title: Human epicardium-derived cells fuse with high efficiency with skeletal myotubes and differentiate toward the skeletal muscle phenotype: a comparison study with stromal and endothelial cells.
abstract: Recent studies have underscored a role for the epicardium as a source of multipotent cells. Here, we investigate the myogenic potential of adult human epicardium-derived cells (EPDCs) and analyze their ability to undergo skeletal myogenesis when cultured with differentiating primary myoblasts. Results are compared to those obtained with mesenchymal stromal cells (MSCs) and with endothelial cells, another mesodermal derivative. We demonstrate that EPDCs spontaneously fuse with pre-existing myotubes with an efficiency that is significantly higher than that of other cells. Although at a low frequency, endothelial cells may also contribute to myotube formation. In all cases analyzed, after entering the myotube, nonmuscle nuclei are reprogrammed to express muscle-specific genes. The fusion competence of nonmyogenic cells in vitro parallels their ability to reconstitute dystrophin expression in mdx mice. We additionally show that vascular cell adhesion molecule 1 (VCAM1) expression levels of nonmuscle cells are modulated by soluble factors secreted by skeletal myoblasts and that VCAM1 function is required for fusion to occur. Finally, treatment with interleukin (IL)-4 or IL-13, two cytokines released by differentiating myotubes, increases VCAM1 expression and enhances the rate of fusion of EPDCs and MSCs, but not that of endothelial cells.
authors.affiliation: Laboratorio di Patologia Vascolare, Istituto Dermopatico dell'Immacolata-IRCCS, 00167 Rome, Italy.
authors.forename: Antonietta
authors.initials: A
authors.lastname: Gentile
authors.forename: Gabriele
authors.initials: G
authors.lastname: Toietta
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Pazzano
authors.forename: Vasileios D
authors.initials: VD
authors.lastname: Tsiopoulos
authors.forename: Ada Francesca
authors.initials: AF
authors.lastname: Giglio
authors.forename: Filippo
authors.initials: F
authors.lastname: Crea
authors.forename: Giulio
authors.initials: G
authors.lastname: Pompilio
authors.forename: Maurizio C
authors.initials: MC
authors.lastname: Capogrossi
authors.forename: Giuliana
authors.initials: G
authors.lastname: Di Rocco
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002459:Cell Fusion; D002467:Cell Nucleus / Q000378:metabolism; D065150:Cellular Reprogramming / Q000235:genetics; D018920:Coculture Techniques; D016189:Dystrophin / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D018793:Interleukin-13 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D018101:Mice, Inbred mdx; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology*; D017570:MyoD Protein / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D010496:Pericardium / Q000166:cytology*; D010641:Phenotype; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism / Q000637:transplantation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D016189:Dystrophin; D018793:Interleukin-13; D017570:MyoD Protein; D019948:Receptors, Interleukin-4; D019010:Vascular Cell Adhesion Molecule-1; D015847:Interleukin-4