title: Bone-marrow-derived CXCR4-positive tissue-committed stem cell recruitment in human right ventricular remodeling.
abstract: 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.
authors.affiliation: Department of Medical-Diagnostic Sciences and Special Therapies, University of Padua, Medical School, 35121 Padua, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Castellani
authors.forename: Massimo
authors.initials: M
authors.lastname: Padalino
authors.forename: Paolo
authors.initials: P
authors.lastname: China
authors.forename: Marny
authors.initials: M
authors.lastname: Fedrigo
authors.forename: Carla
authors.initials: C
authors.lastname: Frescura
authors.forename: Ornella
authors.initials: O
authors.lastname: Milanesi
authors.forename: Giovanni
authors.initials: G
authors.lastname: Stellin
authors.forename: Gaetano
authors.initials: G
authors.lastname: Thiene
authors.forename: Annalisa
authors.initials: A
authors.lastname: Angelini
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D054377:Chemokine CXCL12 / Q000378:metabolism; D002675:Child, Preschool; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome / Q000473:pathology / Q000601:surgery; D007223:Infant; D017493:Leukocyte Common Antigens / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism*; D020257:Ventricular Remodeling
chemical_list: D015415:Biomarkers; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D019009:Proto-Oncogene Proteins c-kit; D017493:Leukocyte Common Antigens; C516769:PTPRC protein, human