title: Targeting endothelial junctional adhesion molecule-A/ EPAC/ Rap-1 axis as a novel strategy to increase stem cell engraftment in dystrophic muscles.
abstract: Muscular dystrophies are severe genetic diseases for which no efficacious therapies exist. Experimental clinical treatments include intra-arterial administration of vessel-associated stem cells, called mesoangioblasts (MABs). However, one of the limitations of this approach is the relatively low number of cells that engraft the diseased tissue, due, at least in part, to the sub-optimal efficiency of extravasation, whose mechanisms for MAB are unknown. Leukocytes emigrate into the inflamed tissues by crossing endothelial cell-to-cell junctions and junctional proteins direct and control leukocyte diapedesis. Here, we identify the endothelial junctional protein JAM-A as a key regulator of MAB extravasation. We show that JAM-A gene inactivation and JAM-A blocking antibodies strongly enhance MAB engraftment in dystrophic muscle. In the absence of JAM-A, the exchange factors EPAC-1 and 2 are down-regulated, which prevents the activation of the small GTPase Rap-1. As a consequence, junction tightening is reduced, allowing MAB diapedesis. Notably, pharmacological inhibition of Rap-1 increases MAB engraftment in dystrophic muscle, which results into a significant improvement of muscle function offering a novel strategy for stem cell-based therapies.
authors.affiliation: FIRC Institute of Molecular Oncology Foundation (IFOM), Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Giannotta
authors.forename: Sara
authors.initials: S
authors.lastname: Benedetti
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Tedesco
authors.forename: Monica
authors.initials: M
authors.lastname: Corada
authors.forename: Marianna
authors.initials: M
authors.lastname: Trani
authors.forename: Rocco
authors.initials: R
authors.lastname: D'Antuono
authors.forename: Queensta
authors.initials: Q
authors.lastname: Millet
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Orsenigo
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Gálvez
authors.forename: Giulio
authors.initials: G
authors.lastname: Cossu
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Dejana
mesh_terms: D000818:Animals; D054715:Cardiotoxins; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000293:injuries / Q000473:pathology; D009136:Muscular Dystrophies / Q000473:pathology / Q000601:surgery / Q000628:therapy*; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*; D049031:Sarcoglycans / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D054715:Cardiotoxins; D015815:Cell Adhesion Molecules; C482601:Epac protein, mouse; C498686:F11r protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D011956:Receptors, Cell Surface; D049031:Sarcoglycans; D020827:rap1 GTP-Binding Proteins