Abstract
Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 216-220 |
| Number of pages | 5 |
| Journal | Nature |
| Volume | 522 |
| Issue number | 7555 |
| DOIs | |
| State | Published - Jun 11 2015 |
Funding
Acknowledgements This research was supported by grants from the US NIH NS085246 (P.J.T. and R.H.M.), NS030800 (R.H.M.), and NS026543 (S.D.M.); New York Stem Cell Foundation (P.J.T.); Myelin Repair Foundation (P.J.T., R.H.M., and S.D.M.); Mt. Sinai Health Care Foundation (P.J.T.); and NIH predoctoral training grants T32GM008056 (R.T.K.) and F30CA183510 (T.E.M). Additional support was provided by the Cytometry & Imaging Microscopy, Proteomics, and Genomics core facilities of the Case Comprehensive Cancer Center (P30CA043703), the CWRU Council to Advance Human Health, and philanthropic support from the Goodman, Long, and Geller families. P.J.T. is a New York Stem Cell Foundation–Robertson Investigator. We are grateful to M. Hitomi, W. Harte, D. Adams, W. Seibel, M. Haag, P. Scacheri, J. Wanta, C. Fang, H. Olsen, T. LaFramboise, J. Song, F. Van den Akker, and M. Shoham for technical assistance and discussion, A. Lager and M. Elitt for comments on the manuscript,B. Trapp for the PLP1 antibody, and B. Barres and B. Zuchero for RNAfrom in vivo isolated OPCs.
ASJC Scopus subject areas
- General
