Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain

  • A Corrigendum to this article was published on 01 February 2004

Abstract

Both late-gestation and adult human forebrain contain large numbers of oligodendrocyte progenitor cells (OPCs). These cells may be identified by their A2B5+PSA-NCAM phenotype (positive for the early oligodendrocyte marker A2B5 and negative for the polysialylated neural cell adhesion molecule). We used dual-color fluorescence-activated cell sorting (FACS) to extract OPCs from 21- to 23-week-old fetal human forebrain, and A2B5 selection to extract these cells from adult white matter. When xenografted to the forebrains of newborn shiverer mice, fetal OPCs dispersed throughout the white matter and developed into oligodendrocytes and astrocytes. By 12 weeks, the host brains showed extensive myelin production, compaction and axonal myelination. Isolates of OPCs derived from adult human white matter also myelinated shiverer mouse brain, but much more rapidly than their fetal counterparts, achieving widespread and dense myelin basic protein (MBP) expression by 4 weeks after grafting. Adult OPCs generated oligodendrocytes more efficiently than fetal OPCs, and ensheathed more host axons per donor cell than fetal cells. Both fetal and adult OPC phenotypes mediated the extensive and robust myelination of congenitally dysmyelinated host brain, although their differences suggested their use for different disease targets.

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Figure 1: Fetal human OPCs disperse rapidly to infiltrate the forebrain.
Figure 2: Engrafted human OPCs myelinate an extensive region of the forebrain.
Figure 3: Axonal ensheathment and myelin compaction by engrafted human OPCs.
Figure 4: Fetal and adult OPCs differed in speed and efficiency of myelinogenesis.

References

  1. 1

    Lachapelle, F., Gumpel, M., Baulac, C. & Jacque, C. Transplantation of fragments of CNS into the brains of shiverer mutant mice: extensive myelination by transplanted oligodendrocytes. Dev. Neurosci. 6, 326–334 (1983).

  2. 2

    Roach, A., Takahashi, N., Pravtcheva, D., Ruddle, F. & Hood, L. Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice. Cell 42, 149–155 (1985).

  3. 3

    Gansmuller, A. et al. Transplantations of newborn CNS fragments into the brain of shiverer mutant mice: extensive myelination by transplanted oligodendrocytes. II. Electron microscopic study. Dev. Neurosci. 8, 197–207 (1986).

  4. 4

    Gumpel, M. et al. Transplantation of human embryonic oligodendrocytes into shiverer brain. Ann. NY Acad. Sci. 495, 71–85 (1987).

  5. 5

    Gumpel, M., Gout, O., Lubetzki, C., Gansmuller, A. & Baumann, N. Myelination and remyelination in the central nervous system by transplanted oligodendrocytes using the shiverer model. Discussion on the remyelinating cell population in adult mammals. Dev. Neurosci. 11, 132–139 (1989).

  6. 6

    Seilhean, D., Gansmuller, A., Baron-Van Evercooren, A., Gumpel, M. & Lachapelle, F. Myelination by transplanted human and mouse central nervous system tissue after long-term cryopreservation. Acta Neuropathol. 91, 82–88 (1996).

  7. 7

    Mitome, M. et al. Towards the reconstruction of central nervous system white matter using neural precursor cells. Brain 124, 2147–2161 (2001).

  8. 8

    Yandava, B., Billinghurst, L. & Snyder, E. Global cell replacement is feasible via neural stem cell transplantation: evidence from the dysmyelinated shiverer mouse brain. Proc. Natl. Acad. Sci. USA 96, 7029–7034 (1999).

  9. 9

    O'Leary, M.T. & Blakemore, W.F. Oligodendrocyte precursors survive poorly and do not migrate following transplantation into the normal adult central nervous system. J. Neurosci. Res. 48, 159–167 (1997).

  10. 10

    Learish, R.D., Brustle, O., Zhang, S.C. & Duncan, I.D. Intraventricular transplantation of oligodendrocyte progenitors into a fetal myelin mutant results in widespread formation of myelin. Ann. Neurol. 46, 716–722 (1999).

  11. 11

    Zhang, S.C., Ge, B. & Duncan, I.D. Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. Proc. Natl. Acad. Sci. USA 96, 4089–4094 (1999).

  12. 12

    Nunes, M.C. et al. Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nat. Med. 9, 439–447 (2003).

  13. 13

    Roy, N.S. et al. Identification, isolation, and promoter-defined separation of mitotic oligodendrocyte progenitor cells from the adult human subcortical white matter. J. Neurosci. 19, 9986–9995 (1999).

  14. 14

    Eisenbarth, G.S., Walsh, F.S. & Nirenberg, M. Monoclonal antibody to a plasma membrane antigen of neurons. Proc. Natl. Acad. Sci. USA 76, 4913–4917 (1979).

  15. 15

    Raff, M.C., Miller, R.H. & Noble, M. A glial progenitor cell that develops in vitro into an astrocyte or an oligodendrocyte depending on culture medium. Nature 303, 390–396 (1983).

  16. 16

    Rao, M. & Mayer-Proschel, M. Glial-restricted precursors are derived from multipotential neuroepithelial stem cells. Dev. Biol. 188, 48–63 (1997).

  17. 17

    Piper, D. et al. Identification and characterization of neuronal precursors and their progeny from human fetal tissue. J. Neurosci. Res. 66, 356–368 (2001).

  18. 18

    Ridge, J., Fuchs, E. & Matzinger, P. Neonatal tolerance revisited: turning on newborn T cells with dendritic cells. Science 271, 1723–1726 (1996).

  19. 19

    Roser, B. Cellular mechanisms in neonatal and adult tolerance. Immunol. Rev. 107, 179–202 (1989).

  20. 20

    Windrem, M. et al. Progenitor cells derived from the adult human subcortical white matter disperse and differentiate as oligodendrocytes within demyelinated regions of the rat brain. J. Neurosci. Res. 69, 966–975 (2002).

  21. 21

    Keyoung, H.M. et al. Specific identification, selection and extraction of neural stem cells from the fetal human brain. Nat. Biotechnol. 19, 843–850 (2001).

  22. 22

    Louissaint, A., Rao, S., Leventhal, C. & Goldman, S.A. Coordinated interaction of angiogenesis and neurogenesis in the adult songbird brain. Neuron 34, 945–960 (2002).

  23. 23

    Benraiss, A., Chmielnicki, E., Lerner, K., Roh, D. & Goldman, S.A. Adenoviral brain-derived neurotrophic factor induces both neostriatal and olfactory neuronal recruitment from endogenous progenitor cells in the adult forebrain. J. Neurosci. 21, 6718–6731 (2001).

  24. 24

    Goldman, S.A., Lemmon, V. & Chin, S.S. Migration of newly generated neurons upon ependymally derived radial guide cells in explant cultures of the adult songbird forebrain. Glia 8, 150–160 (1993).

  25. 25

    Franklin, R.J. & Blakemore, W.F. Transplanting oligodendrocyte progenitors into the adult CNS. J. Anat. 190, 23–33 (1997).

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Acknowledgements

This work was supported by the National Multiple Sclerosis Society and National Institutes of Health/National Institute of Neurological Diseases and Stroke grants R01NS39559 and R01NS33106. We thank B. Poulos of the Albert Einstein College of Medicine tissue bank and S. Kelly of the American Biological Resource tissue bank for assistance with tissue acquisition, and H. Okano for the gift of antiserum to human nestin.

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Correspondence to Steven A Goldman.

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S.A.G., N.S.R. and M.W. have patents and patent applications covering methods of isolating human oligodendrocyte progenitor cells, and aspects of the cells and uses thereof. These have been licensed by Cornell University of Q Therapeutics, a biotech company in which both Cornell University and S.A.G. have equity positions, and for which S.A.G. serves as a paid member of its scientific advisory board.

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Windrem, M., Nunes, M., Rashbaum, W. et al. Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nat Med 10, 93–97 (2004). https://doi.org/10.1038/nm974

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