Bone-marrow-derived CXCR4-positive tissue-committed stem cell recruitment in human right ventricular remodeling

The epicardium contributes to cardiac formation, particularly during embryogenesis. It remains to be seen if it is also involved in postnatal myocardial homeostasis. This study evaluates the topographic distribution of stem cells (c-Kit) and extracardiac progenitor cells (CXCR4+) and their contribution to ventricular remodeling in a model of pressure volume overload leading to right ventricle hypertrophy. Eleven specimens with hypoplastic left heart syndrome were evaluated and compared with 6 normal hearts from subjects matched for age and weight. All underwent Norwood procedure with the right ventricle becoming a systemic one, with pressure and volume overload leading to right ventricle remodeling. Transmural cardiac tissue samples from the right ventricle were analyzed by immunohistochemistry and morphometry. This is the first study to demonstrate that c-Kit-positive progenitor cells and tissue-committed stem cells (CXCR4+/CD45-) are higher in children with systemic right ventricle remodeling. We also show that the localization of cardiac progenitor and recruited CXCR4+ stem cells in the myocardium is site specific in hearts with right ventricle hypertrophy. These cells are mainly scattered in the interstitium of the epicardial layer. In contrast, myocyte proliferation is not a key process in right ventricular hypertrophy. Induced by the overexpression of SDF-1α by the myocardium, CXCR4 cell mobilization resembles SDF-1 homing factor distribution, showing transmural enhanced expression from the endocardium toward the epicardium. The study provides evidences of the site-specific epicardial localization of stem cells in a model of pressure/volume overload and suggests that the epicardium acts as a permissive niche in normal and pathologic conditions.