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:

Basic fibroblast growth factor increases dopaminergic graft survival and function in a rat model of Parkinson's disease

Abstract

The clinical use of fetal neural grafts as an intracerebral source of dopamine for patients with Parkinson's disease has met with limited success. Since basic fibroblast growth factor (bFGF) enhances the survival and growth of dopaminergic neurons in vitro, we explored whether cells genetically modified to produce bFGF would improve the functional efficacy of dopaminergic neurons implanted into rats with experimental Parkinson's disease. Results show that bFGF-producing cells grafted together with fetal dopamine neurons have potent growth-promoting effects on the implanted neurons in vivo. Moreover, rats implanted with such co-grafts display the most pronounced behavioural improvements post-grafting. These findings not only provide insight into the function of bFGF in situ, but also suggest an approach for enhancing the survival and function of dopamine neurons grafted into the damaged brain.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. Björklund, A. & Stenevi, U. Reconstruction of the nigrostriatal dopamine pathway by intracerebral nigral transplants. Brain Res. 177, 555–560 (1979).

    Article  Google Scholar 

  2. Perlow, M.J. et al. Brain grafts reduce motor abnormalities produced by destruction of nigrostriatal dopamine system. Science 204, 643–647 (1979).

    Article  CAS  Google Scholar 

  3. Lindvall, O. Prospects of transplantation in human neurodegenerative diseases. Trends Neurosci. 14, 376–384 (1991).

    Article  CAS  Google Scholar 

  4. Ahlskog, J.E. Cerebral transplantation for Parkinson's disease: current progress and future prospects. Mayo clin. Proc. 68, 578–591 (1993).

    Article  CAS  Google Scholar 

  5. Lindvall, O. et al. Transplantation of fetal dopamine neurons in Parkinson's disease: one-year clinical and neurophysiological observations in two patients with putaminal implants. Ann. Neurol. 31, 166–173 (1992).

    Article  Google Scholar 

  6. Redmond, D.E., et al. Fetal neural graft survival. Lancet 336, 820–822 (1990).

    Article  Google Scholar 

  7. Brundin, P. & Björklund, A. Survival, growth and function of dopaminergic neurons grafted to the brain. Prog. Brain Res. 71, 293–308 (1987).

    Article  CAS  Google Scholar 

  8. Mayer, E., Fawcett, J.W. & Dunnett, S.B. Basic fibroblast growth factor promotes the survival of embryonic ventral mesencephalic dopaminergic neurons. II. Effects on nigral transplants in vivo. Neurosdence 56, 389–398 (1993).

    Article  CAS  Google Scholar 

  9. Steinbusch, H.W.M., Vermeulen, R.J. & Tonnaer, J.A.D.M. Basic fibroblast growth factor enhances survival and sprouting of fetal dopaminergic cells implanted in the denervated rat caudate-putamen: preliminary observations. Prog. Brain res. 82, 81–86 (1990).

    Article  CAS  Google Scholar 

  10. Matsuda, S., Saito, H. & Nishiyama, N. Effect of basic fibroblast growth factor on neurons cultured from various regions of postnatal brain. Japan J. Pharmacol. 59, 365–370 (1992).

    Article  CAS  Google Scholar 

  11. Kawaja, M.D. & Gage, F.H. Morphological and neurochemical features of cultured primary skin fibroblasts of Fischer 344 rats following striatal implantation. J. comp. Neurol. 317, 102–116 (1992).

    Article  CAS  Google Scholar 

  12. Ray, J. et al. Expression of biologically active basic fibroblast growth factor by genetically modified rat primary skin fibroblasts. J. Neurochem. 64 (1995).

    Article  Google Scholar 

  13. Brundin, P., Isacson, O. & Björklund, A. Monitoring of cell viability in suspensions of embryonic CNS tissue and its use as a criterion for intracerebral graft survival. Brain Res. 331, 251–259 (1985).

    Article  CAS  Google Scholar 

  14. Schmidt, R.H., Bjouml;rklund, A., Stenevi, U., Dunnett, S.B. & Gage, F.H. Activity of intrastriatal nigral suspension implants as assessed by measurements of dopamine synthesis and metabolism. Acta physiol. Scand. Suppl. 522, 19–28 (1983).

    CAS  PubMed  Google Scholar 

  15. Blam, S.B. et al. Addition of growth hormone secretion signal to basic fibroblast growth factor results in cell transformation and secretion of aberrant forms of the protein. Oncogene 3, 129–136 (1988).

    CAS  PubMed  Google Scholar 

  16. Baird, A. & Bölhen, P. in: Peptide growth factors and their receptors. 1 (eds Sporn, M.B. & Roberts, A.B.) 369–418 (Springer-Verlang, 1991).

    Book  Google Scholar 

  17. Gonzalez, A.M. et al. Storage, metabolism, and processing of [125I]-fibroblast growth factor-2 after intracerebral injection. Brain Res. (in the press).

  18. Baird, A. & Ling, N. Fibroblast growth factors are present in the extracellular matrix produced by endothelial cells in vitro: implications for a role of heparinase-like enzymes in the neovascular response. Biochem. Biophys. res. Comm. 142, 428–437 (1987).

    Article  CAS  Google Scholar 

  19. Vlodavsky, I. et al. Endothelial cell-derived basic fibroblast growth factor: synthesis and deposition into subendothelial extracellular matrix. Proc. natn. Acad. Sci. USA. 84, 2292–2296 (1987).

    Article  CAS  Google Scholar 

  20. Flaumenhaft, R., Moscatelli, D., Saksela, O. & Rifkin, D.B. Role of extracellular matrix in the action of basic fibroblast growth factor: matrix as a source of growth factor for long-term stimulation of plasminogen activator production and DNA synthesis. J. cell. Physiol. 140, 75–81 (1989).

    Article  CAS  Google Scholar 

  21. Knusel, B., Michel, P.P., Schwaber, J.S. & Hefti, F. Selective and nonselective stimulation of central cholinergic and dopamine development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II. J. Neurosci. 10, 558–570 (1990).

    Article  CAS  Google Scholar 

  22. Engele, J. & Bohn, M.C. The neurotrophic effects of basic fibroblast growth factors on dopaminergic neurons in vitro are nediated by mesencephalic glia. J. Neurosci. 11, 3070–3078 (1991).

    Article  CAS  Google Scholar 

  23. Mayer, E., Dunnett, S.B., Pellitteri, R., & Fawcett, J.W. Basic fibroblast growth factor promotes the survival of embryonic mesencephalic dopaminergic neurons. I. Effects in vitro. Neuroscience 56, 379–388 (1993).

    Article  CAS  Google Scholar 

  24. Lin, L.-F.H., Doherty, D.H., Lile, J.D., Bektesh, S. & Collins, F. GDNF: A glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–1132 (1993).

    Article  CAS  Google Scholar 

  25. Yoshida, K. & Gage, F.H. Fibroblast growth factors stimulate nerve growth factor synthesis and secretion by astrocytes. Brain Res. 538, 118–126 (1991).

    Article  CAS  Google Scholar 

  26. Yoshida, K. & Gage, F.H. Cooperative regulation of nerve growth factor synthesis and secretion in fibroblasts and astrocytes by fibroblast growth factor and other cytokines. Brain Res. 569, 14–25 (1992).

    Article  CAS  Google Scholar 

  27. Yoshida, K. et al. Cytokine regulation of nerve growth factor-mediated cholinergic neurotrophic activity synthesized by astrocytes and fibroblasts. J. Neurochem. 59, 919–931 (1992).

    Article  CAS  Google Scholar 

  28. Finger, S. & Dunnett, S.B. Nimodipine enhances growth and vascularization of neural grafts. Exp. Neurol. 104, 1–9 (1989).

    Article  CAS  Google Scholar 

  29. Shimasaki, S. et al. Complementary DNA cloning and sequencing of rat ovarian basic fibroblast growth factor and tissue distribution study of its mRNA. Biochem. Biophys. res. Comm. 157, 256–263 (1988).

    Article  CAS  Google Scholar 

  30. Kawaja, M.D. et al. in Neural Transplantation. A Practical Approach, (eds. Dunnett, S.B. & Bjorklund, A) 21–55 (Oxford University Press, New York, 1992).

    Google Scholar 

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

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Takayama, H., Ray, J., Raymon, 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). https://doi.org/10.1038/nm0195-53

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm0195-53

This article is cited by

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