CD117-positive cells contributing to cardiac cell turnover in normal and pathological conditions have recently been described in adult human heart. Since the precise spatial and temporal expression of extracellular matrix proteins and their receptors is critical for organ formation, we compared the distribution of cardiac primitive CD117-positive cells in the human adult normal and pathological hearts with ischemic cardiomyopathy, with respect to localization and expression of laminin and integrin isoforms. In the pathological hearts, CD117-positive cells were significantly more numerous than in the normal hearts. They were localized mainly in the atria and were up to 38-fold more numerous in the subepicardium than in the myocardium. Compared with normal hearts, most CD117-positive cells in the subepicardium of pathological hearts were alpha(6) integrin-positive. Laminin-1, typical of developing heart, was found predominantly in the subepicardium of adult heart. Immunoblotting revealed its highest expression in the normal atrium and pathological left ventricle. Both laminin isoforms reduced apoptosis and increased proliferation and migration of CD117-positive cells in vitro with respect to control, but the effects of laminin-1 significantly outweighed those of laminin-2. Signaling mediated by alpha(6) integrin was implicated in the migration and protection from apoptosis, as documented by transfection with specific small interfering RNA. These data reveal that the increase in the number of cardiac CD117-positive cells and the expression of laminin-1 are observed in ischemic cardiomyopathy. Subepicardial localization of CD117-positive cells and expression of laminin-1 and alpha(6) integrin subunits may all correspond to the activation of regeneration involving an epithelial-mesenchymal transition recently described in adult heart.
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