Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo

Fadi J. Najm, Mayur Madhavan, Anita Zaremba, Elizabeth Shick, Robert T. Karl, Daniel C. Factor, Tyler E. Miller, Zachary S. Nevin, Christopher Kantor, Alex Sargent, Kevin L. Quick, Daniela M. Schlatzer, Hong Tang, Ruben Papoian, Kyle R. Brimacombe, Min Shen, Matthew B. Boxer, Ajit Jadhav, Andrew P. Robinson, Joseph R. PodojilStephen D. Miller, Robert H. Miller, Paul J. Tesar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

215 Scopus citations

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 languageEnglish (US)
Pages (from-to)216-220
Number of pages5
JournalNature
Volume522
Issue number7555
DOIs
StatePublished - Jun 11 2015

ASJC Scopus subject areas

  • General

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