Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells.
Stem cells have been widely assumed to be capable of replacing lost or damaged cells in a number of diseases, including Parkinson's disease (PD), in which neurons of the substantia nigra (SN) die and fail to provide the neurotransmitter, dopamine (DA), to the striatum. We report that undifferentiated human neural stem cells (hNSCs) implanted into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Parkinsonian primates survived, migrated, and had a functional impact as assessed quantitatively by behavioral improvement in this DA-deficit model, in which Parkinsonian signs directly correlate to reduced DA levels. A small number of hNSC progeny differentiated into tyrosine hydroxylase (TH) and/or dopamine transporter (DAT) immunopositive cells, suggesting that the microenvironment within and around the lesioned adult host SN still permits development of a DA phenotype by responsive progenitor cells. A much larger number of hNSC-derived cells that did not express neuronal or DA markers was found arrayed along the persisting nigrostriatal path, juxtaposed with host cells. These hNSCs, which express DA-protective factors, were therefore well positioned to influence host TH+ cells and mediate other homeostatic adjustments, as reflected in a return to baseline endogenous neuronal number-to-size ratios, preservation of extant host nigrostriatal circuitry, and a normalizing effect on alpha-synuclein aggregation. We propose that multiple modes of reciprocal interaction between exogenous hNSCs and the pathological host milieu underlie the functional improvement observed in this model of PD.
Redmond
D Eugene
DE
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA.
Bjugstad
Kimberly B
KB
Teng
Yang D
YD
Ourednik
Vaclav
V
Ourednik
Jitka
J
Wakeman
Dustin R
DR
Parsons
Xuejun H
XH
Gonzalez
Rodolfo
R
Blanchard
Barbara C
BC
Kim
Seung U
SU
Gu
Zezong
Z
Lipton
Stuart A
SA
Markakis
Eleni A
EA
Roth
Robert H
RH
Elsworth
John D
JD
Sladek
John R
JR
Sidman
Richard L
RL
Snyder
Evan Y
EY
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D002465:Cell Movement; D002470:Cell Survival; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008297:Male; D009474:Neurons / Q000166:cytology*; D010300:Parkinson Disease / Q000473:pathology*; D011323:Primates / Q000502:physiology*; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000166:cytology*
D015415:Biomarkers; D004298:Dopamine