Stromal cell-derived factor-1alpha activation of tissue-engineered endothelial progenitor cell matrix enhances ventricular function after myocardial infarction by inducing neovasculogenesis.
BACKGROUND
Myocardial ischemia causes cardiomyocyte death, adverse ventricular remodeling, and ventricular dysfunction. Endothelial progenitor cells (EPCs) have been shown to ameliorate this process, particularly when activated with stromal cell-derived factor-1α (SDF), known to be the most potent EPC chemokine. We hypothesized that implantation of a tissue-engineered extracellular matrix (ECM) scaffold seeded with EPCs primed with SDF could induce borderzone neovasculogenesis, prevent adverse geometric remodeling, and preserve ventricular function after myocardial infarction.


RESULTS
Lewis rats (n=82) underwent left anterior descending artery ligation to induce myocardial infarction. EPCs were isolated, characterized, and cultured on a vitronectin/collagen scaffold and primed with SDF to generate the activated EPC matrix (EPCM). EPCM was sutured to the anterolateral left ventricular wall, which included the region of ischemia. Control animals received sutures but no EPCM. Additional groups underwent application of the ECM alone, ECM primed with SDF (ECM+SDF), and ECM seeded with EPCs but not primed with SDF (ECM+SDF). At 4 weeks, borderzone myocardial tissue demonstrated increased levels of vascular endothelial growth factor in the EPCM group. When compared to controls, Vessel density as assessed by immunohistochemical microscopy was significantly increased in the EPCM group (4.1 versus 6.2 vessels/high-powered field; P<0.001), and microvascular perfusion measured by lectin microangiography was enhanced 4-fold (0.7% versus 2.7% vessel volume/section volume; P=0.04). Comparisons to additional groups also showed a significantly improved vasculogenic response in the EPCM group. Ventricular geometry and scar fraction assessed by digital planimetric analysis of sectioned hearts exhibited significantly preserved left ventricular internal diameter (9.7 mm versus 8.6 mm; P=0.005) and decreased infarct scar formation expressed as percent of total section area (16% versus 7%; P=0.002) when compared with all other groups. In addition, EPCM animals showed a significant preservation of function as measured by echocardiography, pressure-volume conductance, and Doppler flow.


CONCLUSIONS
Extracellular matrix seeded with EPCs primed with SDF induces borderzone neovasculogenesis, attenuates adverse ventricular remodeling, and preserves ventricular function after myocardial infarction.
Frederick
John R
JR
Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Fitzpatrick
J Raymond
JR
McCormick
Ryan C
RC
Harris
David A
DA
Kim
Ah-Young
AY
Muenzer
Jeffrey R
JR
Marotta
Nicole
N
Smith
Maximilian J
MJ
Cohen
Jeffrey E
JE
Hiesinger
William
W
Atluri
Pavan
P
Woo
Y Joseph
YJ
D000818:Animals; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D003094:Collagen; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology*; D005109:Extracellular Matrix; D006801:Humans; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051381:Rats; D011917:Rats, Inbred Lew; D013234:Stem Cells / Q000166:cytology*; D023822:Tissue Engineering / Q000379:methods*; D018754:Ventricular Dysfunction / Q000473:pathology / Q000628:therapy; D019096:Vitronectin
D054377:Chemokine CXCL12; D019096:Vitronectin; D003094:Collagen