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Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain

Abstract

Oligodendrocytes—the myelin-forming cells of the central nervous system—can be regenerated during adulthood. In adults, new oligodendrocytes originate from oligodendrocyte progenitor cells (OPCs), but also from neural stem cells (NSCs). Although several factors supporting oligodendrocyte production have been characterized, the mechanisms underlying the generation of adult oligodendrocytes are largely unknown. Here we show that genetic inactivation of SIRT1, a protein deacetylase implicated in energy metabolism, increases the production of new OPCs in the adult mouse brain, in part by acting in NSCs. New OPCs produced following SIRT1 inactivation differentiate normally, generating fully myelinating oligodendrocytes. Remarkably, SIRT1 inactivation ameliorates remyelination and delays paralysis in mouse models of demyelinating injuries. SIRT1 inactivation leads to the upregulation of genes involved in cell metabolism and growth factor signalling, in particular PDGF receptor α (PDGFRα). Oligodendrocyte expansion following SIRT1 inactivation is mediated at least in part by AKT and p38 MAPK—signalling molecules downstream of PDGFRα. The identification of drug-targetable enzymes that regulate oligodendrocyte regeneration in adults could facilitate the development of therapies for demyelinating injuries and diseases, such as multiple sclerosis.

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Figure 1: SIRT1 is expressed in adult NSCs and neural progenitors.
Figure 2: Inducible inactivation of SIRT1 in adult NSCs and neural progenitors expands the oligodendrocyte lineage.
Figure 3: Brain-specific SIRT1 inactivation amplifies the proliferating OPC and NSC populations.
Figure 4: SIRT1 inactivation does not alter the differentiation and myelination potential of oligodendrocytes.
Figure 5: SIRT1 inactivation enhances remyelination in the corpus callosum after lysolecithin-induced demyelination.
Figure 6: SIRT1 inactivation delays onset of paralysis in chronic EAE.
Figure 7: SIRT1 inactivation leads to the upregulation of genes involved in metabolism, protein translation and growth factor signalling.
Figure 8: Inhibition of p38 MAPK and AKT signalling reduces the production of oligodendrocytes from NSCs and neural progenitors lacking active SIRT1.

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Acknowledgements

We thank F. Alt for the generous gift of the Sirt1+/− and Sirt1lox/lox mice. We thank T. Palmer, T. Rando, and T. Wyss-Coray for helpful suggestions. We thank M. Winslow and J. Sage for critical review of the manuscript and discussion of the experiments. We are grateful to B. Benayoun and A. Morgan for their advice on the microarray analysis. We thank members of the A.B. laboratory for their invaluable discussion of the experiments and manuscript, in particular D. Leeman, J. Lim and A. Webb. This work was supported by NIH/NIA grants (R01 AG026648 and P01 AG036695), a California Institute for Regenerative Medicine grant, a Brain Tumour Society grant, an AFAR grant, the Glenn Foundation for Medical Research (A.B.) and the National Multiple Sclerosis Society (J.C.D., A.I. and B.A.B.—RG4059A8). V.A.R. was supported by an NSF graduate fellowship and an NINDS/NRSA graduate fellowship (5F31NS064600). E.A.P. was supported by an NSF graduate fellowship and an NIA/NRSA graduate fellowship (F31AG043232). L.S. and P.P.H were supported by the NIH (R01 NS055997), the National Multiple Sclerosis Society and the Guthy–Jackson Charitable Foundation. S.J.B. was supported by NIH P01CA096832. L.M.L.C. was supported by the Canadian Institutes of Health Research.

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V.A.R. conceived and planned the study with the help of A.B. V.A.R. performed the experiments and wrote the paper with the help of A.B. P.P.H. and V.A.R. designed and performed the EAE experiments (Fig. 6) under the supervision of L.S. J.O.B. performed and analysed the RT–qPCR experiments (Fig. 7c and Supplementary Fig. S7a). D.U. helped with microarray analysis (Fig. 7a and Supplementary Fig. S6a and Table S1). The postnatal OPC experiments (Supplementary Fig. S5) were conceived and planned by J.C.D. and performed by A.I. under the supervision of B.A.B. E.A.P. performed the analysis of global histone acetylation (Supplementary Fig. S7b,c). L.M.L.C. and S.J.B. generated and characterized the NestinCreER mice. All authors discussed the results and commented on the manuscript.

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Correspondence to Anne Brunet.

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Rafalski, V., Ho, P., Brett, J. et al. Expansion of oligodendrocyte progenitor cells following SIRT1 inactivation in the adult brain. Nat Cell Biol 15, 614–624 (2013). https://doi.org/10.1038/ncb2735

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