| 61. |
- Correia, Sofia, et al.
(författare)
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Fibroblast growth factor-20 increases the yield of midbrain dopaminergic neurons derived from human embryonic stem cells.
- 2007
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Ingår i: Frontiers in Neuroanatomy. - : Frontiers Media SA. - 1662-5129. ; 1:Dec 30
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Tidskriftsartikel (refereegranskat)abstract
- In the central nervous system, fibroblast growth factor (FGF)-20 has been reported to act preferentially on midbrain dopaminergic neurons. It also promotes the dopaminergic differentiation of stem cells. We have analyzed the effects of FGF-20 on human embryonic stem cells (hESCs) differentiation into dopaminergic neurons. We induced neuronal differentiation of hESCs by co-culturing those with PA6 mouse stromal cells for 3 weeks. When we supplemented the culture medium with FGF-20, the number of tyrosine hydroxylase (TH)-expressing neurons increased fivefold, from 3% to 15% of the hESC-derived cells. The cultured cells also expressed other midbrain dopaminergic markers (PITX3, En1, Msx1, and Aldh1), suggesting that some had differentiated into midbrain dopaminergic neurons. We observed no effect of FGF-20 on the size of the soma area or neurite length of the TH-immunopositive neurons. Regardless of whether FGF-20 had been added or not, 17% of the hESC-derived cells expressed the pan-neuronal marker b-III-Tubulin. The proportion of proliferating cells positive for Ki-67 was also not affected by FGF-20 (7% of the hESC-derived cells). By contrast, after 3 weeks in culture FGF-20 significantly reduced the proportion of cells undergoing cell death, as revealed by immunoreactivity for cleaved caspase-8, Bcl-2 associated X protein (BAX) and cleaved caspase-3 (2.5% to 1.2% of cleaved caspase-3-positive cells out of the hESC-derived cells). Taken together, our results indicate that FGF-20 specifically increases the yield of dopaminergic neurons from hESCs grown on PA6 feeder cells and at least part of this effect is due to a reduction in cell death.
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| 62. |
- Correia, Sofia, et al.
(författare)
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Growth factors and feeder cells promote differentiation of human embryonic stem cells into dopaminergic neurons: a novel role for fibroblast growth factor-20.
- 2008
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 2:1, s. 26-34
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Tidskriftsartikel (refereegranskat)abstract
- Human embryonic stem cells (hESCs) are a potential source of dopaminergic neurons for treatment of patients with Parkinson's disease (PD). Dopaminergic neurons can be derived from hESCs and display a characteristic midbrain phenotype. Once transplanted, they can induce partial behavioral recovery in animal models of PD. However, the potential research field faces several challenges that need to be overcome before clinical application of hESCs in a transplantation therapy in PD can be considered. These include low survival of the hESC-derived, grafted dopaminergic neurons after transplantation; unclear functional integration of the grafted neurons in the host brain; and, the risk of teratoma/tumor formation from the transplanted cells. This review is focused on our recent efforts to improve the survival of hESC-dervied dopaminergic neurons. In a recent study, we examined the effect of fibroblast growth factor (FGF)-20 in the differentiation of hESCs into dopaminergic neurons. We supplemented cultures of hESCs with FGF-20 during differentiation on PA6 mouse stromal cells for 3 weeks. When we added FGF-20 the yield of neurons expressing tyrosine hydroxylase increased. We demonstrated that at least part of the effect is contributed by enhanced cell differentiation towards the dopaminergic phenotype as well as reduced cell death. We compare our results with those obtained in other published protocols using different sets of growth factors. Taken together, our data indicate that FGF-20 has potent effects to generate large number of dopaminergic neurons derived from hESCs, which may be useful for hESC-based therapy in PD.
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| 63. |
- Correia, Sofia, et al.
(författare)
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Stem cell-based therapy for Parkinson's disease.
- 2005
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Ingår i: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 37:7, s. 487-498
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Forskningsöversikt (refereegranskat)abstract
- Motor dysfunctions in Parkinson's disease are considered to be primarily due to the degeneration of dopaminergic neurons in the substantia nigra pars compacta. Pharmacological therapies based on the principle of dopamine replacement are extremely valuable, but suffer from two main drawbacks: troubling side effects (e.g. dyskinesia) and loss of efficacy with disease progression. Transplantation of embryonic dopaminergic neurons has emerged as a therapeutic alternative. Enthusiasm following the success of the initial open-label trials has been dampened by the negative outcome of double-blind placebo controlled trials. Additionally, the emergence of graft-related dyskinesia indicates that the experimental grafting procedure requires further refinement before it can be developed into a therapy. Shortage of embryonic donor tissue limits large-scale clinical transplantation trials. We review three of the most attractive tissue sources of dopaminergic neurons for cell replacement therapy: human embryonic ventral mesencephalic tissue, embryonic and adult multipotent region-specific stem cells and embryonic stem cells. Recent developments in embryonic stem cell research and on their implications for a future transplantation therapy in Parkinson's disease are described. Finally, we discuss how human embryonic stem cells can be differentiated into dopaminergic neurons, and issues such as the numbers of dopaminergic neurons required for success and the risk for teratoma formation after implantation.
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| 64. |
- Deierborg, Tomas, et al.
(författare)
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Absence of striatal newborn neurons with mature phenotype following defined striatal and cortical excitotoxic brain injuries.
- 2009
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 219, s. 363-367
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Tidskriftsartikel (refereegranskat)abstract
- Experimental stroke and excitotoxic brain lesion to the striatum or cortex increase the proliferation of cells residing within the ventricular wall and cause subsequent migration of newborn neuroblasts into the lesioned brain parenchyma. In this study, we clarify the different events of neurogenesis following striatal or cortical excitotoxic brain lesions in adult rats. Newborn cells were labeled by intraperitoneal injection of bromo-deoxy-uridine (BrdU), or by green fluorescent protein (GFP)-expressing lentiviral vectors injected into the subventricular zone (SVZ). We show that only neural progenitors born the first 5 days in the SVZ reside and expand within this neurogenic niche over time, and that these early labeled cells are more prone to migrate towards the striatum as neuroblasts. However, these neuroblasts could not mature into NeuN(+) neurons in the striatum. Furthermore, we found that cortical lesions, close or distant from the SVZ, could not upregulate SVZ cell proliferation nor promote neurogenesis. Our study demonstrates that both the time window for labeling proliferating cells and the site of lesion are crucial when assessing neurogenesis following brain injury.
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| 65. |
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| 66. |
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| 67. |
- Deierborg, Tomas, et al.
(författare)
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Brain injury activates microglia that induce neural stem cell proliferation ex vivo and promote differentiation of neurosphere-derived cells into neurons and oligodendrocytes
- 2010
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 171:4, s. 1386-1396
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Tidskriftsartikel (refereegranskat)abstract
- Brain damage, such as ischemic stroke, enhances proliferation of neural stem/progenitor cells (NSPCs) in the subventricular zone (SVZ) To date, no reliable in vitro systems, which can be used to unravel the potential mechanisms underlying this lesion induced effect, have been established Here we developed an ex vivo method to investigate how the proliferation of NSPCs changes over time after experimental stroke or excitotoxic striatal lesion in the adult rat brain by studying the effects of microglial cells derived from an in jured brain on NSPCs We isolated NSPCs from the SVZ of brains with lesions and analyzed their growth and differentiation when cultured as neurospheres We found that NSPCs isolated from the brains 1-2 weeks following injury consistently generated more and larger neurospheres than those harvested from naive brains We attributed these effects to the presence of microglial cells in NSPC cultures that originated from injured brains We suggest that the effects are due to released factors because we observed increased proliferation of NSPCs isolated from non-injured brains when they were exposed to conditioned medium from cultures containing microglial cells derived from injured brains Furthermore, we found that NSPCs derived from injured brains were more likely to differentiate into neurons and oligodendrocytes than astrocytes Our ex vivo system reliably mimics what is ob served in vivo following brain injury It constitutes a powerful tool that could be used to identify factors that promote NSPC proliferation and differentiation in response to injury induced activation of microglial cells, by using tools such as proteomics and gene array technology (C) 2010 IBRO Published by Elsevier Ltd All rights reserved
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| 68. |
- Deierborg, Tomas, et al.
(författare)
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Emerging restorative treatments for Parkinson's disease.
- 2008
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Ingår i: Progress in Neurobiology. - : Elsevier BV. - 1873-5118 .- 0301-0082. ; 85, s. 407-432
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Tidskriftsartikel (refereegranskat)abstract
- Several exciting approaches for restorative therapy in Parkinson's disease have emerged over the past two decades. This review initially describes experimental and clinical data regarding growth factor administration. We focus on glial cell line-derived neurotrophic factor (GDNF), particularly its role in neuroprotection and in regeneration in Parkinson's disease. Thereafter, we discuss the challenges currently facing cell transplantation in Parkinson's disease and briefly consider the possibility to continue testing intrastriatal transplantation of fetal dopaminergic progenitors clinically. We also give a more detailed overview of the developmental biology of dopaminergic neurons and the potential of certain stem cells, i.e. neural and embryonic stem cells, to differentiate into dopaminergic neurons. Finally, we discuss adult neurogenesis as a potential tool for restoring lost dopamine neurons in patients suffering from Parkinson's disease.
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| 69. |
- Depboylu, Candan, et al.
(författare)
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Neuregulin-1 receptor tyrosine kinase ErbB4 is upregulated in midbrain dopaminergic neurons in Parkinson disease
- 2012
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940. ; 531:2, s. 209-214
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Tidskriftsartikel (refereegranskat)abstract
- Previously we demonstrated that systemically administered neuregulin-1-beta 1, a nerve growth and differentiation factor, passed the blood-brain barrier and accumulated in brain areas with expression of its receptor ErbB4. In substantia nigra (SN), neuregulin-1-beta 1 phosphorylated ErbB4 and protected dopaminergic neurons in a toxin-based mouse model of Parkinson disease (PD). We studied ErbB4 in the context of human midbrain dopaminergic degeneration in vivo and in vitro. Post-mortem ventral midbrain tissue sections of neuropsychiatric healthy individuals and PD patients (matched for age, gender and post-mortem delay) were immunostained for ErbB4. Cultured Lund human mesencephalic (LUHMES) post-mitotic dopaminergic neurons were treated with dopaminergic toxins and analyzed for ErbB4 expression. In control individuals, 85.0 +/- 5.0% of dopaminergic neurons, containing cytoplasmic neuromelanin, expressed ErbB4 in the SN. In PD cases, the percentage of ErbB4-positive nigral dopaminergic neurons was increased to 94.9 +/- 2.5%. The mean ErbB4 immunoreactivity of melanized neurons was higher in PD than controls. LUHMES neurons upregulated ErbB4 when exposed to toxins 1-methyl-4-phenylpyridinium and 6-hydroxydopamine. Increased rate of ErbB4-positive dopaminergic neurons in PD may either reflect a better survival of ErbB4-positive neurons or an increased expression of ErbB4 by remaining neurons to seek trophic support. Enhanced ErbB4 expression in human in vitro toxin-based PD models supports the latter interpretation. Thus, dopaminergic neurons in SN might be susceptible to neuregulin-1 treatment in PD. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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| 70. |
- Duarte, Ane, et al.
(författare)
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IGF-1 protects against diabetic features in an in vivo model of Huntington's disease.
- 2011
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 231, s. 314-319
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Tidskriftsartikel (refereegranskat)abstract
- Huntington's disease (HD) is the most prevalent polyglutamine expansion disorder. HD is caused by an expansion of CAG triplet in the huntingtin (HTT) gene, associated with striatal and cortical neuronal loss. Central and peripheral metabolic abnormalities and altered insulin-like growth factor-1 (IGF-1) levels have been described in HD. Thus, we hypothesized that restoration of IGF-1-mediated signaling pathways could rescue R6/2 mice from metabolic stress and behavioral changes induced by polyglutamine expansion. We analyzed the in vivo effect of continuous peripheral IGF-1 administration on diabetic parameters, body weight and motor behavior in the hemizygous R6/2 mouse model of HD. We used 9week-old and age-matched wild-type mice, subjected to continuously infused recombinant IGF-I or vehicle, for 14days. IGF-1 treatment prevented the age-related decrease in body weight in R6/2 mice. Although blood glucose levels were higher in R6/2 mice, they did not reach a diabetic state. Even though, IGF-1 ameliorated poor glycemic control in HD mice. This seemed to be associated with a decrease in blood insulin levels in R6/2 mice, which was increased following IGF-1 infusion. Similarly, blood IGF-1 levels decreased during aging in both wild-type and R6/2 mice, being significantly improved upon its continuous infusion. Although no significant differences were found in motor function in R6/2-treated mice, IGF-1 treatment highly improved paw clasping scores. In summary, these results suggest that IGF-1 has a protective role against HD-associated impaired glucose tolerance, by enhancing blood insulin levels.
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