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Brain Advance Access published online on October 6, 2004
Brain, doi:10.1093/brain/awh273
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Received February 11, 2004
Revised May 27, 2004
Accepted June 27, 2004

Article

Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues

Stefania Corti 1, Federica Locatelli 2, Chiara Donadoni 2, Michela Guglieri 2, Dimitra Papadimitriou 2, Sandra Strazzer 3, Roberto Del Bo 2, and Giacomo P. Comi 1*

1 Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, IRCCS Ospedale Maggiore Policlinico, Milano, Italy; Centro di Eccellenza per lo Studio delle Malattie Neurodegenerative, Università degli Studi di Milano, Milano, Italy
2 Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, IRCCS Ospedale Maggiore Policlinico, Milano, Italy
3 IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy

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


  Abstract

Summary Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neurodegenerative disease without any effective therapy. To evaluate the potential of wild-type bone marrow (BM)-derived stem cells to modify the ALS phenotype, we generated BM chimeric Cu/Zn superoxide dismutase (SOD1) mice by transplantation of BM cells derived from mice expressing green fluorescent protein (GFP) in all tissues and from Thy1-YFP mice that express a spectral variant of GFP (yellow fluorescent protein) in neurons only. In the recipient cerebral cortex, we observed rare GFP+ and YFP+ neurons, which were probably generated by cell fusion, as demonstrated by fluorescence in situ hybridization (FISH) analysis, suggesting that this phenomenon is not limited to Purkinje cells. GFP-positive microglial cells were extensively present in both the brain and spinal cord of the affected animals. Completely differentiated and immature GFP+ myofibres were also present in the heart and skeletal muscles of SOD1 mice, confirming that BM cells can participate in striated muscle tissue regeneration. Moreover, wild-type BM chimeric SOD1 mice showed a significantly delayed disease onset and an increased life span, probably due to a positive ‘non-neuronal environmental’ effect rather than to neuronogenesis. This improvement in SOD1-G93A mouse survival is comparable with that previously obtained using some safer pharmacological agents. BM transplantation-related complications in humans preclude its clinical application for ALS treatment. However, our data suggest that further studies aimed at improving the degree of tissue chimerism by BM-derived cells may provide valuable insights into strategies to slow ALS progression.

Keywords: amyotrophic lateral sclerosis; motor neuron; stem cells; transplantation; SOD.
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