title: iPSC-Derived neural stem cells act via kinase inhibition to exert neuroprotective effects in spinal muscular atrophy with respiratory distress type 1.
abstract: Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a motor neuron disease caused by mutations in the IGHMBP2 gene, without a cure. Here, we demonstrate that neural stem cells (NSCs) from human-induced pluripotent stem cells (iPSCs) have therapeutic potential in the context of SMARD1. We show that upon transplantation NSCs can appropriately engraft and differentiate in the spinal cord of SMARD1 animals, ameliorating their phenotype, by protecting their endogenous motor neurons. To evaluate the effect of NSCs in the context of human disease, we generated human SMARD1-iPSCs motor neurons that had a significantly reduced survival and axon length. Notably, the coculture with NSCs ameliorate these disease features, an effect attributable to the production of neurotrophic factors and their dual inhibition of GSK-3 and HGK kinases. Our data support the role of iPSC as SMARD1 disease model and their translational potential for therapies in motor neuron disorders.
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Simone
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Nizzardo
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Rizzo
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Ruggieri
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Giulietta
authors.initials: G
authors.lastname: Riboldi
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Salani
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Bucchia
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy.
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.affiliation: Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation (DEPT), University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122 Milan, Italy. Electronic address: stefania.corti@unimi.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D018920:Coculture Techniques; D004195:Disease Models, Animal; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D053208:Kaplan-Meier Estimate; D051379:Mice; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000401:mortality / Q000628:therapy; D009414:Nerve Growth Factors / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology* / Q000637:transplantation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012127:Respiratory Distress Syndrome, Newborn / Q000401:mortality / Q000628:therapy; D014183:Transplantation, Heterologous
chemical_list: D009414:Nerve Growth Factors; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3