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Blood First Edition Paper, prepublished online October 5, 2006; DOI 10.1182/blood-2006-04-018564.
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STEM CELLS IN HEMATOLOGY

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

Manuela Gavina, Marzia Belicchi, Barbara Rossi, Linda Ottoboni, Fabio Colombo, Mirella Meregalli, Maurizio Battistelli, Laura Forzenigo, Piero Biondetti, Federica Pisati, Daniele Parolini, Andrea Farini, Andrew C. Issekutz, Nereo Bresolin, Franco Rustichelli, Gabriela Constantin, and Yvan Torrente

From the Stem Cell Laboratory, Department of Neurological Sciences, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Ospedale Maggiore Policlinico, Centro Dino Ferrari, University of Milan, Italy; the Department of Pathology, Division of General Pathology, University of Verona, Italy; the Fondazione IRCCS Ospedale Maggiore Policlinico, Institute of Nuclear Medicine, Milan, Italy; the Radiology Unit, Fondazione IRCCS Ospedale Maggiore Policlinico of Milan, Italy; the Department of Pediatrics, Pathology, and Microbiology-Immunology, Dalhousie University, Halifax, NS, Canada; and the Department of Sciences Applied to Complex Systems, Polytechnic University of Marche, Ancona, Italy.

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, {alpha}4-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.


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