Minocycline Directly Enhances the Self-Renewal of Adult Neural Precursor Cells
- 321 Downloads
Minocycline not only has antibacterial action but also produces a variety of pharmacological effects. It has drawn considerable attention as a therapeutic agent for symptoms caused by inflammation in many neurological disorders, leading to several clinical trials. Although some of these effects are mediated through its function of suppressing microglial activation, it is not clear whether minocycline acts on other cell types in the adult brain. In this study, we utilized a colony-forming neurosphere assay, in which neural stem cells (NSCs) clonally proliferate to form floating colonies, called neurospheres. We found that minocycline (at therapeutically relevant concentrations in cerebrospinal fluid) enhances the self-renewal capability of NSCs derived from the subependymal zone of adult mouse brain and facilitates their differentiation into oligodendrocytes. Importantly, these effects were independent of a suppression of microglial activation and were specifically observed with minocycline (among tetracycline derivatives). In addition, the size of the NSC population in the adult brain was increased when minocycline was infused into the lateral ventricle by an osmotic minipump in vivo. While precise molecular mechanisms of how minocycline alters the behavior of adult NSCs remain unknown, our data provide a basis for the clinical use of minocycline to treat neurodegenerative and demyelinating diseases.
KeywordsNeural stem cell Self-renewal Oligodendrocyte Microglia
We thank K. Ono for O4 antibody, N. Kaneko and K. Sawamoto for discussion, and M. Mori and M. Tomoeda for technical assistance. This work was supported by Grants-in-Aid for Scientific Research (B) (16H04671) and for challenging Exploratory Research (16K14578) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (S. H.).
- 27.Du Y, Ma Z, Lin S, Dodel RC, Gao F, Bales KR, Triarhou LC, Chernet E, Perry KW, Nelson DL, Luecke S, Phebus LA, Bymaster FP, Paul SM (2001) Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease. Proc Natl Acad Sci USA 98:14669–14674CrossRefGoogle Scholar
- 30.Naruse M, Ishino Y, Kumar A, Ono K, Takebayashi H, Yamaguchi M, Ishizaki Y, Ikenaka K, Hitoshi S (2016) The dorsoventral boundary of the germinal zone is a specialized niche for the generation of cortical oligodendrocytes during a restricted temporal window. Cereb Cortex 26:2800–2810CrossRefGoogle Scholar
- 33.Sanosaka T, Imamura T, Hamazaki N, Chai M, Igarashi K, Ideta-Otsuka M, Miura F, Ito T, Fujii N, Ikeo K, Nakashima K (2017) DNA methylome analysis identifies transcription factor-based epigenomic signatures of multilineage competence in neural stem/progenitor cells. Cell Rep 20:2992–3003CrossRefGoogle Scholar
- 42.Metz LM, Li DKB, Traboulsee AL, Duquette P, Eliasziw M, Cerchiaro G, Greenfield J, Riddehough A, Yeung M, Kremenchutzky M, Vorobeychik G, Freedman MS, Bhan V, Blevins G, Marriott JJ, Grand’Maison F, Lee L, Thibault M, Hill MD, Yong VW; Minocycline in MS Study Team (2017) Trial of minocycline in a clinically isolated syndrome of multiple sclerosis. N Engl J Med 376:2122–2133CrossRefGoogle Scholar