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Human Molecular Genetics Advance Access published online on December 8, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi446
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received June 25, 2005
Revised August 25, 2005
Accepted August 25, 2005

Article

Transplanted ALDHhiSSClo Neural Stem Cells Generate Motor Neurons and Delay Disease Progression of nmd Mice, an Animal Model of SMARD1

Stefania Corti 1, Federica Locatelli 2, Dimitra Papadimitriou 2, Chiara Donadoni 2, Roberto Del Bo 2, Marco Crimi 2, Andreina Bordoni 2, Francesco Fortunato 2, Sandra Strazzer 3, Giorgia Menozzi 3, Sabrina Salani 2, Nereo Bresolin 4, and Giacomo P. Comi 5 *

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

* To whom correspondence should be addressed.
Giacomo P. Comi, E-mail: giacomo.comi{at}unimi.it


  Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal recessive motor neuron disease, caused by mutations in the Immunoglobulin µ-binding protein 2 (IGHMBP2).

We investigated the potential of a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase activity (ALDH) to modify disease progression of nmd mice, an animal model of SMARD1.

ALDHhiSSClo stem cells are self-renewing and multipotent and when intratechally transplanted in nmd mice generate motor neurons properly localized in the spinal cord ventral horns.

Transplanted nmd animals presented delayed disease progression, sparing of motor neurons and ventral root axons and increased life-span.

To further investigate the molecular events responsible for these differences, microarray and Real time RT-PCR analysis of wild-type, mutated and transplanted nmd spinal cord were undertaken.

We demonstrated a down-regulation of genes involved in excitatory amino acid toxicity and oxidative stress handling, as well as an up-regulation of genes related to the chromatin organization in nmd compared to wild-type mice, suggesting that they may play a role in SMARD1 pathogenesis. Spinal cord of nmd transplanted mice expressed high transcript levels for genes related to neurogenesis such as Doublecortin (DCX), LIS1 and drebrin. The presence of DCX-expressing cells in adult nmd spinal cord suggests that both exogenous and endogenous neurogenesis may contribute to the observed nmd phenotype amelioration.


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