Intravenous infusion of mesenchymal stem cells enhances regional perfusion and improves ventricular function in a porcine model of myocardial infarction

Abstract

Transplantation of stem cells may improve regional perfusion and post-infarct ventricular function, but the optimal dose and efficacy of cell delivery via the intravenous route has not been determined. This study tested the hypothesis that intravenous infusion of bone marrow-derived mesenchymal stem cells (MSCs) enhances regional perfusion and improves ventricular function after myocardial infarction. In a closed-chest pig model, the LAD coronary artery was occluded for 75 min by angioplasty balloon inflation followed by 12 weeks of reperfusion. After 15 min of reperfusion, pigs randomly received 1 of 4 treatments: (1) Vehicle (Control, n = 10); (2) 1 x 10(6) MSCs/kg (1 mill, n = 7); (3) 3 x 10(6) MSCs/kg (3 mill, n = 8) and (4) 10 x 10(6) MSCs/kg (10 mill, n = 8). Angiogenesis was demonstrated by immunohistochemical staining, myocardial blood flow (steady state and vasodilator reserve) was measured using 15 microm neutron-activated microspheres, and cardiac function was determined by contrast left ventriculography (ejection fraction) and pressure-volume relationships. After 12 week of reperfusion, von Willebrand Factor-positive vessels and tissue vascular endothelial growth factor (VEGF) expression in the scar zone was significantly greater in all MSCs-treated animals relative to Control. Steady state myocardial blood flow in the scar tissue was comparable among groups. However, adenosine recruited vasodilator reserve in the scar zone induced by intracoronary adenosine was significantly higher in the MSC-treated animals compared to Control. Furthermore, preload-recruitable stroke work and systolic performance were significantly greater compared to Control. In conclusion, these data demonstrate that intravenous delivery of MSCs during early reperfusion augments vasculogenesis, enhances regional perfusion, and improves post-infarct ventricular function. The results suggest that intravenous infusion of MSCs is an effective modality for the treatment of ischemia/reperfusion induced myocardial injury.

Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity

“…As we have previously reported in an acute MI model, the area of greatest engraftment and regeneration resides in the border zone between infarcted tissue and viable myocardium. In addition, as we and others have previously reported (23,25,26), increased tissue perfusion is the earliest observable outcome of cell therapy in the early post infarct heart, an effect that occurs here as well. Infarct size reduction and enhanced global and regional function are progressive effects that occur time dependently over a 3-month period.…”

Dose Comparison Study of Allogeneic Mesenchymal Stem Cells in Patients With Ischemic Cardiomyopathy (The TRIDENT Study)

“…Although several studies have demonstrated the safety of both autologous and allogeneic cell products, 3,5,[14][15][16][17][18] the few preclinical [19][20][21][22] and clinical studies [4][5][6][23][24][25] that examined dosing present conflicting and inconsistent results about the relationship between the quantity of cells delivered and clinical efficacy. Because they are biological products, the well-established principles of pharmacokinetics may not be applicable to stem cells.…”

Cord Lining-Mesenchymal Stem Cells Graft Supplemented with an Omental Flap Induces Myocardial Revascularization and Ameliorates Cardiac Dysfunction in a Rat Model of Chronic Ischemic Heart Failure

“…Both local 25,27,41,42 and systemic 43 delivery of allogeneic MSC increases vasculogenesis, enhances myocardial perfusion, 27,43 and improves postinfarct cardiac function. Growing evidence supports a paracrine-mediated stem cell action in tissue protection and repair.…”