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Brain Advance Access originally published online on July 22, 2008
Brain 2008 131(8):2127-2139; doi:10.1093/brain/awn144
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Parthenogenetic dopamine neurons from primate embryonic stem cells restore function in experimental Parkinson's disease

Rosario Sanchez-Pernaute1,2, Hyojin Lee3, Michaela Patterson2, Casper Reske-Nielsen2, Takahito Yoshizaki1,2, Kai C. Sonntag1,2, Lorenz Studer3 and Ole Isacson1,2

1McLean Hospital/Harvard University Udall Parkinson's Disease Research Center of Excellence, 2Neuroregeneration Laboratories, McLean Hospital, Belmont, MA 02478, USA and 3Laboratory of Stem Cell & Tumor Biology, Division of Neurosurgery & Developmental Biology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Correspondence to: Rosario Sanchez-Pernaute, Neuronal Stem Cells Laboratory, Fundacion Inbiomed, Paseo Mikeletegi 61, 20009 San Sebastian, Spain E-mail: rosario_pernaute{at}hms.harvard.edu, rpernaute{at}inbiomed.org

The identity and functional potential of dopamine neurons derived in vitro from embryonic stem cells are critical for the development of a stem cell-based replacement therapy for Parkinson's disease. Using a parthenogenetic primate embryonic stem cell line, we have generated dopamine neurons that display persistent expression of midbrain regional and cell-specific transcription factors, which establish their proper identity and allow for their survival. We show here that transplantation of parthenogenetic dopamine neurons restores motor function in hemi-parkinsonian, 6-hydroxy-dopamine-lesioned rats. Exposure to Wnt5a and fibroblast growth factors (FGF) 20 and 2 at the final stage of in vitro differentiation enhanced the survival of dopamine neurons and, correspondingly, the extent of motor recovery of transplanted animals. Importantly for future development of clinical applications, dopamine neurons were post-mitotic at the time of transplantation and there was no tumour formation. These data provide proof for the concept that parthenogenetic stem cells are a suitable source of functional neurons for therapeutic applications.

Key Words: stem cells; transplantation; midbrain; Parkinson's disease; parthenogenesis

Abbreviations: BDNF, brain-derived neurotrophic factor; ES, Embryonic stem; FGF, fibroblast growth factors; GDNF, glial cell-derived neurotrophic factor; HNA, human nuclear antigen; hVAMP, human-specific synaptobrevin; SHH, sonic hedgehog; SN, substantia nigra; TH, tyrosine hydroxylase

Received December 19, 2007. Revised June 9, 2008. Accepted June 12, 2008.


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