Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson's disease

Nature Medicine volume 3, pages 350–353 (1997)Cite this article

Abstract

The movement disorder in Parkinson's disease results from the selective degeneration of a small group of dopaminergic neurons in the substantia nigra pars compacta region of the brain. A number of exploratory studies using human fetal tissue allografts have suggested that transplantation of dopaminergic neurons may become an effective treatment for patients with Parkinson's disease and the difficulty in obtaining human fetal tissue has generated interest in finding corresponding non-human donor cells. Here we report a post-mortem histological analysis of fetal pig neural cells that were placed unilaterally into the caudate-putamen brain region of a patient suffering from Parkinson's disease. Long-term (over seven months) graft survival was found and the presence of pig dopaminergic neurons and other pig neural and glial cells is documented. Pig neurons extended axons from the graft sites into the host brain. Furthermore, other graft derived cells were observed several millimeters from the implantation sites. Markers for human microglia and T-cells showed only low reactivity in direct proximity to the grafts. This is the first documentation of neural xenograft survival in the human brain and of appropriate growth of non-human dopaminergic neurons for a potential therapeutic response in Parkinson's disease.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Hantraye, P., Riche, D., Maziere, M. & Isacson, O. Intrastriatal transplantation of cross-species fetal striatal Cells reduces abnormal movements in a primate model of Huntington disease. Proc. Natl. Acad. Sci. USA 89, 4187–4191 (1992).

    Article  CAS  Google Scholar 

  2. Wictorin, K., Brundin, P., Gustavii, B., Lindvall, O. & Björklund, A. Reformation of long axon pathways in adult rat central nervous system by human forebrain neu-roblasts. Nature 347, 556–558 (1990).

    Article  CAS  Google Scholar 

  3. Redmond, D.E. et al. Cryopreservation, culture, and transplantation of human fetal mesencephaiic tissue into monkeys. Science 242, 768–771 (1988).

    Article  Google Scholar 

  4. Freeman, T.B. et al. Cross-species intracerebral grafting of embryonic swine dopaminergic neurons. Prog. Brain Res. 78, 473–477 (1988).

    Article  CAS  Google Scholar 

  5. Huffaker, T.K. et al. Xenografting of fetal pig ventral mesencephalon corrects motor asymmetry in the rat model of Parkinson's disease. Brain Res. 77, 329–336 (1989

    Article  CAS  Google Scholar 

  6. Isacson, O., Riche, D., Hantraye, P., Sofroniew, M. & Maziere, M. A primate model of Huntington's disease: Cross-species implantation of striatal precursor Cells to the excitotoxically lesioned baboon caudate-putamen. Exp. Brain Res. 75, 213–220 (1989).

    Article  CAS  Google Scholar 

  7. Pakzaban, P. & Isacson, O. Neural xenotransplantation: Reconstruction of neuronal circuitry across species barriers. Neurosdence 62, 989–1001 (1994).

    Article  CAS  Google Scholar 

  8. Isacson, O. et al. Transplanted xenogeneic neural Cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth patterns of glial and axonal fibres. Nature Med. 1, 1189–1194 (1995).

    Article  CAS  Google Scholar 

  9. Galpern, W.C., Burns, L.H., Deacon, T.W., Dinsmore, J. & Isacson, O. Xenotransplantation of porcine fetal ventral mesencephalon in a rat model of Parkinson's disease: Functional recovery and graft morphology. Exp. Neural. 140, 1–13 (1996).

    Article  CAS  Google Scholar 

  10. Strömberg, I. et al. Human fetal mesencephaiic tissue grafted to dopamine-denervated striatum of athymic rats: Light-and electron-microscopical histochem-istry and in vivo chronoamperometric studies. J. Neurosd. 9, 614–624 (1989).

    Article  Google Scholar 

  11. Lindvall, O. et al. Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease. Ann. Neural. 35, 172–180 (1994).

    Article  CAS  Google Scholar 

  12. Kordower, J.H. et al. Neuropathological evidence of graft survival and striatal rein-nervation after the transplantation of fetal mesencephaiic tissue in a patient with Parkinson's disease. New Engl. J. Med. 332, 1118–1124 (1995).

    Article  CAS  Google Scholar 

  13. Freed, C. et al. Survival of implanted fetal dopamine Cells and neurologic improvement 12 to 24 months after transplantation for Parkinson's disease. N. Engl. J. Med. 327, 1549–1555 (1992).

    Article  CAS  Google Scholar 

  14. Clarke, D.J. et al. Human fetal dopamine neurons grafted in a rat model of Parkinson's disease: Ultrastructural evidence for synapse formation using tyrosine hydroxylase immunocytochemistry. Exp. Brain Res. 73, 115–126 (1988).

    Article  CAS  Google Scholar 

  15. Steele, D.J. & Auchincloss, H.J., Annu. Rev. Med. 46, 345–360 (1995).

    Article  CAS  Google Scholar 

  16. Sachs, D.H. & Bach, F.H. Immunology of xenograft rejection. Hum. Immunol. 28, 245–251 (1990).

    Article  CAS  Google Scholar 

  17. Hammer, C., Suckfull, M. & Saumweber, D. Evolutionary and immunological aspects of xenotransplantation. Transplant. Proc. 24, 2397–2400 (1992).

    CAS  PubMed  Google Scholar 

  18. Pedersen, E.B., Poulson, F.R., Zimmer, J. & Finsen, B. Prevention of mouse-rat xenograft rejection by a combination therapy of cyclosporin A, prednisolone and azathioprine. Exp. Brain Res. 106, 181–186 (1995).

    Article  CAS  Google Scholar 

  19. Pakzaban, P., Deacon, T.W., Burns, L.H., Dinsmore, J. & Isacson, O. A novel mode of immunoprotection of neural xenotransplants: masking of donor major histocompatibility complex class I enhances transplant survival in the CMS. Neurosdence 65, 983–996 (1995).

    Article  CAS  Google Scholar 

  20. Bartlett, P.F. et al. Allograft rejection overcome by immunoselection of neural precursor Cells. Prog. Brain Res. 82, 153–160 (1990).

    Article  CAS  Google Scholar 

  21. Honey, C.R., Charlton, H.M. & Wood, K.J. Rat brain xenografts reverse hypogonadism in mice immunosuppressed with anti-CD4 monoclonal antibody. Exp. Brain Res. 85, 149–152 (1991).

    Article  CAS  Google Scholar 

  22. Honey, C.R., Clarke, D.J., Dallman, M.J. & Charlton, H.M. Human neural graft function in rats treated with anti-interleukin II receptor antibody. Neuroreport 1, 247–249 (1991).

    Article  Google Scholar 

  23. Sanberg, P.R., Borlongan, C.V., Saporta, S. & Cameron, D.F., Testis-derived Sertoli cells survive and provide localized immunoprotection for xenografts in rat brain. Nature Biotechnol. 14, 1692–1695 (1996).

    Article  CAS  Google Scholar 

  24. Pakkenberg, B., Moller, A., Gundersen, H.J., Mouritzen-Dam, A. & Pakkenberg, H. The absolute number of nerve Cells in substantia nigra in normal subjects and in patients with Parkinson's disease estimated with an unbiased stereological method. J. Neural. Neurosurg. Psychiat. 54, 30–33 (1991).

    Article  CAS  Google Scholar 

  25. Abercrombie, A. Estimation of nuclear population from microtome sections. Anat. Rec. 94, 239–247 (1946).

    Article  CAS  Google Scholar 

  26. Kordower, J.H. et al. Functional fetal nigral grafts in a patient with Parkinson's disease: Chemoanatomic, Ultrastructural, and metabolic studies. J. Camp. Neural. 370, 203–230 (1996).

    Article  CAS  Google Scholar 

  27. Mott, J.L. et al. Effects of glial Cell line-derived neurotrophic factor on dopaminergic transplants to the 6-OHDA denervated striatum. Soc. Neurosd. Abs. 22, 1492 (1996).

  28. Aubert, I., Ridet, J.-L. & Gage, F.H. Regeneration in the adult mammalian CNS: Guided by development. Curr. Opin. Neurobiol. 5, 625–635 (1995).

    Article  CAS  Google Scholar 

  29. Sloan, D.J., Wood, M.J. & Charlton, H.M. The immune response to intracerebral neural grafts. Trends Neurosd. 14, 341–346 (1991).

    Article  CAS  Google Scholar 

  30. Starzl, T.E. et al. Baboon-to-human liver transplantation. Lancet 341, 65–71 (1993).

    Article  CAS  Google Scholar 

  31. Bailey, L.L., Nehlsen-Cannarella, S.L., Concepcion, W. & Jolley, W.B. Baboon-to-human cardiac xenotransplantation in a neonate. JAMA 254, 3321–3329 (1985).

    Article  CAS  Google Scholar 

  32. Iidstad, S.T. Xenotransplantation for AIDS. Lancet 347, 761 (1996).

  33. Groth, C.G. et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet 344, 1402–1404 (1994).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuroregeneration Laboratory, Harvard Medical School, McLean Hospital MRC119, Belmont, Massachusetts, 02178, USA

    Terrence Deacon & Ole Isacson

  2. Lahey Hitchcock Clinic, Burlington, Massachusetts, 01805, USA

    Christine Thomas, Prather Palmer, Stephen Kott, Dana Penney, Samir Kassissieh & Peter Dempsey

  3. Program in Neuroscience, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Ole Isacson

  4. Diacrin, Inc., 13th Street, Charlestown, Masschusetts, 02129, USA

    Jonathan Dinsmore & Albert Edge

  5. Department of Neurology, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts, 02114, USA

    Ole Isacson

Authors
  1. Terrence Deacon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jonathan Dinsmore
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christine Thomas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Prather Palmer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Stephen Kott
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Albert Edge
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dana Penney
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Samir Kassissieh
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Peter Dempsey
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ole Isacson
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Deacon, T., Schumacher, J., Dinsmore, J. et al. Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson's disease. Nat Med 3, 350–353 (1997). https://doi.org/10.1038/nm0397-350

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0397-350

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing