title: Minimally invasive transplantation of iPSC-derived ALDHhiSSCloVLA4+ neural stem cells effectively improves the phenotype of an amyotrophic lateral sclerosis model.
abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by the degeneration of motor neurons. Currently, there is no effective therapy for ALS. Stem cell transplantation is a potential therapeutic strategy for ALS, and the reprogramming of adult somatic cells into induced pluripotent stem cells (iPSCs) represents a novel cell source. In this study, we isolated a specific neural stem cell (NSC) population from human iPSCs based on high aldehyde dehydrogenase activity, low side scatter and integrin VLA4 positivity. We assessed the therapeutic effects of these NSCs on the phenotype of ALS mice after intrathecal or intravenous injections. Transplanted NSCs migrated and engrafted into the central nervous system via both routes of injection. Compared with control ALS, treated ALS mice exhibited improved neuromuscular function and motor unit pathology and significantly increased life span, in particular with the systemic administration of NSCs (15%). These positive effects are linked to multiple mechanisms, including production of neurotrophic factors and reduction of micro- and macrogliosis. NSCs induced a decrease in astrocyte number through the activation of the vanilloid receptor TRPV1. We conclude that minimally invasive injections of iPSC-derived NSCs can exert a therapeutic effect in ALS. This study contributes to advancements in iPSC-mediated approaches for treating ALS and other neurodegenerative diseases.
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Nizzardo
authors.forename: Chiara
authors.initials: C
authors.lastname: Simone
authors.forename: Federica
authors.initials: F
authors.lastname: Rizzo
authors.forename: Margherita
authors.initials: M
authors.lastname: Ruggieri
authors.forename: Sabrina
authors.initials: S
authors.lastname: Salani
authors.forename: Giulietta
authors.initials: G
authors.lastname: Riboldi
authors.forename: Irene
authors.initials: I
authors.lastname: Faravelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Zanetta
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism* / Q000637:transplantation*; D010641:Phenotype; D033581:Stem Cell Transplantation / Q000379:methods; D013482:Superoxide Dismutase / Q000235:genetics* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D039041:Integrin alpha4beta1; C000606290:SOD1 protein, human; D050916:TRPV Cation Channels; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000444:Aldehyde Dehydrogenase