How to improve the survival of the fetal ventral mesencephalic cell transplanted in Parkinson’s disease?

Liu, Jia; Huang, Hongyun

doi:10.1007/s12264-007-0056-4

Cited by 14 publications

(9 citation statements)

References 55 publications

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“…First of all, findings in a number of experimental models showed that neuronal precursor cell survival within the host tissue after transplantation was too weak (10-20%) and that cell death occurred within the first 3 weeks (Delcroix et al, 2010b;Liu and Huang, 2007;Olanow et al, 2003). In situ differentiation of stem cells was insufficient (at best 3-20%) (Delcroix et al, 2010b;Garbayo et al, 2011a).…”

Section: Cell Therapy Unanswered Questionsmentioning

confidence: 99%

“…Cell therapy for the central nervous system (CNS) consists in cell injection into a lesioned brain tissue to restore a loss of function (Dunnett and Rosser, 2011). However, apart from poor cell engraftment issues that still need to be addressed cell availability and ethical concerns have limited the development and current clinical application of this therapy (Delcroix et al, 2010b;Liu and Huang, 2007). Stem cells that can differentiate into mature neural/neuronal cells can be used as alternative source of cells, as their self-renewal capacity allows the establishment of a cell bank avoiding availability and ethical difficulties.…”

Section: Introductionmentioning

confidence: 99%

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Organotypic cultures as tools for optimizing central nervous system cell therapies

Daviaud

Garbayo

Schiller

et al. 2013

Experimental Neurology

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Stem cell therapy is a promising treatment for neurological disorders such as cerebral ischemia, Parkinson's disease and Huntington's disease. In recent years, many clinical trials with various cell types have been performed often showing mixed results. Major problems with cell therapies are the limited cell availability and engraftment and the reduced integration of grafted cells into the host tissue. Stem cell-based therapies can provide a limitless source of cells but survival and differentiation remain a drawback. An improved understanding of the behaviour of stem cells and their interaction with the host tissue, upon implantation, is needed to maximize the therapeutic potential of stem cells in neurological disorders. Organotypic cultures made from brain slices from specific brain regions that can be kept in culture for several weeks after injecting molecules or cells represent a remarkable tool to address these issues. This model allows the researcher to monitor/assess the behaviour and responses of both the endogenous as well as the implanted cells and their interaction with the microenvironment leading to cell engraftment. Moreover, organotypic cultures could be useful to partially model the pathological state of a disease in the brain and to study graft-host interactions prior to testing such grafts for pre-clinical applications. Finally, they can be used to test the therapeutic potential of stem cells when combined with scaffolds, or other therapeutic enhancers, among other aspects, needed to develop novel successful therapeutic strategies or improve on existing ones.

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Section: Cell Therapy Unanswered Questionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Organotypic cultures as tools for optimizing central nervous system cell therapies

Daviaud

Garbayo

Schiller

et al. 2013

Experimental Neurology

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“…Although these clinical trials clearly indicate room for improvement to enhance graft function as well as reduce unwarranted dyskinetic side effects, they also indicate positive short‐term clinical benefit in a subset of patients similar to open‐label trials and highlight potential problems to tackle, understand, and eventually resolve in future studies (reviews150–154). Specifically, a consensus must come to a standardization for method of dissection, age and number of donor fetuses, length of tissue incubation postisolation, as well as the target site, number of sites to graft, and a variety of other surgical parameters with clinical relevance reviewed elsewhere 45,155.…”

Section: Neuronal Transplantation In Parkinson's Diseasementioning

confidence: 99%

Cell Transplantation and Gene Therapy in Parkinson's Disease

Wakeman

Dodiya

Kordower

2011

Mount Sinai J Medicine

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Parkinson's disease is a progressive neurodegenerative disorder affecting, in part, dopaminergic motor neurons of the ventral midbrain and their terminal projections that course to the striatum. Symptomatic strategies focused on dopamine replacement have proven effective at remediating some motor symptoms during the course of disease but ultimately fail to deliver long-term disease modification and lose effectiveness due to the emergence of side effects. Several strategies have been experimentally tested as alternatives for Parkinson's disease, including direct cell replacement and gene transfer through viral vectors. Cellular transplantation of dopamine-secreting cells was hypothesized as a substitute for pharmacotherapy to directly provide dopamine, whereas gene therapy has primarily focused on restoration of dopamine synthesis or neuroprotection and restoration of spared host dopaminergic circuitry through trophic factors as a means to enhance sustained controlled dopamine transmission. This seems now to have been verified in numerous studies in rodents and nonhuman primates, which have shown that grafts of fetal dopamine neurons or gene transfer through viral vector delivery can lead to improvements in biochemical and behavioral indices of dopamine deficiency. However, in clinical studies, the improvements in parkinsonism have been rather modest and variable and have been plagued by graft-induced dyskinesias. New developments in stem-cell transplantation and induced patient-derived cells have opened the doors for the advancement of cell-based therapeutics. In addition, viral-vector-derived therapies have been developed preclinically with excellent safety and efficacy profiles, showing promise in clinical trials thus far. Further progress and optimization of these therapies will be necessary to ensure safety and efficacy before widespread clinical use is deemed appropriate.

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“…To date, these studies have used cells at all levels of neural differentiation, from neuronal stem cells to post-mitotic Pitx3-expressing neurons [8] , [9] , [10] , [11] , [12] , [13] , [14] , [15] . One problem that continues to plague transplantation therapies is the low survival rate of transplanted neurons [16] , [17] , [18] , [19] . This is not surprising since transplanted neurons will be subject to a wide variety of insults, from hypoxia to mechanical trauma, free radical production, growth factor deprivation and amino acid excitotoxicity.…”

Section: Introductionmentioning

confidence: 99%

In Vitro Maturation of Dopaminergic Neurons Derived from Mouse Embryonic Stem Cells: Implications for Transplantation

Watmuff¹,

Pouton

Haynes

2012

PLoS ONE

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The obvious motor symptoms of Parkinson's disease result from a loss of dopaminergic neurons from the substantia nigra. Embryonic stem cell-derived neural progenitor or precursor cells, adult neurons and fetal midbrain tissue have all been used to replace dying dopaminergic neurons. Transplanted cell survival is compromised by factors relating to the new environment, for example; hypoxia, mechanical trauma and excitatory amino acid toxicity. In this study we investigate, using live-cell fluorescence Ca2+ and Cl− imaging, the functional properties of catecholaminergic neurons as they mature. We also investigate whether GABA has the capacity to act as a neurotoxin early in the development of these neurons. From day 13 to day 21 of differentiation [Cl−]i progressively dropped in tyrosine hydroxylase positive (TH+) neurons from 56.0 (95% confidence interval, 55.1, 56.9) mM to 6.9 (6.8, 7.1) mM. At days 13 and 15 TH+ neurons responded to GABA (30 µM) with reductions in intracellular Cl− ([Cl−]i); from day 21 the majority of neurons responded to GABA (30 µM) with elevations of [Cl−]i. As [Cl−]i reduced, the ability of GABA (30 µM) to elevate intracellular Ca2+ ([Ca2+]i) did also. At day 13 of differentiation a three hour exposure to GABA (30 µM) or L-glutamate (30 µM) increased the number of midbrain dopaminergic (TH+ and Pitx3+) neurons labeled with the membrane-impermeable nuclear dye TOPRO-3. By day 23 cultures were resistant to the effects of both GABA and L-glutamate. We believe that neuronal susceptibility to amino acid excitotoxicity is dependent upon neuronal maturity, and this should be considered when isolating cells for transplantation studies.

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How to improve the survival of the fetal ventral mesencephalic cell transplanted in Parkinson’s disease?

Cited by 14 publications

References 55 publications

Organotypic cultures as tools for optimizing central nervous system cell therapies

Organotypic cultures as tools for optimizing central nervous system cell therapies

Cell Transplantation and Gene Therapy in Parkinson's Disease

In Vitro Maturation of Dopaminergic Neurons Derived from Mouse Embryonic Stem Cells: Implications for Transplantation

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