Intracranial transplantation of neural stem cells (NSCs) delayed disease onset, preserved motor function, reduced pathology and prolonged survival in a mouse model of Sandhoff disease, a lethal gangliosidosis. Although donor-derived neurons were electrophysiologically active within chimeric regions, the small degree of neuronal replacement alone could not account for the improvement. NSCs also increased brain beta-hexosaminidase levels, reduced ganglioside storage and diminished activated microgliosis. Additionally, when oral glycosphingolipid biosynthesis inhibitors (beta-hexosaminidase substrate inhibitors) were combined with NSC transplantation, substantial synergy resulted. Efficacy extended to human NSCs, both to those isolated directly from the central nervous system (CNS) and to those derived secondarily from embryonic stem cells. Appreciating that NSCs exhibit a broad repertoire of potentially therapeutic actions, of which neuronal replacement is but one, may help in formulating rational multimodal strategies for the treatment of neurodegenerative diseases.

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 ␣-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.1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ͉ dopamine ͉ Parkinson's disease ͉ synuclein ͉ tyrosine hydroxylase D egeneration of dopamine (DA) neurons in the substantia nigra (SN) and the consequent deficit of DA release in the striatum and other target areas appear to be responsible for the characteristic manifestations of Parkinson's disease (PD). Although substantial improvements result from the systemic administration of the DA precursor L-DOPA or DA agonists, such pharmacological replacement does not address the etiology of the disease, provide a permanent redress of the pathophysiology, or forestall progression of the degenerative process. It does, however, support the idea that DA provided by exogenous replacement cells might be therapeutic, a notion verified in rodents (1-3) and monkeys (4 -6), where grafts of fetal DA neurons led to improvements in biochemical and behavioral indices of DA deficiency. However, in graft studies, the improvements in Parkinsonism have been limited and variable (see review in ref. 7). Therefore, we hypothesized that, in addition to DA replenishment, PD treatment should also restore functional equilibrium in the host SN-striatal system. A clinically relevant strategy might be to implant human neural stem cells (hNSCs) and progenitor cells constitutively capable of multiple actions, including neural differentiation and cytokine secretion, and allow them to develop within the PDaffected brains of nonhuman ...