Parthenogenetic dopamine neurons from primate embryonic stem cells restore function in experimental Parkinson's disease.
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.
Sanchez-Pernaute
Rosario
R
McLean Hospital/Harvard University Udall Parkinson's Disease Research Center of Excellence, McLean Hospital, Belmont, MA 02478, USA.
Lee
Hyojin
H
Patterson
Michaela
M
Reske-Nielsen
Casper
C
Yoshizaki
Takahito
T
Sonntag
Kai C
KC
Studer
Lorenz
L
Isacson
Ole
O
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D004298:Dopamine / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000637:transplantation*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D008636:Mesencephalon; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism / Q000637:transplantation*; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000601:surgery*; D010312:Parthenogenesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D051153:Wnt Proteins / Q000494:pharmacology; D000071818:Wnt-5a Protein
C498813:Fgf20 protein, rat; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D016627:Oxidopamine; D004298:Dopamine