Extrinsic immune cell-derived, but not intrinsic oligodendroglial factors contribute to oligodendroglial differentiation
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ORIGINAL PAPER
Extrinsic immune cell‑derived, but not intrinsic oligodendroglial factors contribute to oligodendroglial differentiation block in multiple sclerosis Laura Starost1,2 · Maren Lindner3 · Martin Herold3 · Yu Kang T. Xu4 · Hannes C. A. Drexler5 · Katharina Heß1 · Marc Ehrlich1,2 · Linda Ottoboni6 · Francesca Ruffini6 · Martin Stehling2 · Albrecht Röpke7 · Christian Thomas1 · Hans R. Schöler2 · Jack Antel8 · Jürgen Winkler9 · Gianvito Martino6,10 · Luisa Klotz3 · Tanja Kuhlmann1 Received: 29 March 2020 / Revised: 30 July 2020 / Accepted: 22 August 2020 © The Author(s) 2020
Abstract Multiple sclerosis (MS) is the most frequent demyelinating disease in young adults and despite significant advances in immunotherapy, disease progression still cannot be prevented. Promotion of remyelination, an endogenous repair mechanism resulting in the formation of new myelin sheaths around demyelinated axons, represents a promising new treatment approach. However, remyelination frequently fails in MS lesions, which can in part be attributed to impaired differentiation of oligodendroglial progenitor cells into mature, myelinating oligodendrocytes. The reasons for impaired oligodendroglial differentiation and defective remyelination in MS are currently unknown. To determine whether intrinsic oligodendroglial factors contribute to impaired remyelination in relapsing–remitting MS (RRMS), we compared induced pluripotent stem cell-derived oligodendrocytes (hiOL) from RRMS patients and controls, among them two monozygous twin pairs discordant for MS. We found that hiOL from RRMS patients and controls were virtually indistinguishable with respect to remyelinationassociated functions and proteomic composition. However, while analyzing the effect of extrinsic factors we discovered that supernatants of activated peripheral blood mononuclear cells (PBMCs) significantly inhibit oligodendroglial differentiation. In particular, we identified C D4+ T cells as mediators of impaired oligodendroglial differentiation; at least partly due to interferon-gamma secretion. Additionally, we observed that blocked oligodendroglial differentiation induced by PBMC supernatants could not be restored by application of oligodendroglial differentiation promoting drugs, whereas treatment of PBMCs with the immunomodulatory drug teriflunomide prior to supernatant collection partly rescued oligodendroglial differentiation. In summary, these data indicate that the oligodendroglial differentiation block is not due to intrinsic oligodendroglial factors but rather caused by the inflammatory environment in RRMS lesions which underlines the need for drug screening approaches taking the inflammatory environment into account. Combined, these findings may contribute to the development of new remyelination promoting strategies. Keywords Induced pluripotent stem cells · Oligodendrocytes · Proteome · Relapsing–remitting multiple sclerosis · Remyelination · Ifnγ
Introduction Gianvito Martino, Luisa Klotz and Tanja Kuhlmann shared last authorship. Electronic suppleme
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