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



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.



Rap-1 inhibitors block junction tightening and allow muscle-cell progenitors extravasation, thereby enhancing their engraftment to dystrophic muscles, highlighting them as potential agents to optimize cell therapy protocols for muscular dystrophies.

  • Myogenic vessel associated progenitors (mesoangioblasts) transmigrate through endothelial cell-to-cell junctions to engraft into dystrophic skeletal muscle
  • Impairment of endothelial Junction Adhesion Molecule-A (JAM-A) expression or function increases significantly mesoangioblast diapedesis into skeletal muscle.
  • A higher number of infiltrated mesangioblasts correlates with improved skeletal muscle regeneration and function.
  • Abrogation of JAM-A expression or function in endothelial cells hampers small GTPase Rap-1 activation and proper localization via EPAC-1 and 2 down-regulation.
  • Pharmacological inhibition of Rap-1 increases mesoangioblast engraftment in dystrophic muscle and results into a significant functional amelioration