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.

Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats

Abstract

In vitro expansion of central nervous system (CNS) precursors might overcome the limited availability of dopaminergic neurons in transplantation for Parkinson's disease, but generating dopaminergic neurons from in vitro dividing precursors has proven difficult. Here a three-dimensional cell differentiation system was used to convert precursor cells derived from E12 rat ventral mesencephalon into dopaminergic neurons. We demonstrate that CNS precursor cell populations expanded in vitro can efficiently differentiate into dopaminergic neurons, survive intrastriatal transplantation and induce functional recovery in hemiparkinsonian rats. The numerical expansion of primary CNS precursor cells is a new approach that could improve both the ethical and the technical outlook for the use of human fetal tissue in clinical transplantation.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Schematic illustration of the experimental procedures.
Figure 2: Expansion of mesencephalic precursors in vitro.
Figure 3: Differentiated mesencephalic precursors in vitro.
Figure 4: In vivo results.

References

  1. Takayama, H. et al. Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson's disease. Nat. Med. 1, 53–58 (1995).

    CAS  Article  Google Scholar 

  2. Choi-Lundberg, D. L. et al. Dopaminergic neurons protected from degeneration by GDNF gene therapy . Science 275, 838– 841 (1997).

    CAS  Article  Google Scholar 

  3. Deacon, T. 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).

    CAS  Article  Google Scholar 

  4. Olanow, C. W., Kordower, J. H. & Freeman, T. B. Fetal nigral transplantation as a therapy for Parkinson's disease. Trends Neurosci. 19, 102 –109 (1996).

    CAS  Article  Google Scholar 

  5. Wenning, G. K. et al. Short- and long-term survival and function of unilateral intrastriatal dopaminergic grafts in Parkinson's disease. Ann. Neurol. 42, 95–107 (1997).

    CAS  Article  Google Scholar 

  6. Kordower, J. H. et al. Neuropathological evidence of graft survival and striatal reinnervation after the transplantation of fetal mesencephalic tissue in a patient with Parkinson's disease. N. Engl. J. Med. 332, 1118 –1124 (1995).

    CAS  Article  Google Scholar 

  7. Johe, K. K., Hazel, T. G., Mü ller, T., Dugich-Djordjevic, M. M. & McKay, R. D. G.Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Devel. 10, 3129–3140 (1996).

    CAS  Article  Google Scholar 

  8. McKay, R. D. Stem cells in the central nervous system. Science 276, 66–71 (1997).

    CAS  Article  Google Scholar 

  9. Shah, N. M., Marchionni, M. A., Isaacs, I., Stroobant, P. & Anderson, D. J. Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cell 77, 349–360 (1994).

    CAS  Article  Google Scholar 

  10. Shah, N. M., Groves, A. K. & Anderson, D. J. Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell 85, 331–343 (1996).

    CAS  Article  Google Scholar 

  11. Suhonen, J. O., Peterson, D. A ., Ray, J. & Gage, F. H. Differentiation of adult hippocampus-derived progenitors into olfactory neurons in vivo. Nature 383, 624–627 (1996).

    CAS  Article  Google Scholar 

  12. Frederiksen, K. & McKay, R. D. Proliferation and differentiation of rat neuroepithelial precursor cells in vivo. J. Neurosci. 8, 1144–1151 ( 1988).

    CAS  Article  Google Scholar 

  13. Lendahl, U., Zimmerman, L. B. & McKay, R. D. CNS stem cells express a new class of intermediate filament protein. Cell 60, 585– 595 (1990).

    CAS  Article  Google Scholar 

  14. Guyenet, P. G. & Crane, J. K. Non-dopaminergic nigrostriatal pathway. Brain Res. 213, 291– 305 (1981).

    CAS  Article  Google Scholar 

  15. Rosenthal, A. Auto transplants for Parkinson's disease? Neuron 20, 169–172 (1998).

    CAS  Article  Google Scholar 

  16. Spenger, C. et al. Fetal ventral mesencephalon of human and rat origin maintained in vitro and transplanted to 6-hydroxydopamine-lesioned rats gives rise to grafts rich in dopaminergic neurons. Exp. Brain Res. 112 , 47–57 (1996).

    CAS  Article  Google Scholar 

  17. Lindvall, O. et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 247, 574– 577 (1990).

    CAS  Article  Google Scholar 

  18. Jiao, S., Gurevich, V. & Wolff, J. A. Long-term correction of rat model of Parkinson's disease by gene therapy. Nature 362, 450–453 (1993).

    CAS  Article  Google Scholar 

  19. Fisher, L. J., Jinnah, H. A., Kale, L. C., Higgins, G. A. & Gage, F. H. Survival and function of intrastriatally grafted primary fibroblasts genetically modified to produce L-Dopa. Neuron 6, 371–380 ( 1991).

    CAS  Article  Google Scholar 

  20. Sabaté, O. et al. Transplantation to the rat brain of human neural progenitors that were genetically modified using adenoviruses . Nat. Genet. 9, 256– 260 (1995).

  21. Beck, K. D. et al. Mesencephalic dopaminergic neurons protected by GDNF from axotomy- induced degeneration in the adult brain. Nature 373, 339–341 (1995).

    CAS  Article  Google Scholar 

  22. Tomac, A. et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373, 335– 339 (1995).

    CAS  Article  Google Scholar 

  23. Crossley, P. H., Martinez, S. & Martin, G. R. Midbrain development induced by FGF8 in the chick embryo. Nature 380, 66– 68 (1996).

    CAS  Article  Google Scholar 

  24. Danielian, P. S. & McMahon, A. P. Engrailed-1 as a target of the Wnt-1 signalling pathway in vertebrate midbrain development. Nature 383, 332–334 (1996).

    CAS  Article  Google Scholar 

  25. Hynes, M., Poulsen, K., Tessier-Lavigne, M. & Rosenthal, A. Control of neuronal diversity by the floor plate: Contact-mediated induction of midbrain dopaminergic neurons. Cell 80, 95–101 (1995).

    CAS  Article  Google Scholar 

  26. Hynes, M. et al. Induction of midbrain dopaminergic neurons by sonic hedgehog. Neuron 15, 35–44 ( 1995).

    CAS  Article  Google Scholar 

  27. Polymeropoulos, M. H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).

    CAS  Article  Google Scholar 

  28. Zetterströ m, R. H. et al. Dopamine neuron agenesis in Nurr1-deficient mice. Science 276, 248–250 (1997).

    Article  Google Scholar 

  29. Hynes, M. et al. Control of cell pattern in the neural tube by the zinc finger transcription factor and oncogene Gli-1. Neuron 19, 15–26 (1997).

    CAS  Article  Google Scholar 

  30. Wang, M. Z. et al. Induction of dopaminergic neuron phenotype in the midbrain by Sonic hedgehog protein. Nat. Med. 1, 1184– 1188 (1995).

    CAS  Article  Google Scholar 

  31. Brü stle, O., Maskos, U. & McKay, R. D. G. Host-guided migration allows targeted introduction of neurons into the embryonic brain. Neuron 15, 1275–1285 (1995).

    Article  Google Scholar 

  32. Campbell, K., Olsson, M. & Bjö rklund, A. Regional incorporation and site-specific differentiation of striatal precursors transplanted to the embryonic forebrain ventricle. Neuron 15, 1259–1273 (1995).

    CAS  Article  Google Scholar 

  33. Fishell, G. Striatal precursors adopt cortical identities in response to local cues. Development 121, 803–812 ( 1995).

    CAS  Google Scholar 

  34. Vicario-Abejó n, C., Cunningham, M. G. & McKay, R. D. G. Cerebellar precursors transplanted to the neonatal dentate gyrus express features characteristic of hippocampal neurons. J. Neurosci. 15, 6351–6363 (1995).

    Article  Google Scholar 

  35. Svendsen, C. N., Clarke, D. J., Rosser, A. E. & Dunnett, S. B. Survival and differentiation of rat and human epidermal growth factor-responsive precursor cells following grafting into the lesioned adult central nervous system. Exp. Neurol. 137, 376– 388 (1996).

    CAS  Article  Google Scholar 

  36. Svendsen, C. N. et al. Long-term survival of human central nervous system progenitor cells transplanted into a rat model of Parkinson's disease. Exp. Neurol. 148, 135–146 (1997).

    CAS  Article  Google Scholar 

  37. Brundin, P. et al. Survival and function of dissociated dopamine neurons grafted at different developmental stages or after being cultured in vitro. Dev. Brain Res. 39, 233–243 (1988).

    CAS  Article  Google Scholar 

  38. Martinez-Serrano, A., Fischer, W. & Björklund, A. Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secreting neural progenitors grafted to the basal forebrain. Neuron 15, 473 –484 (1995).

    CAS  Article  Google Scholar 

  39. Snyder, E. Y., Taylor, R. M. & Wolfe, J. H. Neural progenitor cell engraftment corrects lysosomal storage throughout the MPS VII mouse brain. Nature 374, 367–370 (1995).

    CAS  Article  Google Scholar 

  40. Mayer-Proschel, M., Kalyani, A. J., Mujtaba, T. & Rao, M. S. Isolation of lineage-restricted neuronal precursors from multipotent neuroepithelial stem cells. Neuron 19, 773– 785 (1997)30.

    CAS  Article  Google Scholar 

  41. Williams, B. P. et al. A PDGF-regulated immediate early gene response initiates neuronal differentiation in ventricular zone progenitor cells. Neuron 18, 553–562 (1997).

    CAS  Article  Google Scholar 

  42. Studer, L. in Current Protocols in Neuroscience (eds Crawley, J. et al. ) 3.3.1–3.3.12 (Wiley, New York, 1997 ).

  43. Studer, L. et al. Non-invasive dopamine determination by reversed phase HPLC in the medium of free-floating roller tube cultures of rat fetal ventral mesencephalon. A tool to assess dopaminergic tissue prior to grafting. Brain Res. Bull. 41, 143–150 ( 1996).

    CAS  Article  Google Scholar 

  44. Brustie, O., Cunningham, M.G., Tabar, V. & Studer L. in Current Protocols in Neuroscience (eds Crawley, J. et al. ) 3.10.1–3.10.28 (Wiley, New York, 1997).

  45. Gundersen, H. J. G. et al. Some new, simple and efficient stereological methods and their use in pathological research and diagnosis. APMIS 96, 379–394 (1988).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank Nadine Kabbani and Elizabeth Rha for their help in the histological analyses and Drs C. Spenger and C. Gerfen for critically reviewing the manuscript. L.S. was supported by a grant of the Swiss foundation for biomedical grants.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ron McKay.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Studer, L., Tabar, V. & McKay, R. Transplantation of expanded mesencephalic precursors leads to recovery in parkinsonian rats. Nat Neurosci 1, 290–295 (1998). https://doi.org/10.1038/1105

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/1105

Further reading

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