; D020127:Recovery of Function; D012038:Regeneration; D013997:Time Factors; D014161:Transduction, Genetic; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C515301:Ccr1 protein, mouse; D054389:Receptors, CCR1; D023063:Receptors, Interleukin-8B; D049452:Green Fluorescent Proteins; D003094:Collagen