Targeting endothelial junctional adhesion molecule-A/ EPAC/ Rap-1 axis as a novel strategy to increase stem cell engraftment in dystrophic muscles.
EMBO Mol Med
; 6(2): 239-58, 2014 02.
Article
in En
| MEDLINE
| ID: mdl-24378569
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stem Cells
/
Signal Transduction
/
Cell Adhesion Molecules
/
Receptors, Cell Surface
/
Rap1 GTP-Binding Proteins
/
Guanine Nucleotide Exchange Factors
/
Stem Cell Transplantation
/
Muscular Dystrophies
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
EMBO Mol Med
Journal subject:
BIOLOGIA MOLECULAR
Year:
2014
Document type:
Article
Affiliation country:
Italy