Subepicardium of the adult human heart hosts CD117 positive cells that undergo activation in the presence of laminin-1

The precise spatial and temporal expression of extracellular matrix proteins and their receptors, integrins, is critical for proper heart structure and cardiac cell function. We have analyzed and compared the distribution of CD117 positive cells in the human adult normal (n=6) and pathological hearts with chronic ischemic cardiomyopathy (n=10), in relation to the expression and localization of laminin and integrin isoforms. Examination of tissue sections by immunofluorescence revealed that the left atrium contained the highest number of CD117 (+) cells. Moreover, their number in the diseased hearts was significantly higher than in the normal hearts (about 10-fold higher in the mid section of the left ventricle and 6-fold higher in the apex). Within the same heart, CD117 (+) cells were up to 57-fold more numerous in the subepicardium than in the myocardium. The presence of laminin α1 chain, typical for developing myocardium, was observed in the subepicardium and interstitial spaces of the normal hearts and in the subepicardium and endomysium in the pathological hearts, where the branches of laminin-1 were also spread between the subepicardial space and the main myocardium, co-localizing with CD117 (+) α6 integrin (+) cells. While most of the cells in the subepicardium expressed also α6 integrin subunit, within the myocardium α6 integrin was detected on about 50% of CD117 (+) cells in the diseased hearts. In the normal hearts, the percentage of α6 integrin (+) cells was always much lower than in the pathological conditions and identical between the subepicardium and myocardium. The expression of laminin α1β1 chains detected by immunoprecipitation and western blot in the extracts of atria was always higher in the normal hearts, while within the mid-section of the left ventricle it was higher in the pathological hearts. In vitro, laminin-1 coating of the culture dish stimulated migration and proliferation of the cardiac CD117 (+) cells and their migration was inhibited in the presence of the antibodies blocking α6 integrin function. We conclude that chronic post-ischemic remodeling of the heart involves the mechanisms aiming at the regeneration of the myocardium and affecting all: cardiac CD117 (+) cells, extracellular matrix proteins and their receptors. Our observations support the hypothesis that the regeneration process follows the mechanisms operative in the early heart development, during which the epicardiumderived cells give rise to the cells of cardiac lineages and laminin-1 guides primitive cells in their migration from the subepicardial space into the myocardium.