Brain Advance Access originally published online on October 6, 2004
Brain 2004 127(11):2518-2532; doi:10.1093/brain/awh273
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Brain Vol. 127 No. 11 © Guarantors of Brain 2004; all rights reserved
Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues
1 Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, IRCCS Ospedale Maggiore Policlinico, Milano, 2 Centro di Eccellenza per lo Studio delle Malattie Neurodegenerative, Università degli Studi di Milano, Milano and 3 IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy
Correspondence to: Professor Giacomo P. Comi, Dipartimento di Scienze Neurologiche, Università di Milano, Padiglione Ponti, Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy E-mail: giacomo.comi{at}unimi.it
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.
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