title: Transmyocardial Revascularization Enhances Bone Marrow Stem Cell Engraftment in Infarcted Hearts Through SCF-C-kit and SDF-1-CXCR4 Signaling Axes.
abstract: BACKGROUND
  We investigated the roles of stem cell factor (SCF)-c-kit and stromal derived factor-1 (SDF-1)-CXCR4 signaling axes in transmyocardial revascularization (TMR)-enhanced engraftment of transplanted bone marrow stem cells (BMSCs) in infarcted hearts.
  
  
  METHODS
  3 weeks after LAD ligation, female Lewis rats underwent 10-channel needle-TMR, followed by daily IV injections of 1 million male donor BMSC for 5 days, either wild type (WT) or with knockdown (K/D) of c-kit or CXCR4, accomplished via a shRNA + plasmid in a lentiviral vector (N = 6/group).
  
  
  RESULTS
  In our rat infarct model, 3 days after last BMSC injection, the number of BMSCs that homed into infarct was affected by both TMR and donor cell type, with greater BMSC engraftment with TMR and with WT BMSC (TMR, cell type, and interaction, P < 0.05). At 1 week, these differences persisted (TMR and cell type, P < 0.05). At 3 days, TMR significantly upregulated transcription of c-kit (TMR, p < 0.05), SCF (TMR and cell type, P < 0.05), CXCR4 (TMR and cell type, p < 0.05), and SDF-1 (TMR and cell type, P < 0.05). At 1 week, we saw similar declines in expression of c-kit (cell type, P < 0.05), SCF (TMR, P < 0.05), CXCR4 (TMR and cell type, P < 0.05), and SDF-1 (TMR, P < 0.05). At 1 week, TMR improved LV ejection fraction (LVEF) (N = 5) when WT BMSCs were infused, but knockdown of either c-kit or CXCR4 completely abrogated this TMR-mediated augmentation of BMSC reparative effect (TMR and cell type, P < 0.05).
  
  
  CONCLUSIONS
  Downregulation of either c-kit or CXCR4 in BMSC decreased engraftment of circulating BMSC and inhibited reparative effects of TMR.
authors.affiliation: Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Uswa
authors.initials: U
authors.lastname: Shahzad
authors.forename: Guangming
authors.initials: G
authors.lastname: Li
authors.forename: Yaoguang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ren-Ke
authors.initials: RK
authors.lastname: Li
authors.forename: Vivek
authors.initials: V
authors.lastname: Rao
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Yau
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D051381:Rats; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D057769:Transmyocardial Laser Revascularization
chemical_list: D019718:Receptors, CXCR4; D019009:Proto-Oncogene Proteins c-kit