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 via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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).
Choi-Lundberg, D. L. et al. Dopaminergic neurons protected from degeneration by GDNF gene therapy . Science 275, 838– 841 (1997).
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).
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).
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).
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).
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).
McKay, R. D. Stem cells in the central nervous system. Science 276, 66–71 (1997).
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).
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).
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).
Frederiksen, K. & McKay, R. D. Proliferation and differentiation of rat neuroepithelial precursor cells in vivo. J. Neurosci. 8, 1144–1151 ( 1988).
Lendahl, U., Zimmerman, L. B. & McKay, R. D. CNS stem cells express a new class of intermediate filament protein. Cell 60, 585– 595 (1990).
Guyenet, P. G. & Crane, J. K. Non-dopaminergic nigrostriatal pathway. Brain Res. 213, 291– 305 (1981).
Rosenthal, A. Auto transplants for Parkinson's disease? Neuron 20, 169–172 (1998).
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).
Lindvall, O. et al. Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 247, 574– 577 (1990).
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).
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).
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).
Beck, K. D. et al. Mesencephalic dopaminergic neurons protected by GDNF from axotomy- induced degeneration in the adult brain. Nature 373, 339–341 (1995).
Tomac, A. et al. Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. Nature 373, 335– 339 (1995).
Crossley, P. H., Martinez, S. & Martin, G. R. Midbrain development induced by FGF8 in the chick embryo. Nature 380, 66– 68 (1996).
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).
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).
Hynes, M. et al. Induction of midbrain dopaminergic neurons by sonic hedgehog. Neuron 15, 35–44 ( 1995).
Polymeropoulos, M. H. et al. Mutation in the alpha-synuclein gene identified in families with Parkinson's disease. Science 276, 2045–2047 (1997).
Zetterströ m, R. H. et al. Dopamine neuron agenesis in Nurr1-deficient mice. Science 276, 248–250 (1997).
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).
Wang, M. Z. et al. Induction of dopaminergic neuron phenotype in the midbrain by Sonic hedgehog protein. Nat. Med. 1, 1184– 1188 (1995).
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).
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).
Fishell, G. Striatal precursors adopt cortical identities in response to local cues. Development 121, 803–812 ( 1995).
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).
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).
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).
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).
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).
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).
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.
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).
Studer, L. in Current Protocols in Neuroscience (eds Crawley, J. et al. ) 3.3.1–3.3.12 (Wiley, New York, 1997 ).
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).
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).
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).
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
Corresponding author
Rights 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
Issue Date:
DOI: https://doi.org/10.1038/1105
This article is cited by
-
Directional induction of neural stem cells, a new therapy for neurodegenerative diseases and ischemic stroke
Cell Death Discovery (2023)
-
Inhibition of the NLRP3 Inflammasome Activation/Assembly through the Activation of the PI3K Pathway by Naloxone Protects Neural Stem Cells from Ischemic Condition
Molecular Neurobiology (2023)
-
Mitochondria damaged by Oxygen Glucose Deprivation can be Restored through Activation of the PI3K/Akt Pathway and Inhibition of Calcium Influx by Amlodipine Camsylate
Scientific Reports (2019)
-
Atorvastatin Rejuvenates Neural Stem Cells Injured by Oxygen–Glucose Deprivation and Induces Neuronal Differentiation Through Activating the PI3K/Akt and ERK Pathways
Molecular Neurobiology (2019)
-
MPP+ decreases store-operated calcium entry and TRPC1 expression in Mesenchymal Stem Cell derived dopaminergic neurons
Scientific Reports (2018)