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Brain Advance Access originally published online on April 17, 2007
Brain 2007 130(5):1289-1305; doi:10.1093/brain/awm043
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Neural stem cells LewisX + CXCR4 + modify disease progression in an amyotrophic lateral sclerosis model

Stefania Corti1,2, Federica Locatelli1, Dimitra Papadimitriou1, Roberto Del Bo1, Monica Nizzardo1, Martina Nardini1, Chiara Donadoni1, Sabrina Salani1, Francesco Fortunato1, Sandra Strazzer3, Nereo Bresolin1,2,3 and Giacomo P. Comi1,2

1Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Milan, 2Centre of Excellence on Neurodegenerative Diseases, University of Milan, Milan and 3IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy

Correspondence to: Department of Neurological Sciences, University of Milan, IRCCS Foundation Ospedale Maggiore Policlinico, Mangiagalli and Regina Elena, Padiglione Ponti, Via Francesco Sforza 35, 20122 Milan, Italy E-mail: giacomo.comi{at}unimi.it

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the degeneration of the motor neurons. We tested whether treatment of superoxide dismutase (SOD1)-G93A transgenic mouse, a model of ALS, with a neural stem cell subpopulation double positive for Lewis X and the chemokine receptor CXCR4 (LeX+CXCR4+) can modify the disease's progression. In vitro, after exposure to morphogenetic stimuli, LeX+CXCR4+ cells generate cholinergic motor neuron-like cells upon differentiation. LeX+CXCR4+ cells deriving from mice expressing Green Fluorescent Protein in all tissues or only in motor neurons, after a period of priming in vitro, were grafted into spinal cord of SOD1-G93A mice.

Transplanted transgenic mice exhibited a delayed disease onset and progression, and survived significantly longer than non-treated animals by 23 days. Examination of the spinal cord revealed integration of donor-derived cells that differentiated mostly in neurons and in a lower proportion in motor neuron-like cells. Quantification of motor neurons of the spinal cord suggests a significant neuroprotection by LeX+CXCR4+ cells. Both VEGF- and IGF1-dependent pathways were significantly modulated in transplanted animals compared to controls, suggesting a role of these neurotrophins in MN protection.

Our results support the therapeutic potential of neural stem cell fractions through both neurogenesis and growth factors release in motor neuron disorders.

Key Words: neural stem cell; transplantation; motor neuron; amyotrophic lateral sclerosis

Abbreviations: ALS, amyotrophic lateral sclerosis; NSC, neural stem cells; CNS, central nervous system; NGF, neural growth factor

Received August 15, 2006. Revised February 13, 2007. Accepted February 15, 2007.


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