Epicardium-derived cells and CD117-positive cells in the adult human heart: common origin through epithelial-mesenchymal transition.

Growing number of studies indicate epicardium-derived cells (EPDCs) as cardiac stem cells. While it is beyond doubt that these cells contribute to the normal developmentof the heart during organogenesis, it remains an open question whether mesothelial epicardial cells can undergo epithelial–mesenchymal transition, giving origin to cardiac primitive cells, in the adult human heart. We examined epicardium and subepicardium of the atria of human adult normal (n=11, mean age 41±12 years, 7 males, 4 females) and pathological hearts with chronic heart failure due to ischemic cardiomyopathy (n=22, mean age 55±5.5 years, 14 males, 8 females, mean ejection fraction 25±1%). Strikingly, only the normal adult human hearts were layered with epicardial cells. On the contrary, cell nuclei were absent from the surface lining of the diseased hearts. While normal epicardium resulted positive for cytokeratin 5/6, E-cadherin and Bves, in the pathological hearts the cells with epithelial markers were distributed among loose connective tissue of the subepicardium. Remarkably, these cells were CD117-positive and, when compared with subepicardium of normal heart, their number was 8.7-fold (p‹0.005) higher in the subepicardium of hearts with ischemic cardiomyopathy. In the PCR-based array of CD117-positive cells isolated from normal and pathological hearts, TGFβ and HGF receptor signaling pathways (both known inducers of EMT) resulted activated in the latter. Considering the hypothesis that EPDCs contribute to the cardiac CD117-positive cells population in the adult heart, fragments of epicardium of adult human cardiac atria were cultured on the extracellular matrix produced by cardiac fibroblasts, to obtain the outgrowth of the mesothelial cells forming epithelial sheets. When stimulated with TGFβ and HGF, intercellular contacts were lost and cells acquired mesenchymal characteristics and CD117 expression. Altogether, these results indicate that EPDCs enrich the pool of cardiac primitive cells that contribute to the regenerative properties of the adult human heart. It could be reasonably argued that CD117-positive and EPDCs represent the same primitive cell population.