Abstract 3902: Human Adult Epicardium-Derived Cells and Cardiomyocyte Progenitor Cells Act Synergistically in the Infarcted Adult Heart
Applying cooperating cell types to treat the infarcted heart is encouraging, since several complex pathways are involved in scar formation. We demonstrated that combining adult human epicardium-derived cells (EPDCs), known as supporting cells that stimulate the surrounding tissue, and cardiomyocyte progenitor cells (CMPCs) synergistically increased recovery of the infarcted heart. CMPCs, identified by expression of an epitope recognizing mouse sca-1, and EPDCs were isolated from human adult atrial tissue. Cells were cultured either separately or together or with conditioned medium of the other cell type, and studied for proliferation and migratory behavior. After coronary artery ligation in immune-compromised mice, EPDCs (n=20), CMPCs (n=13), a mixture of EPDCs and CMPCs (n=14), or vehicle only (n=17) was injected into the infarcted area (4x105 cells per heart). Cardiac function was determined with a 9.4T animal MRI six weeks after surgery. Proliferation of EPDCs and migration capacity of CMPCs was significantly increased when cells were cultured with conditioned medium of the other cell type, indicating a paracrine mutual stimulation. Ejection fraction (EF) was significantly higher and end-systolic (ESV) and end-diastolic volumes (EDV) were significantly smaller after transplantation of EPDCs, CMPCs, or a combination of CMPCs and EPDCs than after vehicle injection (p<0.05). Strikingly, EF was significantly increased in the group that received a combination of CMPCs and EPDCs compared to the groups in which only one of these cell types was injected (CMPCs + EPDCs together: 45.4±2.6% vs. CMPCs: 32.7± 3.0% or vs. EPDCs: 35.6± 2.0%, p<0.05). Moreover, ESV and EDV of the combination group were comparable to values of non-infarcted hearts, while volumes of the other groups were significantly larger. When applied separately, CMPCs and EPDCs preserve cardiac function after a myocardial infarction. In combination, CMPCs and EPDCs act synergistically and further ameliorate left ventricular function of the infarcted heart, probably through a paracrine effect. These results suggest that a cocktail of synergistically working cells might further improve clinical regeneration therapy of the infarcted heart.