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Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord

Nature Biotechnology volume 18, pages 949–953 (2000)Cite this article

Abstract

Here we describe transplantation of olfactory ensheathing cells (OECs) or Schwann cells derived from transgenic pigs expressing the human complement inhibitory protein, CD59 (hCD59), into transected dorsal column lesions of the spinal cord of the immunosuppressed rat to induce axonal regeneration. Non-transplanted lesion-controlled rats exhibited no impulse conduction across the transection site, whereas in animals receiving transgenic pig OECs or Schwann cells impulse conduction was restored across and beyond the lesion site for more than a centimeter. Cell labeling indicated that the donor cells migrated into the denervated host tract. Conduction velocity measurements showed that the regenerated axons conducted impulses faster than normal axons. By morphological analysis, the axons seemed thickly myelinated with a peripheral pattern of myelin expected from the donor cell type. These results indicate that xenotranplantation of myelin-forming cells from pigs genetically altered to reduce the hyperacute response in humans are able to induce elongative axonal regeneration and remyelination and restore impulse conduction across the transected spinal cord.

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Figure 1: FACS analysis of transgenic Schwann cells and transgenic olfactory ensheathing cells (OECs) expressing CD59.
Figure 2: Conduction across the transplantation zone.
Figure 3: Conduction properties of transplant-induced regenerated spinal cord axons.
Figure 4: Presence of transgenic pig donor OECs in the recipient spinal cord.
Figure 5: Ultrastructural characteristics of regenerated axons following transgenic pig OEC and Schwann cells transplantation.

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References

  1. Edge, A. S. B., Gosse, M. E. & Dinsmore, J. Xenogeneic cell therapy: current progress and future developments in porcine cell transplantation. Cell Transplantation 7, 525–539 ( 1998).

    Article  CAS  Google Scholar 

  2. Auchincloss, H. Jr. & Sachs, D.H. Xenogeneic Transplantation. Annu. Rev. Immunol. 16, 433–470 (1998).

    Article  CAS  Google Scholar 

  3. Li, Y., Field, P.M., Raisman, G. Repair of adult rat corticospinal tract by transplants of olfactory ensheathing cells. Science 277, 2000– 2002 (1997).

    Article  CAS  Google Scholar 

  4. Imaizumi, T., Lankford, K.L. & Kocsis, J.D. Transplantation of olfactory ensheathing cells or Schwann cells restores rapid and secure conduction across the transected spinal cord. Brain Res. 854, 70– 78 (1999).

    Article  Google Scholar 

  5. Ramon-Cueto, A., Plant, G.W., Avila, J. & Bunge, M.B. Long-distance axonal regeneration in the transected adult rat spinal cord is promoted by olfactory ensheathing glia transplants. J. Neurosci. 18, 3803–3815 (1998).

    Article  CAS  Google Scholar 

  6. Devon, R. & Doucette, R. Olfactory ensheathing cells myelinate dorsal root ganglion neurites. Brain Res. 589, 175–179 (1992).

    Article  CAS  Google Scholar 

  7. Levi, A.D. & Bunge, R.P. Studies of myelin formation after transplantation of human Schwann cells into the severe combined immunodeficient mouse. Exp. Neurol. 130, 41– 52 (1994).

    Article  CAS  Google Scholar 

  8. Honmou, O., Felts, P.A, Waxman, S.G. & Kocsis, J.D. Restoration of normal conduction properties in demyelinated spinal cord axons in the adult rat by transplantation of exogenous Schwann cells. J. Neurosci. 16, 3199–3208 ( 1996).

    Article  CAS  Google Scholar 

  9. Imaizumi, T., Lankford, K.L., Waxman, S.G., Greer, C.A. and Kocsis, J.D. Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. J. Neurosci. 18, 6176–6185 (1998).

    Article  CAS  Google Scholar 

  10. Fodor, W.L. et al. Expression of a functional human complement inhibitor in a transgenic pig as a model for the prevention of xenogeneic hyperacute rejection. Proc. Natl. Acad. Sci. USA 91, 11153 ( 1994).

    Article  CAS  Google Scholar 

  11. Franklin, R.J., Gilson, J.M., Franceschini, I.A. & Barnett, S.C. Schwann cell-like myelination following transplantation of an olfactory bulb-ensheathing cell line into areas of demyelination in the adult CNS. Glia 17, 217–224 (1996).

    Article  CAS  Google Scholar 

  12. Blakemore, W.F. & Crang, A.J. The use of cultured autologous Schwann cells to remyelinate areas of persistent demyelination in the central nervous system. J. Neurol. Sci. 70, 207–223 (1985).

    Article  CAS  Google Scholar 

  13. Li, Y. & Raisman, G. Schwann cells induce sprouting in motor and sensory axons in the adult rat spinal cord. J. Neurosci. 14, 4050–4063 ( 1994).

    Article  CAS  Google Scholar 

  14. Kuhlengel, K.R., Bunge, M.B., Bunge, R.P. & Burton, H. Implantation of cultured sensory neurons and Schwann cells into lesioned neonatal rat spinal cord: II. Implant characteristics and examination of corticospinal tract growth . J. Comp. Neurol. 293, 73– 91 (1990).

    Google Scholar 

  15. Kato, T., Honmou, O., Uede, T., Hashi, K. & Kocsis, J.D. Transplantation of human olfactory ensheathing cells elicits remyelination. Glia (In Press) (2000).

  16. Berthold, C.H. in Physiology and pathobiology of axons. (ed. Waxman, S.G.) 3–64 (Raven, New York 1978).

    Google Scholar 

  17. Aguayo, D.A. Axonal elongation into peripheral nervous system “bridges” after central nervous system injury rat. Science 214, 913–933 (1981).

    Article  Google Scholar 

  18. Schwab, M.E., Kapfhammer, J.P. & Bandtlow, C.E. Inhibitors of neurite growth. Annu. Rev. Neurosci. 16, 565–595 ( 1993).

    Article  CAS  Google Scholar 

  19. Ramon-Cueto, A. & Valverde, F. Olfactory bulb ensheathing glia: a unique cell type with axonal growth-promoting properties . Glia 14, 163–173 (1995).

    Article  CAS  Google Scholar 

  20. Taniuchi, M., Clark, H.B., Schweitzer, J.B. & Johnson, E.M. Expression of nerve growth factor receptors by Schwann cells of axotomized peripheral nerves: ultrastructural location, suppression by contact, and binding properties. J. Neurosci. 8, 664– 681 (1988).

    Article  CAS  Google Scholar 

  21. Windebank, J.A. & Poduslo, J.F. Neuronal growth factors produced by adult peripheral nerve after injury. Brain Res. 385, 197–200 ( 1986).

    Article  CAS  Google Scholar 

  22. Trapp, B.D., et al. Axonal transection in the lesion of multiple sclerosis. N. Engl. J. Med. 338, 278–285 (1998).

    Article  CAS  Google Scholar 

  23. Deacon, T., et al. Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson's disease. Nature Med. 3, 350–353 (1997).

    Article  CAS  Google Scholar 

  24. Chen, S. C. et al. Treatment of severe liver failure with a bioartificial liver. Ann. N. Y. Acad. Sci. 831, 350–336 (1997).

    Article  CAS  Google Scholar 

  25. Watanabe, E. et al. Cardiomyocyte transplantation in a porcine myocardial infarction model. Cell Transplantation 7, 239– 246 (1998).

    Article  CAS  Google Scholar 

  26. Costa, C., Zhao, L., Decesare, S. & Fodor, W.L. Comparative analysis of three genetic modifications designed to inhibit hyperacute rejection of xenografts. Xenotransplantation. 6, 6– 16 (1999).

    Article  CAS  Google Scholar 

  27. Fujioka, H. et al. Carboxyfluorewcin (CFSE) labelling of hepatocytes for short-term localization following intraportal transplantaion. Cell transplantation 3, 397–408 ( 1994).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported in part by an Advanced Technology Program grant from the National Institutes of Standards and Technology to W.L.F, the National Institutes of Health (NIH) (NS 10174); the National Multiple Sclerosis Society (RG2135) and the Medical Research and Rehabilitation and Development Research Services of the Department of Veterans Affairs.

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Authors and Affiliations

  1. Department of Neurology, Yale University School of Medicine, New Haven, 06510, CT

    Toshio Imaizumi, Karen L. Lankford & Jeffery D. Kocsis

  2. Department of Veterans Affairs Medical Center, Neuroscience Research Center, West Haven, 06516 , CT

    Toshio Imaizumi, Karen L. Lankford & Jeffery D. Kocsis

  3. Alexion Pharmaceuticals, Inc, 25 Science Park, New Haven, 06511, CT

    Willis V. Burton & William L. Fodor

Authors
  1. Toshio Imaizumi
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  2. Karen L. Lankford
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  3. Willis V. Burton
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  4. William L. Fodor
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  5. Jeffery D. Kocsis
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Correspondence to Jeffery D. Kocsis.

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Imaizumi, T., Lankford, K., Burton, W. et al. Xenotransplantation of transgenic pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord. Nat Biotechnol 18, 949–953 (2000). https://doi.org/10.1038/79432

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