Genetically manipulated progenitor cell sheet with diprotin A improves myocardial function and repair of infarcted hearts.
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.
Zhang
Dongsheng
D
Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0529, USA.
Huang
Wei
W
Dai
Bo
B
Zhao
Tiemin
T
Ashraf
Atif
A
Millard
Ronald W
RW
Ashraf
Muhammad
M
Wang
Yigang
Y
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
D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009842:Oligopeptides; D019718:Receptors, CXCR4; C041445:diprotin A; D018819:Dipeptidyl Peptidase 4
N Engl J Med. 2006 Jul 20;355(3):231-5
16855261
J Mol Histol. 2004 Mar;35(3):233-45
15339043
Nature. 2001 Apr 5;410(6829):701-5
11287958
Circ Res. 2008 May 23;102(10):1155-68
18497316
Cell Stem Cell. 2009 Apr 3;4(4):313-23
19341621
Nat Med. 2006 Apr;12(4):459-65
16582917
J Mol Cell Cardiol. 2010 Apr;48(4):702-12
19913551
J Thorac Cardiovasc Surg. 2005 Nov;130(5):1333-41
16256786
J Leukoc Biol. 2002 Apr;71(4):711-7
11927659
Arterioscler Thromb Vasc Biol. 2007 Feb;27(2):263-5
17229969
Transplantation. 2005 Sep 15;80(5):660-5
16177642
Circulation. 2009 Apr 7;119(13):1814-23
19349334
Am J Physiol Heart Circ Physiol. 2010 Jan;298(1):H275-86
19897711
Circ Res. 2008 Feb 1;102(2):209-17
17991882
J Am Soc Mass Spectrom. 2006 Jun;17(6):815-822
16616859
Clin Chem. 1988 Nov;34(11):2299-301
2902942
FASEB J. 2007 Oct;21(12):3197-207
17496162
Future Cardiol. 2010 Jan;6(1):11-7
20014984
J Mol Cell Cardiol. 2004 Nov;37(5):1041-52
15522281
Circ Res. 2009 May 22;104(10):1209-16
19407239
Circ J. 2008;72 Suppl A:A49-55
18772528
J Mol Cell Cardiol. 2006 Sep;41(3):478-87
16926022
J Mol Cell Cardiol. 2008 Feb;44(2):281-92
18201717
Blood. 2005 Jan 1;105(1):40-8
15328152
Nat Cell Biol. 1999 Jul;1(3):E69-71
10559914
Circulation. 2004 Nov 23;110(21):3300-5
15533866
Nat Rev Cardiol. 2010 Jan;7(1):30-7
19949426
J Biol Chem. 2006 Dec 22;281(51):39542-9
17056591
Blood. 2003 Apr 1;101(7):2609-16
12468435
Blood. 2004 Apr 15;103(8):2942-9
15070669
Science. 2004 Aug 13;305(5686):1000-3
15310902
Natl Vital Stat Rep. 2009 Apr 17;57(14):1-134
19788058
Ann Thorac Surg. 2008 Apr;85(4):1344-6
18355523