Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts

Dongsheng Zhang, Wei Huang, Bo Dai, Tiemin Zhao, Atif Ashraf, Ronald W. Millard, Muhammad Ashraf, Yigang Wang

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume299
Issue number5
DOIs
StatePublished - Nov 1 2010

Fingerprint

diprotin A
Mesenchymal Stromal Cells
Stem Cells
Heart Ventricles
Small Interfering RNA
Ligation
Myocardial Infarction
Apoptosis
Y Chromosome
Pericardium
Cell Transplantation

Keywords

  • CXCR4
  • Cell sheet
  • Mesenchymal stem cells
  • Myocardial infarction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts. / Zhang, Dongsheng; Huang, Wei; Dai, Bo; Zhao, Tiemin; Ashraf, Atif; Millard, Ronald W.; Ashraf, Muhammad; Wang, Yigang.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 299, No. 5, 01.11.2010.

Research output: Contribution to journalArticle

Zhang, Dongsheng ; Huang, Wei ; Dai, Bo ; Zhao, Tiemin ; Ashraf, Atif ; Millard, Ronald W. ; Ashraf, Muhammad ; Wang, Yigang. / Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts. In: American Journal of Physiology - Heart and Circulatory Physiology. 2010 ; Vol. 299, No. 5.
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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.

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