Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues.
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.
Corti
Stefania
S
Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università degli Studi di Milano, IRCCS Ospedale Maggiore Policlinico, Milano, Italy.
Locatelli
Federica
F
Donadoni
Chiara
C
Guglieri
Michela
M
Papadimitriou
Dimitra
D
Strazzer
Sandra
S
Del Bo
Roberto
R
Comi
Giacomo P
GP
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002540:Cerebral Cortex / Q000473:pathology; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D009474:Neurons / Q000473:pathology; D010641:Phenotype; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics*; D016019:Survival Analysis; D018183:Transplantation Chimera
C109415:SOD1 G93A protein; D013482:Superoxide Dismutase