Implantation of c-mycER TAM immortalized human mesencephalic-derived clonal cell lines ameliorates behavior dysfunction in a rat model of Parkinson's disease.
Human neural stem cells offer the hope that a cell therapy treatment for Parkinson's disease (PD) could be made widely available. In this study, we describe two clonal human neural cell lines, derived from two different 10-week-old fetal mesencephalic tissues and immortalized with the c-mycER(TAM) transgene. Under the growth control of 4-hydroxytamoxifen, both cell lines display stable long-term growth in culture with a normal karyotype. In vitro, these nestin-positive cells are able to differentiate into tyrosine hydroxylase (TH)-positive neurons and are multipotential. Implantation of the undifferentiated cells into the 6-OHDA substantia nigral lesioned rat model displayed sustained improvements in a number of behavioral tests compared with noncell-implanted, vehicle-injected controls over the course of 6 months. Histological analysis of the brains showed survival of the implanted cells but no evidence of differentiation into TH-positive neurons. An average increase of approximately 26% in host TH immunoreactivity in the lesioned dorsal striatum was observed in the cell-treated groups compared to controls, with no difference in loss of TH cell bodies in the lesioned substantia nigra. Further analysis of the cell lines identified a number of expressed trophic factors, providing a plausible explanation for the effects observed in vivo. The exact mechanisms by which the implanted human neural cell lines provide behavioral improvements in the PD model are not completely understood; however, these findings provide evidence that cell therapy can be a potent treatment for PD acting through a mechanism independent of dopaminergic neuronal cell replacement.
Miljan
Erik A
EA
ReNeuron Ltd., Surrey Research Park, Guildford, Surrey, United Kingdom.
Hines
Susan J
SJ
Pande
Priyadarshini
P
Corteling
Randolph L
RL
Hicks
Caroline
C
Zbarsky
Virginia
V
Umachandran
Meera
M
Sowinski
Peter
P
Richardson
Sheila
S
Tang
Ellen
E
Wieruszew
Malgorzata
M
Patel
Sara
S
Stroemer
Paul
P
Sinden
John D
JD
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D001921:Brain / Q000201:enzymology / Q000473:pathology; D002454:Cell Differentiation; D002461:Cell Line, Transformed; D002470:Cell Survival; D002999:Clone Cells; D004195:Disease Models, Animal; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008636:Mesencephalon / Q000637:transplantation*; D009474:Neurons / Q000166:cytology; D010300:Parkinson Disease / Q000503:physiopathology* / Q000628:therapy*; D019919:Prosthesis Implantation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D045442:Rotarod Performance Test; D013629:Tamoxifen / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D016271:Proto-Oncogene Proteins c-myc; D013629:Tamoxifen; D014446:Tyrosine 3-Monooxygenase