Article

Cell Therapy in Parkinson's Disease

Wallenberg Neuroscience Center and Lund Strategic Center for Stem Cell Biology and Cell Therapy, BMC A11, SE-221 84 Lund, Sweden.
NeuroRx 11/2004; 1(4):382-93. DOI: 10.1602/neurorx.1.4.382
Source: PubMed

ABSTRACT

The clinical studies with intrastriatal transplants of fetal mesencephalic tissue in Parkinson's disease (PD) patients have provided proof-of-principle for the cell replacement strategy in this disorder. The grafted dopaminergic neurons can reinnervate the denervated striatum, restore regulated dopamine (DA) release and movement-related frontal cortical activation, and give rise to significant symptomatic relief. In the most successful cases, patients have been able to withdraw L-dopa treatment after transplantation and resume an independent life. However, there are currently several problems linked to the use of fetal tissue: 1) lack of sufficient amounts of tissue for transplantation in a large number of patients, 2) variability of functional outcome with some patients showing major improvement and others modest if any clinical benefit, and 3) occurrence of troublesome dyskinesias in a significant proportion of patients after transplantation. Thus, neural transplantation is still at an experimental stage in PD. For the development of a clinically useful cell therapy, we need to define better criteria for patient selection and how graft placement should be optimized in each patient. We also need to explore in more detail the importance for functional outcome of the dissection and cellular composition of the graft tissue as well as of immunological mechanisms. Strategies to prevent the development of dyskinesias after grafting have to be developed. Finally, we need to generate large numbers of viable DA neurons in preparations that are standardized and quality controlled. The stem cell technology may provide a virtually unlimited source of DA neurons, but several scientific issues need to be addressed before stem cell-based therapies can be tested in PD patients.

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    • "Even if placed in their site of origin, i.e., the substantia nigra, new dopaminergic neurons do not regenerate axons to the striatum. There have been hundreds of PD patients worldwide who have undergone striatal injections of human fetal mesencephalic stem cells containing post-mitotic dopaminergic neurons with varying results and complications (Lindvall and Bjorklund, 2004). Five open label clinical trials conducted between 1999 and 2003 all showed a clinical benefit characterized by symptomatic relief lasting up to 24 months and a reduction in L-dopa requirement (Hagell et al., 1999; Hauser et al., 1999; Brundin et al., 2000; Freed et al., 2001; Olanow et al., 2003). "
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    ABSTRACT: The promise of stem cell regeneration has been the hope of many neurologic patients with permanent damage to the central nervous system. There are hundreds of stem cell trials worldwide intending to test the regenerative capacity of stem cells in various neurological conditions from Parkinson's disease to multiple sclerosis. Although no stem cell therapy is clinically approved for use in any human disease indication, patients are seeking out trials and asking clinicians for guidance. This review summarizes the current state of regenerative stem cell transplantation divided into seven conditions for which trials are currently active: demyelinating diseases/spinal cord injury, amyotrophic lateral sclerosis, stroke, Parkinson's disease, Huntington's disease, macular degeneration and peripheral nerve diseases. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Jul 2015 · Brain research
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    • "Transplantation of midbrain human fetal tissue provided a solid basis for a cellular approach to PD, confirming the ability of transplanted neurons to integrate into the host striatal tissues and sustain functional integration and a therapeutic effect (Barker et al., 2013). However, this approach had little clinical benefit, mainly because of the broad cell heterogeneity of the transplanted tissue, its minimal availability, and scarce immuno-compatibility (Lindvall and Björklund, 2004; Barker et al., 2013). Even worse, these issues were responsible for the development of the troubling side effect of graft-induced dyskinesia, which is experienced by some of the patients (Lane et al., 2010). "
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    ABSTRACT: New advances in directing the neuronal differentiation of human embryonic and induced pluripotent stem cells (hPSCs, abbreviation intended to convey both categories of pluripotent stem cells) have promoted the development of culture systems capable of modeling early neurogenesis and neural specification at some of their critical milestones. The hPSC-derived neural rosette can be considered the in vitro counterpart of the developing neural tube, since both structures share a virtually equivalent architecture and related functional properties. Epigenetic stimulation methods can modulate the identity of the rosette neural progenitors in order to generate authentic neuronal subtypes, as well as a full spectrum of neural crest derivatives. The intrinsic capacity of induced pluripotent cell-derived neural tissue to self-organize has become fully apparent with the emergence of innovative in vitro systems that are able to shape the neuronal differentiation of hPSCs into organized tissues that develop in three dimensions. However, significant hurdles remain that must be completely solved in order to facilitate the use of hPSCs in modeling (e.g., late-onset disorders) or in building therapeutic strategies for cell replacement. In this direction, new procedures have been established to promote the maturation and functionality of hPSC-derived neurons. Meanwhile, new methods to accelerate the aging of in vitro differentiating cells are still in development. hPSC-based technology has matured enough to offer a significant and reliable model system for early and late neurogenesis that could be extremely informative for the study of the physiological and pathological events that occur during this process. Thus, full exploitation of this cellular system can provide a better understanding of the physiological events that shape human brain structures, as well as a solid platform to investigate the pathological mechanisms at the root of human diseases.
    Full-text · Article · Jul 2014 · Frontiers in Neuroscience
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    • "A number of explorative studies using human fetal, ventral mesencephalic (VM) dopaminergic neurons have shown that intrastriatal transplantation may become an effective future treatment for patients with PD [2]–[5]. However, the use of human fetal tissue is compromised by ethical concerns, suboptimal survival and integration of grafted DA neurons, development of graft-induced dyskinesias in some patients as well as practical problems and logistics related to the procurement and storage of human donor tissue [6]–[10]. "
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    ABSTRACT: Neural stem cells (NSCs) constitute a promising source of cells for transplantation in Parkinson's disease (PD), but protocols for controlled dopaminergic differentiation are not yet available. Here we investigated the influence of oxygen on dopaminergic differentiation of human fetal NSCs derived from the midbrain and forebrain. Cells were differentiated for 10 days in vitro at low, physiological (3%) versus high, atmospheric (20%) oxygen tension. Low oxygen resulted in upregulation of vascular endothelial growth factor and increased the proportion of tyrosine hydroxylase-immunoreactive (TH-ir) cells in both types of cultures (midbrain: 9.1±0.5 and 17.1±0.4 (P<0.001); forebrain: 1.9±0.4 and 3.9±0.6 (P<0.01) percent of total cells). Regardless of oxygen levels, the content of TH-ir cells with mature neuronal morphologies was higher for midbrain as compared to forebrain cultures. Proliferative Ki67-ir cells were found in both types of cultures, but the relative proportion of these cells was significantly higher for forebrain NSCs cultured at low, as compared to high, oxygen tension. No such difference was detected for midbrain-derived cells. Western blot analysis revealed that low oxygen enhanced β-tubulin III and GFAP expression in both cultures. Up-regulation of β-tubulin III was most pronounced for midbrain cells, whereas GFAP expression was higher in forebrain as compared to midbrain cells. NSCs from both brain regions displayed less cell death when cultured at low oxygen tension. Following mictrotransplantation into mouse striatal slice cultures predifferentiated midbrain NSCs were found to proliferate and differentiate into substantial numbers of TH-ir neurons with mature neuronal morphologies, particularly at low oxygen. In contrast, predifferentiated forebrain NSCs microtransplanted using identical conditions displayed little proliferation and contained few TH-ir cells, all of which had an immature appearance. Our data may reflect differences in dopaminergic differentiation capacity and region-specific requirements of NSCs, with the dopamine-depleted striatum cultured at low oxygen offering an attractive micro-environment for midbrain NSCs.
    Full-text · Article · May 2014 · PLoS ONE
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