Cellular repair in the parkinsonian nonhuman primate brain.
Parkinson disease (PD) is a neurodegenerative disorder that provides a useful model for testing cell replacement strategies to rejuvenate the affected dopaminergic neural systems, which have been destroyed by aging and the disease. We first showed that grafts of fetal dopaminergic neurons can reverse parkinsonian motor deficits induced by the toxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), validating the feasibility of cellular repair in a primate nervous system. Subsequent clinical trials in Parkinson patients showed encouraging results, including long-term improvement of neurological signs and reduction of medications in some patients. However, many experienced little therapeutic benefit, and some recipients experienced dyskinesias, suggesting a lack of regulated control of the grafts. We have since attempted to improve cell replacements by placing grafts in their correct anatomical location in the substantia nigra and using strategies such as co-grafting fetal striatal tissue or growth factors into the physiologic striatal targets. Moreover, the use of fetal cells depends on a variable supply of donor material, making it difficult to standardize cell quality and quantity. Therefore, we have also explored possibilities of using human neural stem cells (hNSCs) to ameliorate parkinsonism in nonhuman primates with encouraging results. hNSCs implanted into the striatum showed a remarkable migratory ability and were found in the substantia nigra, where a small number appeared to differentiate into dopamine neurons. The majority became growth factor-producing glia that could provide beneficial effects on host dopamine neurons. Studies to determine the optimum stage of differentiation from embryonic stem cells and to derive useful cells from somatic cell sources are in progress.
Redmond
Donald Eugene
DE
Department of Psychiatry and Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06511, USA. eugene.redmond@yale.edu
Weiss
Stephanie
S
Elsworth
John D
JD
Roth
Robert H
RH
Wakeman
Dustin R
DR
Bjugstad
Kimberly B
KB
Collier
Timothy J
TJ
Blanchard
Barbara C
BC
Teng
Yang D
YD
Synder
Evan Y
EY
Sladek
John R
JR
D000818:Animals; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D004298:Dopamine / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000637:transplantation; D006801:Humans; D009416:Nerve Regeneration / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000637:transplantation; D020734:Parkinsonian Disorders / Q000473:pathology / Q000503:physiopathology*; D011323:Primates / Q000502:physiology; D033581:Stem Cell Transplantation / Q000662:veterinary
D004298:Dopamine