期刊
EMBO MOLECULAR MEDICINE
卷 6, 期 2, 页码 239-258出版社
WILEY
DOI: 10.1002/emmm.201302520
关键词
endothelial cells; junctional adhesion molecule-A; muscular dystrophy; stem cell therapies
资金
- European Research Council
- European Union [223098, ENDOSTEM-HEALTH-2009-241440, 202213, JUSTBRAIN-HEALTH-2009-241861]
- UK Medical Research Council
- Associazione Italiana per la Ricerca sul Cancro
- Special Program Molecular Clinical Oncology [5 9 1000]
- Italian Ministry of University and Research
- Duchenne Parent Project
- Cariplo Foundation
- Fondation Leducq Transatlantic Network of Excellence
- NIH from National Heart, Lung, and Blood Institute [HL24136, HL59157]
- MRC [MR/J006785/1] Funding Source: UKRI
- Medical Research Council [MR/J006785/1] Funding Source: researchfish
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.
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