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dc.contributor.authorGiannotta, Monica
dc.contributor.authorBenedetti, Sara
dc.contributor.authorTedesco, Francesco Saverio
dc.contributor.authorCorada, Monica
dc.contributor.authorTrani, Marianna
dc.contributor.authorD'Antuono, Rocco
dc.contributor.authorMillet, Queensta
dc.contributor.authorOrsenigo, Fabrizio
dc.contributor.authorGalvez, Beatriz G. 
dc.contributor.authorCossu, Giulio
dc.contributor.authorDejana, Elisabetta
dc.identifier.citationEMBO Mol Med. 2014; 6(2):239-58es_ES
dc.description.abstractMuscular 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.es_ES
dc.description.sponsorshipThis work was supported in part by the European Research Council and the European Union (OPTISTEM-contract-223098, ENDOSTEM-HEALTH-2009-241440, EUSTROKEcontract-202213, and JUSTBRAIN-HEALTH-2009-241861; ITN-2012 Vessels), UK Medical Research Council, Associazione Italiana per la Ricerca sul Cancro, and Special Program Molecular Clinical Oncology 5 9 1000 to AGIMM (AIRCGruppo Italiano Malattie Mieloproliferative), Italian Ministry of University and Research, Duchenne Parent Project, Cariplo Foundation, Fondation Leducq Transatlantic Network of Excellence. NIH grants HL24136 and HL59157 from the National Heart, Lung, and Blood Institute and AngelWorks Foundation (DMcD)es_ES
dc.publisherEMBO Press es_ES
dc.subject.meshAnimals es_ES
dc.subject.meshCardiotoxins es_ES
dc.subject.meshCell Adhesion Molecules es_ES
dc.subject.meshCell Movement es_ES
dc.subject.meshEndothelial Cells es_ES
dc.subject.meshEndothelium, Vascular es_ES
dc.subject.meshGuanine Nucleotide Exchange Factors es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMice es_ES
dc.subject.meshMuscle, Skeletal es_ES
dc.subject.meshMuscular Dystrophies es_ES
dc.subject.meshReceptors, Cell Surface es_ES
dc.subject.meshSarcoglycans es_ES
dc.subject.meshStem Cells es_ES
dc.subject.meshrap1 GTP-Binding Proteins es_ES
dc.subject.meshSignal Transduction es_ES
dc.subject.meshStem Cell Transplantation es_ES
dc.titleTargeting endothelial junctional adhesion molecule-A/ EPAC/ Rap-1 axis as a novel strategy to increase stem cell engraftment in dystrophic muscleses_ES
dc.typejournal articlees_ES
dc.rights.licenseAtribución 4.0 Internacional*
dc.contributor.funderEuropean Research Council 
dc.contributor.funderUnión Europea. Comisión Europea 
dc.contributor.funderMedical Research Council (Reino Unido) 
dc.contributor.funderItalian Association for Cancer Research 
dc.contributor.funderNational Institutes of Health (Estados Unidos) 
dc.contributor.funderMinistero dell Istruzione, dell Universita e della Ricerca (Italia) 
dc.contributor.funderFondation Leducq 
dc.identifier.journalEMBO molecular medicinees_ES
dc.repisalud.orgCNICCNIC::Grupos de investigación::Antiguos CNICes_ES
dc.rights.accessRightsopen accesses_ES

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Atribución 4.0 Internacional
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