VCAM-1 expression on dystrophic muscle vessels has a critical role in the recruitment of human blood-derived CD133+ stem cells after intra-arterial transplantation.
Recently our group demonstrated the myogenic capacity of human CD133(+) cells isolated from peripheral blood when delivered in vivo through the arterial circulation into the muscle of dystrophic scid/mdx mice. CD133(+) stem cells express the adhesion molecules CD44, LFA-1, PSGL-1, alpha4-integrins, L-selectin, and chemokine receptor CCR7. Moreover these cells adhere in vitro to VCAM-1 spontaneously and after stimulation with CCL19. Importantly, after muscle exercise, we found that the expression of VCAM-1 is strongly up-regulated in dystrophic muscle vessels, whereas the number of rolling and firmly adhered CD133(+) stem cells significantly increased. Moreover, human dystrophin expression was significantly increased when muscle exercise was performed 24 hours before the intra-arterial injection of human CD133(+) cells. Finally, treatment of exercised dystrophic mice with anti-VCAM-1 antibodies led to a dramatic blockade of CD133(+) stem cell migration into the dystrophic muscle. Our results show for the first time that the expression of VCAM-1 on dystrophic muscle vessels induced by exercise controls muscle homing of human CD133(+) stem cells, opening new perspectives for a potential therapy of muscular dystrophy based on the intra-arterial delivery of CD133(+) stem cells.
Gavina
Manuela
M
Stem Cell Laboratory, Department of Neurological Sciences, IRCCS, Centro Dino Ferrari, University of Milan, Ospedale Maggiore Policlinico, via Francesco Sforza 35, 20122 Milan, Italy.
Belicchi
Marzia
M
Rossi
Barbara
B
Ottoboni
Linda
L
Colombo
Fabio
F
Meregalli
Mirella
M
Battistelli
Maurizio
M
Forzenigo
Laura
L
Biondetti
Piero
P
Pisati
Federica
F
Parolini
Daniele
D
Farini
Andrea
A
Issekutz
Andrew C
AC
Bresolin
Nereo
N
Rustichelli
Franco
F
Constantin
Gabriela
G
Torrente
Yvan
Y
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002448:Cell Adhesion; D016189:Dystrophin / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007269:Injections, Intra-Arterial; D051379:Mice; D018101:Mice, Inbred mdx; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism*; D009137:Muscular Dystrophy, Animal / Q000378:metabolism* / Q000628:therapy*; D010455:Peptides / Q000378:metabolism; D036102:Peripheral Blood Stem Cell Transplantation; D019707:Receptors, Chemokine / Q000378:metabolism; D014183:Transplantation, Heterologous; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*
D000071916:AC133 Antigen; D015703:Antigens, CD; D016189:Dystrophin; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D019707:Receptors, Chemokine; D019010:Vascular Cell Adhesion Molecule-1