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Brain Advance Access published online on December 23, 2009
Brain, doi:10.1093/brain/awp318
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© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Embryonic stem cell-derived neural stem cells improve spinal muscular atrophy phenotype in mice

Stefania Corti1,2, Monica Nizzardo1, Martina Nardini1, Chiara Donadoni1, Sabrina Salani1, Dario Ronchi1, Chiara Simone1, Marianna Falcone1, Dimitra Papadimitriou1, Federica Locatelli3, Nicoletta Mezzina1, Francesca Gianni1, Nereo Bresolin1,2,3 and Giacomo P. Comi1,2

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

Correspondence to: Giacomo P. Comi, 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

Spinal muscular atrophy, characterized by selective loss of lower motor neurons, is an incurable genetic neurological disease leading to infant mortality. We previously showed that primary neural stem cells derived from spinal cord can ameliorate the spinal muscular atrophy phenotype in mice, but this primary source has limited translational value. Here, we illustrate that pluripotent stem cells from embryonic stem cells show the same potential therapeutic effects as those derived from spinal cord and offer great promise as an unlimited source of neural stem cells for transplantation. We found that embryonic stem cell-derived neural stem cells can differentiate into motor neurons in vitro and in vivo. In addition, following their intrathecal transplantation into spinal muscular atrophy mice, the neural stem cells, like those derived from spinal cord, survived and migrated to appropriate areas, ameliorated behavioural endpoints and lifespan, and exhibited neuroprotective capability. Neural stem cells obtained using a drug-selectable embryonic stem cell line yielded the greatest improvements. As with cells originating from primary tissue, the embryonic stem cell-derived neural stem cells integrated appropriately into the parenchyma, expressing neuron- and motor neuron–specific markers. Our results suggest translational potential for the use of pluripotent cells in neural stem cell-mediated therapies and highlight potential safety improvements and benefits of drug selection for neuroepithelial cells.

Key Words: stem cells; transplantation; spinal muscular atrophy; motor neuron

Abbreviations: BDNF, brain-derived neurotrophic factor; ChAT, choline acetyl transferase; ELISA, enzyme-linked immunosorbent assay; GDNF, glial cell line-derived neurotrophic factor; GFP, green fluorescent protein; HB9, homeobox-9; MAP2, microtubule-associated protein 2; NT3, neurotrophin-3; PD, postnatal day; SMI32, neurofilament H non-phosphorylated; SMN, survival of motor neuron protein; SOX, sex-determining region Y box; TGF-{alpha}, transforming growth factor-{alpha}

Received July 4, 2009. Revised October 8, 2009. Accepted November 6, 2009.


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