Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation


Endogenous metabolites play essential roles in the regulation of cellular identity and activity. Here we have investigated the process of oligodendrocyte precursor cell (OPC) differentiation, a process that becomes limiting during progressive stages of demyelinating diseases, including multiple sclerosis, using mass-spectrometry-based metabolomics. Levels of taurine, an aminosulfonic acid possessing pleotropic biological activities and broad tissue distribution properties, were found to be significantly elevated (20-fold) during the course of oligodendrocyte differentiation and maturation. When added exogenously at physiologically relevant concentrations, taurine was found to dramatically enhance the processes of drug-induced in vitro OPC differentiation and maturation. Mechanism of action studies suggest that the oligodendrocyte-differentiation-enhancing activities of taurine are driven primarily by its ability to directly increase available serine pools, which serve as the initial building block required for the synthesis of the glycosphingolipid components of myelin that define the functional oligodendrocyte cell state.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Observed metabolic differences between T3- and DMSO-treated OPCs.
Figure 2: Impact of taurine treatment on the efficacy of drug-induced OPC differentiation.
Figure 3: Impact of taurine treatment on observed indices of MBP colocalization with co-cultured axons.
Figure 4: The impact of taurine treatment on OL mitochondrial function and the role of redox state on OPC differentiation.
Figure 5: Binary global metabolomics analysis of taurine co-treatment and evaluation of the impact of inhibition of taurine biosynthesis on OL differentiation.


  1. 1

    Pouly, S. & Antel, J.P. Multiple sclerosis and central nervous system demyelination. J. Autoimmun. 13, 297–306 (1999).

    CAS  Article  Google Scholar 

  2. 2

    Franklin, R.J. & Ffrench-Constant, C. Remyelination in the CNS: from biology to therapy. Nat. Rev. Neurosci. 9, 839–855 (2008).

    CAS  Article  Google Scholar 

  3. 3

    Gallo, V. & Armstrong, R.C. Myelin repair strategies: a cellular view. Curr. Opin. Neurol. 21, 278–283 (2008).

    Article  Google Scholar 

  4. 4

    Dubois-Dalcq, M. et al. From fish to man: understanding endogenous remyelination in central nervous system demyelinating diseases. Brain 131, 1686–1700 (2008).

    Article  Google Scholar 

  5. 5

    Franklin, R.J. & Hinks, G.L. Understanding CNS remyelination: clues from developmental and regeneration biology. J. Neurosci. Res. 58, 207–213 (1999).

    CAS  Article  Google Scholar 

  6. 6

    Chamberlain, K.A., Nanescu, S.E., Psachoulia, K. & Huang, J.K. Oligodendrocyte regeneration: Its significance in myelin replacement and neuroprotection in multiple sclerosis. Neuropharmacology 110 Pt B, 633–643 (2016).

    CAS  Article  Google Scholar 

  7. 7

    Franklin, R.J.M. Why does remyelination fail in multiple sclerosis? Nat. Rev. Neurosci. 3, 705–714 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Wolswijk, G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J. Neurosci. 18, 601–609 (1998).

    CAS  Article  Google Scholar 

  9. 9

    Chang, A., Tourtellotte, W.W., Rudick, R. & Trapp, B.D. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N. Engl. J. Med. 346, 165–173 (2002).

    Article  Google Scholar 

  10. 10

    Franklin, R.J. & Gallo, V. The translational biology of remyelination: past, present, and future. Glia 62, 1905–1915 (2014).

    Article  Google Scholar 

  11. 11

    Huang, J.K. et al. Myelin regeneration in multiple sclerosis: targeting endogenous stem cells. Neurotherapeutics 8, 650–658 (2011).

    Article  Google Scholar 

  12. 12

    Huang, J.K. et al. Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat. Neurosci. 14, 45–53 (2011).

    CAS  Article  Google Scholar 

  13. 13

    Lucchinetti, C.F., Noseworthy, J.H. & Rodriguez, M. Promotion of endogenous remyelination in multiple sclerosis. Mult. Scler. 3, 71–75 (1997).

    CAS  Article  Google Scholar 

  14. 14

    Mei, F. et al. Identification of the kappa-opioid receptor as a therapeutic target for oligodendrocyte remyelination. J. Neurosci. 36, 7925–7935 (2016).

    CAS  Article  Google Scholar 

  15. 15

    Najm, F.J. et al. Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo. Nature 522, 216–220 (2015).

    CAS  Article  Google Scholar 

  16. 16

    Buckley, C.E. et al. Drug reprofiling using zebrafish identifies novel compounds with potential pro-myelination effects. Neuropharmacology 59, 149–159 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Deshmukh, V.A. et al. A regenerative approach to the treatment of multiple sclerosis. Nature 502, 327–332 (2013).

    CAS  Article  Google Scholar 

  18. 18

    Mei, F. et al. Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis. Nat. Med. 20, 954–960 (2014).

    CAS  Article  Google Scholar 

  19. 19

    Yanes, O. et al. Metabolic oxidation regulates embryonic stem cell differentiation. Nat. Chem. Biol. 6, 411–417 (2010).

    CAS  Article  Google Scholar 

  20. 20

    Folmes, C.D.L. et al. Somatic oxidative bioenergetics transitions into pluripotency-dependent glycolysis to facilitate nuclear reprogramming. Cell Metab. 14, 264–271 (2011).

    CAS  Article  Google Scholar 

  21. 21

    Shyh-Chang, N., Daley, G.Q. & Cantley, L.C. Stem cell metabolism in tissue development and aging. Development 140, 2535–2547 (2013).

    CAS  Article  Google Scholar 

  22. 22

    Ito, K. & Suda, T. Metabolic requirements for the maintenance of self-renewing stem cells. Nat. Rev. Mol. Cell Biol. 15, 243–256 (2014).

    CAS  Article  Google Scholar 

  23. 23

    TeSlaa, T. et al. α-Ketoglutarate accelerates the initial differentiation of primed human pluripotent stem cells. Cell Metab. 24, 485–493 (2016).

    CAS  Article  Google Scholar 

  24. 24

    Huan, T. et al. Systems biology guided by XCMS Online metabolomics. Nat. Methods 14, 461–462 (2017).

    CAS  Article  Google Scholar 

  25. 25

    Fernandez, M. et al. Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease. Proc. Natl. Acad. Sci. USA 101, 16363–16368 (2004).

    CAS  Article  Google Scholar 

  26. 26

    Meissen, J.K. et al. Induced pluripotent stem cells show metabolomic differences to embryonic stem cells in polyunsaturated phosphatidylcholines and primary metabolism. PLoS One 7, e46770 (2012).

    CAS  Article  Google Scholar 

  27. 27

    Panopoulos, A.D. et al. The metabolome of induced pluripotent stem cells reveals metabolic changes occurring in somatic cell reprogramming. Cell Res. 22, 168–177 (2012).

    CAS  Article  Google Scholar 

  28. 28

    Fields, R.D. A new mechanism of nervous system plasticity: activity-dependent myelination. Nat. Rev. Neurosci. 16, 756–767 (2015).

    CAS  Article  Google Scholar 

  29. 29

    Ramos-Mandujano, G., Hernández-Benítez, R. & Pasantes-Morales, H. Multiple mechanisms mediate the taurine-induced proliferation of neural stem/progenitor cells from the subventricular zone of the adult mouse. Stem Cell Res. 12, 690–702 (2014).

    CAS  Article  Google Scholar 

  30. 30

    Shivaraj, M.C. et al. Taurine induces proliferation of neural stem cells and synapse development in the developing mouse brain. PLoS One 7, e42935 (2012).

    CAS  Article  Google Scholar 

  31. 31

    El Idrissi, A. & Trenkner, E. Growth factors and taurine protect against excitotoxicity by stabilizing calcium homeostasis and energy metabolism. J. Neurosci. 19, 9459–9468 (1999).

    CAS  Article  Google Scholar 

  32. 32

    French, H.M., Reid, M., Mamontov, P., Simmons, R.A. & Grinspan, J.B. Oxidative stress disrupts oligodendrocyte maturation. J. Neurosci. Res. 87, 3076–3087 (2009).

    CAS  Article  Google Scholar 

  33. 33

    Smith, J., Ladi, E., Mayer-Pröschel, M. & Noble, M. Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc. Natl. Acad. Sci. USA 97, 10032–10037 (2000).

    CAS  Article  Google Scholar 

  34. 34

    Jurkowska, H., Stipanuk, M.H., Hirschberger, L.L. & Roman, H.B. Propargylglycine inhibits hypotaurine/taurine synthesis and elevates cystathionine and homocysteine concentrations in primary mouse hepatocytes. Amino Acids 47, 1215–1223 (2015).

    CAS  Article  Google Scholar 

  35. 35

    Jackman, N., Ishii, A. & Bansal, R. Oligodendrocyte development and myelin biogenesis: parsing out the roles of glycosphingolipids. Physiology (Bethesda) 24, 290–297 (2009).

    CAS  Google Scholar 

  36. 36

    Bansal, R. & Pfeiffer, S.E. Reversible inhibition of oligodendrocyte progenitor differentiation by a monoclonal antibody against surface galactolipids. Proc. Natl. Acad. Sci. USA 86, 6181–6185 (1989).

    CAS  Article  Google Scholar 

  37. 37

    Bansal, R. & Pfeiffer, S.E. Regulation of gene expression in mature oligodendrocytes by the specialized myelin-like membrane environment: antibody perturbation in culture with the monoclonal antibody R-mAb. Glia 12, 173–179 (1994).

    CAS  Article  Google Scholar 

  38. 38

    Albrecht, J. & Schousboe, A. Taurine interaction with neurotransmitter receptors in the CNS: an update. Neurochem. Res. 30, 1615–1621 (2005).

    CAS  Article  Google Scholar 

  39. 39

    Tourbah, A. et al. MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study. Mult. Scler. 22, 1719–1731 (2016).

    CAS  Article  Google Scholar 

  40. 40

    t Hart, B.A. et al. 1H-NMR spectroscopy combined with pattern recognition analysis reveals characteristic chemical patterns in urines of MS patients and non-human primates with MS-like disease. J. Neurol. Sci. 212, 21–30 (2003).

    CAS  Article  Google Scholar 

  41. 41

    Gebregiworgis, T. et al. Potential of urinary metabolites for diagnosing multiple sclerosis. ACS Chem. Biol. 8, 684–690 (2013).

    CAS  Article  Google Scholar 

  42. 42

    Mangalam, A. et al. Profile of circulatory metabolites in a relapsing-remitting animal model of multiple sclerosis using global metabolomics. J. Clin. Cell. Immunol. 4, (2013).

  43. 43

    Preece, N.E. et al. Experimental encephalomyelitis modulates inositol and taurine in the spinal cord of Biozzi mice. Magn. Reson. Med. 32, 692–697 (1994).

    CAS  Article  Google Scholar 

  44. 44

    Noga, M.J. et al. Metabolomics of cerebrospinal fluid reveals changes in the central nervous system metabolism in a rat model of multiple sclerosis. Metabolomics 8, 253–263 (2012).

    CAS  Article  Google Scholar 

  45. 45

    Tautenhahn, R. et al. XCMS online: A web-based platform to process untargeted metabolomic data. Anal. Chem. 84, 5035–5039 (2012).

    CAS  Article  Google Scholar 

  46. 46

    Pang, Y. et al. Neuron-oligodendrocyte myelination co-culture derived from embryonic rat spinal cord and cerebral cortex. Brain Behav. 2, 53–67 (2012).

    Article  Google Scholar 

  47. 47

    Diemel, L.T., Wolswijk, G., Jackson, S.J. & Cuzner, M.L. Remyelination of cytokine- or antibody-demyelinated CNS aggregate cultures is inhibited by macrophage supplementation. Glia 45, 278–286 (2004).

    Article  Google Scholar 

Download references


We gratefully acknowledge financial support from the National Institutes of Health (Grants R01 GM114368-02, R24 EY017540-04, P30 MH062261-10, P01 DA026146-02, and 1S10OD16357).

Author information




B.A.B., M.F., G.S. and L.L.L. initiated the project, developed the strategy and generated experimental design. B.A.B., W.C.P. and B.S. performed molecular biology and cell-based experiments. M.F. and J.R.M.-B. performed mass spectrometry and metabolomics experiments. B.P.C.K., B.A.B. and M.F. performed OCR experiments. B.A.B., M.F., W.C.P., B.S., J.R.M.-B., G.S. and L.L.L. interpreted data. E.S. and T.K. contributed essential ideas and comments. B.A.B., M.F., G.S. and L.L.L. wrote the manuscript.

Corresponding authors

Correspondence to Gary Siuzdak or Luke L Lairson.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Figures 1–9 and Supplementary Table 1 (PDF 14347 kb)

Life Sciences Reporting Summary (PDF 159 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Beyer, B., Fang, M., Sadrian, B. et al. Metabolomics-based discovery of a metabolite that enhances oligodendrocyte maturation. Nat Chem Biol 14, 22–28 (2018).

Download citation

Further reading