title: iPSC-derived neural precursors exert a neuroprotective role in immune-mediated demyelination via the secretion of LIF.
abstract: The possibility of generating neural stem/precursor cells (NPCs) from induced pluripotent stem cells (iPSCs) has opened a new avenue of research that might nurture bench-to-bedside translation of cell transplantation protocols in central nervous system myelin disorders. Here we show that mouse iPSC-derived NPCs (miPSC-NPCs)-when intrathecally transplanted after disease onset-ameliorate clinical and pathological features of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Transplanted miPSC-NPCs exert the neuroprotective effect not through cell replacement, but through the secretion of leukaemia inhibitory factor that promotes survival, differentiation and the remyelination capacity of both endogenous oligodendrocyte precursors and mature oligodendrocytes. The early preservation of tissue integrity limits blood-brain barrier damage and central nervous system infiltration of blood-borne encephalitogenic leukocytes, ultimately responsible for demyelination and axonal damage. While proposing a novel mechanism of action, our results further expand the therapeutic potential of NPCs derived from iPSCs in myelin disorders.
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology (INSpe), Division of Neuroscience, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Laterza
authors.forename: Arianna
authors.initials: A
authors.lastname: Merlini
authors.forename: Donatella
authors.initials: D
authors.lastname: De Feo
authors.forename: Francesca
authors.initials: F
authors.lastname: Ruffini
authors.forename: Ramesh
authors.initials: R
authors.lastname: Menon
authors.forename: Marco
authors.initials: M
authors.lastname: Onorati
authors.forename: Evelien
authors.initials: E
authors.lastname: Fredrickx
authors.forename: Luca
authors.initials: L
authors.lastname: Muzio
authors.forename: Angelo
authors.initials: A
authors.lastname: Lombardo
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Carla
authors.initials: C
authors.lastname: Taveggia
authors.forename: Cinthia
authors.initials: C
authors.lastname: Farina
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D003711:Demyelinating Diseases / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D015870:Gene Expression; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000502:physiology*; D007278:Injections, Spinal; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology* / Q000637:transplantation; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse