title: Efficient generation of myelinating oligodendrocytes from primary progressive multiple sclerosis patients by induced pluripotent stem cells.
abstract: Multiple sclerosis (MS) is a chronic demyelinating disease of unknown etiology that affects the CNS. While current therapies are primarily directed against the immune system, the new challenge is to address progressive MS with remyelinating and neuroprotective strategies. Here, we develop a highly reproducible protocol to efficiently derive oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes from induced pluripotent stem cells (iPSCs). Key elements of our protocol include adherent cultures, dual SMAD inhibition, and addition of retinoids from the beginning of differentiation, which lead to increased yields of OLIG2 progenitors and high numbers of OPCs within 75 days. Furthermore, we show the generation of viral and integration-free iPSCs from primary progressive MS (PPMS) patients and their efficient differentiation to oligodendrocytes. PPMS OPCs are functional, as demonstrated by in vivo myelination in the shiverer mouse. These results provide encouraging advances toward the development of autologous cell therapies using iPSCs.
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Douvaras
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Zimmer
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hanchuk
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Melanie A
authors.initials: MA
authors.lastname: O'Bara
authors.affiliation: Tisch Multiple Sclerosis Research Center of New York, New York, NY 10019, USA.
authors.forename: Saud
authors.initials: S
authors.lastname: Sadiq
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Fraser J
authors.initials: FJ
authors.lastname: Sim
authors.affiliation: Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
authors.forename: James
authors.initials: J
authors.lastname: Goldman
authors.affiliation: The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA. Electronic address: vfossati@nyscf.org.
authors.forename: Valentina
authors.initials: V
authors.lastname: Fossati
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005260:Female; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D009186:Myelin Sheath / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D053823:Hedgehog Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D051785:Smad Proteins; D014212:Tretinoin; C405708:OLIG2 protein, human; C499308:Rag2 protein, mouse