title: Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts.
abstract: We postulated that the combination of overexpression of CXCR4 in mesenchymal stem cells (MSC) with diprotin A would enhance MSC recruitment and penetration into ischemic myocardium, leading to an improvement in heart function after myocardial infarction (MI). Male rat MSC were genetically engineered with adenoviral vectors coexpressing CXCR4 and enhanced green fluorescent protein (EGFP) (MSC(CXCR4)), GFP alone (MSC(Null), control), or siRNA-targeted CXCR4 (MSC(siRNA)). Cell sheets were applied over the surface of infarcted left ventricle (LV) in female rats 7 days after ligation of the left anterior descending coronary artery (LAD) pretreated with either vehicle (VEH) or diprotin A (DIP). At 28 days after cell sheet implantation, echocardiography was performed. Hearts were harvested for histological analysis 7 days after LAD ligation or 28 days after cell sheet implantation. DPP-IV and stroma-derived factor-1α (SDF-1α) in the LV were analyzed. Efficacy of engraftment was determined by the presence of Y chromosome in nuclei (Y(ch+)). LV blood vessel density and apoptosis were also analyzed. Myocardial SDF-1α was elevated before placement of the cell sheet in the DIP group compared with vehicle group on day 7 after LAD. On day 28 after cell sheet transplantation, the number of Y(ch+) was increased in the MSC(CXCR4) + VEH group compared with the MSC(Null) + VEH group and further increased in the MSC(CXCR4) + DIP treated group. This enhanced response was associated with increased angiogenesis in both sides of epicardium and improvement of LV function. Combination of gene-manipulated MSC(CXCR4) patch with DIP pretreatment inhibits myocardial ischemia-induced apoptosis, promotes tissue angiogenesis, and enhances cell engraftment, leading to improved LV mechanical function after MI.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0529, USA.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.forename: Bo
authors.initials: B
authors.lastname: Dai
authors.forename: Tiemin
authors.initials: T
authors.lastname: Zhao
authors.forename: Atif
authors.initials: A
authors.lastname: Ashraf
authors.forename: Ronald W
authors.initials: RW
authors.lastname: Millard
authors.forename: Muhammad
authors.initials: M
authors.lastname: Ashraf
authors.forename: Yigang
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D054377:Chemokine CXCL12 / Q000378:metabolism; D003131:Combined Modality Therapy; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006321:Heart / Q000187:drug effects / Q000502:physiology; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D023421:Models, Animal; D009203:Myocardial Infarction / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009842:Oligopeptides; D019718:Receptors, CXCR4; C041445:diprotin A; D018819:Dipeptidyl Peptidase 4
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