Abstract 492: Dual Stem Cell Therapy Improves the Cardiac Function After Experimental Myocardial Infarction

Abstract

As the mortality associated with cardiovascular diseases has accelerated in the past 10 years, advances in treatment options can have significant impact on the global population health. Mesenchymal Stromal Cells (MSC) have shown limited efficacy in clinical trials as sole contributors to tissue regeneration. Thus, we questioned whether the presence of Endothelial Colony Forming Cells (ECFC) could improve MSC-based cellular therapy of the infarcted myocardium. Acute myocardial infarction was induced in immunodeficient NSG mice by left coronary artery ligation and then MSCs or MSCs+ECFCs were immediately injected in the ventricular wall. Both healthy and sham-treated infarcted mice served as controls. At 7 days post-transplantation, echocardiography, qPCR and Western Blot (WB) were performed to assess cardiac function and protein expression. MSC - ECFC reciprocal modulation was studied in vitro by 24-hour co-culture in dual-chamber system or in direct contact, followed by qPCR and WB. The secretome collected from cultures was characterized by Matrigel angiogenesis assay, Proteome Profiler Arrays and ELISA. The results revealed that in dual-cell transplant compared to single transplant group the cardiac function (ejection fraction and stroke volume) was significantly improved. The protein expression of junctional molecules such as Connexin 43 and Integrin α-5 was increased by more than twofold in the MSC+ECFC vs. MSC-only group. Moreover, both MSC and ECFC secreted high levels of pro-angiogenic molecules, with only partially overlapping profiles, capable of inducing tube-like vascular structures on Matrigel. These observations suggest a putative complementary contribution of MSC and ECFC to the cardiac repair process. Significant increase in the Integrin α-5 expression was achieved in both culture settings, indicating a mechanism independent of cell to cell contact. However, a synergistic paracrine effect of the MSC-ECFC pair only occured after close cell interaction, especially for VEGF, SDF-1 and YKL-40, thus suggesting that both cell types are needed for sustained effects. In conclusion, we provide evidence that the complementary, dual stem cell-based therapy could positively modulate the function of infarcted myocardium.