Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells

Abstract

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 ...

The culture of neural stem cells

“…To date there is little evidence that new neurons derived from NSCs can regenerate circuitry. A more likely role for NSCs in transplantation is to act as support cells providing neurotrophic factors and reversing some of the damage caused by injury and disease [Redmond et al, 2007]. For example, some researchers have bypassed the use of NSCs altogether and used GDNF implants as a means to treat Parkinson's disease [Patel et al, 2005].…”

Communication via gap junctions underlies early functional and beneficial interactions between grafted neural stem cells and the host

“…The number of neural stem cells (NSCs), for example, that differentiate into mature well-integrated neurons, and the lengthy time this process requires, are usually insufficient to account for the improvement. Although it is becoming recognized that grafted NSCs interact with-indeed, sustain, rescue, or protect-endogenous imperiled neurons in vivo (1)(2)(3), the underlying mechanisms are poorly characterized. Although, in some cases, we and others have attributed this action to the release of diffusible cytokines from NSCs (1,2), this mechanism alone is inadequate for explaining all cases (3).…”

Neural stem cells for Parkinson's disease: To protect and repair

“…(iv) Given that these were severestage Parkinsonian primates (Hoehn and Yahr stage 5 equivalent), will the results be more robust in earlier-stage patients if the cells can protect and repair more of the dopamine nigrostriatal system? Redmond et al (2) reported no dyskinesias, tumors, deformations, or overgrowth in the transplanted primates. There also did not appear to be inappropriate stem cell migration.…”

“…In a National Institutes of Health-funded study reported in this issue of PNAS, Redmond et al (2) have now taken the first step toward demonstrating the successful use of fetal stem cells in a primate Parkinson's model.…”

“…6 and 7). Instead, Redmond et al (2) decided to take advantage of two areas of research that have become increasingly important. Some researchers speculate that the microenvironment of the damaged part of the brain will inf luence the phenotype of the cells or that the transplanted cells will inf luence the microenvironment of the diseased or injured brain (8 -10).…”