title: Intravenous mesenchymal stem cells improve survival and motor function in experimental amyotrophic lateral sclerosis.
abstract: Despite some advances in the understanding of amyotrophic lateral sclerosis (ALS) pathogenesis, significant achievements in treating this disease are still lacking. Mesenchymal stromal (stem) cells (MSCs) have been shown to be effective in several models of neurological disease. To determine the effects of the intravenous injection of MSCs in an ALS mouse model during the symptomatic stage of disease, MSCs (1 × 10⁶) were intravenously injected in mice expressing human superoxide dismutase 1 (SOD1) carrying the G93A mutation (SOD1/G93A) presenting with experimental ALS. Survival, motor abilities, histology, oxidative stress markers and [³H]D-aspartate release in the spinal cord were investigated. MSC injection in SOD1/G93A mice improved survival and motor functions compared with saline-injected controls. Injected MSCs scantly home to the central nervous system and poorly engraft. We observed a reduced accumulation of ubiquitin agglomerates and of activated astrocytes and microglia in the spinal cord of MSC-treated SOD1/G93A mice, with no changes in the number of choline acetyltransferase- and glutamate transporter type 1-positive cells. MSC administration turned around the upregulation of metallothionein mRNA expression and of the activity of the antioxidant enzyme glutathione S-transferase, both associated with disease progression. Last, we observed that MSCs reverted both spontaneous and stimulus-evoked neuronal release of [³H]D-aspartate, a marker of endogenous glutamate, which is upregulated in SOD1/G93A mice. These findings suggest that intravenous administration of MSCs significantly improves the clinical outcome and pathological scores of mutant SOD1/G93A mice, thus providing the rationale for their exploitation for the treatment of ALS.
authors.affiliation: Department of Neurosciences Ophthalmology and Genetics, University of Genoa, Genoa, Italy. auccelli@neurologia.unige.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Uccelli
authors.forename: Marco
authors.initials: M
authors.lastname: Milanese
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Principato
authors.forename: Sara
authors.initials: S
authors.lastname: Morando
authors.forename: Tiziana
authors.initials: T
authors.lastname: Bonifacino
authors.forename: Laura
authors.initials: L
authors.lastname: Vergani
authors.forename: Debora
authors.initials: D
authors.lastname: Giunti
authors.forename: Adriana
authors.initials: A
authors.lastname: Voci
authors.forename: Enrico
authors.initials: E
authors.lastname: Carminati
authors.forename: Francesco
authors.initials: F
authors.lastname: Giribaldi
authors.forename: Claudia
authors.initials: C
authors.lastname: Caponnetto
authors.forename: Giambattista
authors.initials: G
authors.lastname: Bonanno
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000401:mortality / Q000628:therapy*; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism; D002465:Cell Movement; D002490:Central Nervous System / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity; D018384:Oxidative Stress; D013116:Spinal Cord / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; D001224:Aspartic Acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1