TY - JOUR
T1 - Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts
AU - Zhang, Dongsheng
AU - Huang, Wei
AU - Dai, Bo
AU - Zhao, Tiemin
AU - Ashraf, Atif
AU - Millard, Ronald W.
AU - Ashraf, Muhammad
AU - Wang, Yigang
PY - 2010/11
Y1 - 2010/11
N2 - 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.
AB - 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.
KW - CXCR4
KW - Cell sheet
KW - Mesenchymal stem cells
KW - Myocardial infarction
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U2 - 10.1152/ajpheart.00592.2010
DO - 10.1152/ajpheart.00592.2010
M3 - Article
C2 - 20802132
AN - SCOPUS:78249259703
SN - 0363-6135
VL - 299
SP - H1339-H1347
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 5
ER -