Efficient Generation of Myelinating Oligodendrocytes from Primary Progressive Multiple Sclerosis Patients by Induced Pluripotent Stem Cells

• Published in: Stem cell reports 2014-08, Vol.3 (2), p.250-259
• Main Authors: Douvaras, Panagiotis, Wang, Jing, Zimmer, Matthew, Hanchuk, Stephanie, O’Bara, Melanie A., Sadiq, Saud, Sim, Fraser J., Goldman, James, Fossati, Valentina
• Format: Article
• Language: English
• Subjects: Animals; Axons - metabolism; Basic Helix-Loop-Helix Transcription Factors - genetics; Basic Helix-Loop-Helix Transcription Factors - metabolism; Brain - metabolism; Cell Differentiation - drug effects; Cells, Cultured; DNA-Binding Proteins - deficiency; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Female; Hedgehog Proteins - genetics; Hedgehog Proteins - metabolism; Humans; Induced Pluripotent Stem Cells - cytology; Male; Mice; Mice, Knockout; Middle Aged; Multiple Sclerosis - pathology; Myelin Sheath - metabolism; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Oligodendrocyte Transcription Factor 2; Oligodendroglia - cytology; Oligodendroglia - metabolism; Oligodendroglia - transplantation; Smad Proteins - antagonists & inhibitors; Smad Proteins - metabolism; Transplantation, Heterologous; Tretinoin - pharmacology
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2014.06.012

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. [Display omitted] •Development of a rapid, highly efficient, and robust protocol to produce O4+ hOPCs•Generation of iPSCs from primary progressive MS patients•Differentiation of PPMS iPSCs to mature oligodendrocytes in vitro•Successful in vivo myelination from PPMS-iPSC-derived OPCs In this article, Fossati and colleagues describe an efficient and highly reproducible differentiation protocol to generate oligodendrocyte progenitor cells (OPCs) from induced pluripotent stem cells. Using this protocol, they show that OPCs from primary progressive multiple sclerosis (MS) patients are able to myelinate neurons in the shiverer mouse model, providing the premise for the development of future autologous cell transplantation therapies in MS.