Targeting endothelial junctional adhesion molecule‐A/ EPAC/ Rap‐1 axis as a novel strategy to increase stem cell engraftment in dystrophic muscles

Autor: Monica Giannotta, Sara Benedetti, Francesco Saverio Tedesco, Monica Corada, Marianna Trani, Rocco D'Antuono, Queensta Millet, Fabrizio Orsenigo, Beatriz G Gálvez, Giulio Cossu, Elisabetta Dejana
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 6, Iss 2, Pp 239-258 (2013)
Druh dokumentu: article
ISSN: 20130252
1757-4676
1757-4684
DOI: 10.1002/emmm.201302520
Popis: 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.
Databáze: Directory of Open Access Journals
Externí odkaz: