Technical Report | Published:

Micropillar arrays as a high-throughput screening platform for therapeutics in multiple sclerosis

Nature Medicine volume 20, pages 954960 (2014) | Download Citation


Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.


  1. 1.

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

  2. 2.

    & Identification of post-mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord. J. Neuropathol. Exp. Neurol. 56, 1191–1201 (1997).

  3. 3.

    , & Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord. Glia 22, 161–170 (1998).

  4. 4.

    et al. Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 121, 2221–2228 (1998).

  5. 5.

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

  6. 6.

    , , , & NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J. Neurosci. 20, 6404–6412 (2000).

  7. 7.

    , & Purification and characterization of adult oligodendrocyte precursor cells from the rat optic nerve. J. Neurosci. 18, 4627–4636 (1998).

  8. 8.

    , & Long-term culture of purified postnatal oligodendrocyte precursor cells. Evidence for an intrinsic maturation program that plays out over months. J. Cell Biol. 148, 971–984 (2000).

  9. 9.

    et al. CNS-resident glial progenitor/stem cells produce Schwann cells as well as oligodendrocytes during repair of CNS demyelination. Cell Stem Cell 6, 578–590 (2010).

  10. 10.

    & Cooperation between PDGF and FGF converts slowly dividing O-2Aadult progenitor cells to rapidly dividing cells with characteristics of O-2Aperinatal progenitor cells. J. Cell Biol. 118, 889–900 (1992).

  11. 11.

    , , & Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol. Cell. Neurosci. 25, 252–262 (2004).

  12. 12.

    & Signals that initiate myelination in the developing mammalian nervous system. Mol. Neurobiol. 15, 83–100 (1997).

  13. 13.

    Control of myelin formation by axon caliber (with a model of the control mechanism). J. Comp. Neurol. 144, 233–252 (1972).

  14. 14.

    Target size regulates calibre and myelination of sympathetic axons. Nature 342, 430–433 (1989).

  15. 15.

    et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703 (2004).

  16. 16.

    et al. Neuregulin-1 type III determines the ensheathment fate of axons. Neuron 47, 681–694 (2005).

  17. 17.

    , , , & The geometric and spatial constraints of the microenvironment induce oligodendrocyte differentiation. Proc. Natl. Acad. Sci. USA 105, 14662–14667 (2008).

  18. 18.

    et al. A culture system to study oligodendrocyte myelination processes using engineered nanofibers. Nat. Methods 9, 917–922 (2012).

  19. 19.

    , , , & A rapid and reproducible assay for modeling myelination by oligodendrocytes using engineered nanofibers. Nat. Protoc. 8, 771–782 (2013).

  20. 20.

    et al. Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination. Nat. Neurosci. 14, 1009–1016 (2011).

  21. 21.

    et al. NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes. Neuron 43, 183–191 (2004).

  22. 22.

    et al. Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS. Genes Dev. 23, 1571–1585 (2009).

  23. 23.

    et al. Neurite outgrowth inhibitor Nogo-A establishes spatial segregation and extent of oligodendrocyte myelination. Proc. Natl. Acad. Sci. USA 109, 1299–1304 (2012).

  24. 24.

    , , & Adult-born SVZ progenitors receive transient synapses during remyelination in corpus callosum. Nat. Neurosci. 13, 287–289 (2010).

  25. 25.

    , & Zebrafish myelination: a transparent model for remyelination? Dis. Model. Mech. 1, 221–228 (2008).

  26. 26.

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

  27. 27.

    , , , & Muscarinic receptor subtypes as potential targets to modulate oligodendrocyte progenitor survival, proliferation, and differentiation. Dev. Neurobiol. 72, 713–728 (2012).

Download references


We thank the Multiple Sclerosis Research Group at the University of California, San Francisco (UCSF) for support, advice and insightful discussions. This work was supported by the US National Multiple Sclerosis Society Harry Weaver Neuroscience Scholar Award (JF 2142-A2/T), UCSF CTSI Catalyst Award for Innovation, gifts from friends of the Multiple Sclerosis Research Group at UCSF and the Joint Research Fund for Overseas Chinese Young Scholars (NSCF, 31228011). The rabbit monoclonal antibody to PDGFRα was a gift from W.B. Stallcup (Sanford Burnham Medical Research Institute).

Author information

Author notes

    • Feng Mei
    •  & Stephen P J Fancy

    These authors contributed equally to this work.


  1. Department of Neurology and Program in Neuroscience, University of California, San Francisco, San Francisco, California, USA.

    • Feng Mei
    • , Stephen P J Fancy
    • , Yun-An A Shen
    • , Edna Miao
    • , Seonok Lee
    • , Sonia R Mayoral
    • , Stephanie A Redmond
    • , Ainhoa Etxeberria
    • , Ari Green
    • , Stephen L Hauser
    •  & Jonah R Chan
  2. Department of Pediatrics, University of California, San Francisco, San Francisco, California, USA.

    • Stephen P J Fancy
  3. Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Third Military Medical University, Chongqing, China.

    • Jianqin Niu
    •  & Lan Xiao
  4. Wellcome Trust Medical Research Council, Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.

    • Chao Zhao
    •  & Robin J M Franklin
  5. Trianja Technologies, Allen, Texas, USA.

    • Bryan Presley


  1. Search for Feng Mei in:

  2. Search for Stephen P J Fancy in:

  3. Search for Yun-An A Shen in:

  4. Search for Jianqin Niu in:

  5. Search for Chao Zhao in:

  6. Search for Bryan Presley in:

  7. Search for Edna Miao in:

  8. Search for Seonok Lee in:

  9. Search for Sonia R Mayoral in:

  10. Search for Stephanie A Redmond in:

  11. Search for Ainhoa Etxeberria in:

  12. Search for Lan Xiao in:

  13. Search for Robin J M Franklin in:

  14. Search for Ari Green in:

  15. Search for Stephen L Hauser in:

  16. Search for Jonah R Chan in:


F.M., S.P.J.F., Y.-A.A.S., J.N., C.Z., E.M., S.L. and J.R.C. performed experiments. F.M., S.P.J.F., B.P., L.X., R.J.M.F., S.L.H. and J.R.C. provided reagents. F.M., S.P.J.F., S.R.M., S.A.R., A.E., R.J.M.F., A.G., S.L.H. and J.R.C. provided intellectual contributions. F.M., S.P.J.F. and J.R.C. analyzed the data and wrote the paper.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jonah R Chan.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–3

About this article

Publication history





Further reading