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

Myocardial restoration using tissue-engineered grafts to regenerate the ischemic myocardium offers improved donor cell retention, yet a limited cell survival resulting from poor vascularization needs to be addressed. A cell type derived from the subamnion, namely, cord-lining mesenchymal stem cells (CL-MSC), has recently been identified. Here we present a restorative strategy that combines a fibrin graft containing human CL-MSC and omental flap providing, thereby, cell-, structural-, and angiogenic support to the injured myocardium. The graft consisted of a mixture of 2 x 10(6) CL-MSC-GFP-Fluc and fibrin. Myocardial infarction (MI) was induced in nude rats and following confirmation of ensued heart failure with echocardiography 2 weeks after injury, therapeutic intervention was performed as follows: untreated (MI, n = 7), CL-MSC graft (CL-MSCG, n = 8), CL-MSCG and omental flap (CL-MSCG+ OM, n = 11), and omental flap (OM, n = 8). In vivo bioluminescence imaging at 1, 3, 7, and 14 days post-treatment indicated comparable early donor cell viability between the CL-MSCG and CL-MSCG + OM. Treatment with CL-MSCG + OM improved the myocardial function as assessed by the measurement of end-diastolic left ventricular (LV) pressure (3.53 +/- 0.34 vs. 5.21 +/- 0.54 mmHg, p<0.05), contractility (+dP/dt, 3383.8 +/- 250.78 mmHg vs. 2464.9 +/- 191.8 mmHg, p<0.05), and the relaxation rate (-dP/dt, -2707.2 +/- 250.7 mmHg vs. 1948.7 +/- 207.8 mmHg, p<0.05), compared to MI control 6 weeks after ischemic injury. Furthermore, evidence of a 20.32% increase in the ejection fraction was observed in CL-MSCG+ OM rats from week 2 to 6 after injury. Both CL-MSCG and CL-MSCG + OM led to an enhanced cardiac output (p<0.05), and attenuated the infarct size (35.7%+/- 4.2% and 34.7%+/- 4.8%), as compared to MI (60.7%+/- 3.1%; p<0.01 and p<0.001, respectively). All treated groups had a higher arteriole density than controls. Yet, a higher amount of functional blood vessels, and a 20-fold increase in arteriole numbers were found in CL-MSCG+ OM. Altogether, CL-MSCGs supplemented with vascular supply have the potential to repair the failing, chronically ischemic heart by improving myocardial revascularization, attenuating remodeling, and ameliorating cardiac dysfunction.