| 1. |
- Magnusson, Jens P, et al.
(författare)
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A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse.
- 2014
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 346:6206, s. 237-241
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Tidskriftsartikel (refereegranskat)abstract
- Neurogenesis is restricted in the adult mammalian brain; most neurons are neither exchanged during normal life nor replaced in pathological situations. We report that stroke elicits a latent neurogenic program in striatal astrocytes in mice. Notch1 signaling is reduced in astrocytes after stroke, and attenuated Notch1 signaling is necessary for neurogenesis by striatal astrocytes. Blocking Notch signaling triggers astrocytes in the striatum and the medial cortex to enter a neurogenic program, even in the absence of stroke, resulting in 850 ± 210 (mean ± SEM) new neurons in a mouse striatum. Thus, under Notch signaling regulation, astrocytes in the adult mouse brain parenchyma carry a latent neurogenic program that may potentially be useful for neuronal replacement strategies.
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| 2. |
- Ahlenius, Henrik, et al.
(författare)
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Isolation and generation of neurosphere cultures from embryonic and adult mouse brain.
- 2010
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Ingår i: Methods in Molecular Biology. - Totowa, NJ : Humana Press. - 1940-6029. ; 633, s. 241-252
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Tidskriftsartikel (refereegranskat)abstract
- Neural stem cells are defined as cells that either gives rise to or derives from the cells of the central nervous system and have the unique properties of stem cells, i.e. self-renewal and multipotentiality. One of the widely used methods of expanding neural stem cells under culture conditions is based on the capacity of these cells to divide continuously when cultured in serum-free medium supplemented with various growth factors. One common method used is to grow neural stem cells as free-floating aggregates of cells called neurospheres. Neurospheres can be generated from several structures of the embryonic and adult mammalian brain. Although viable lines can be generated from crude extracts of brain, a precise dissection is crucial to get a pure population of cells. Here we describe methods for dissection, isolation and generation of neurospheres from embryonic ganglionic eminences and adult subventricular zone of mice and rats.
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| 3. |
- Aked, Joseph, et al.
(författare)
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Attitudes to Stem Cell Therapy among Ischemic Stroke Survivors in the Lund Stroke Recovery Study
- 2017
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Ingår i: Stem Cells and Development. - : Mary Ann Liebert Inc. - 1547-3287 .- 1557-8534. ; 26:8, s. 566-572
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Tidskriftsartikel (refereegranskat)abstract
- Preclinical studies suggest that stem cell therapy (SCT) may improve poststroke recovery, and clinical trials investigating safety are ongoing. However, knowledge about patients' attitudes to SCT in stroke is limited. We evaluated the knowledge and attitudes to this therapeutic approach as well as possible factors influencing this among stroke patients potentially suitable for SCT. Consecutive first-ever acute ischemic stroke patients aged 20-75 years with NIH stroke scale scores 1-18 were included. Exclusion criteria were severe comorbidities or infratentorial stroke. Clinical follow-up after 3-5 years assessed severity of residual stroke symptoms, cognitive function, functional status, patient-reported outcome, and comorbidity, and after receiving standardized information, the participants also completed an eight-item questionnaire on knowledge and attitudes about SCT. The relationships between clinical variables and positive attitude to SCT were assessed with logistic regression analyses. Of 108 patients included at baseline, 84 participated at follow-up and completed the questionnaire. In total, 12% had prior knowledge of SCT. When informed, 63% were positive toward it and 36% reported willingness to participate in SCT trials. Only 5%-8% expressed ethical considerations regarding different stem cell sources. Positive attitudes to SCT were associated with male gender (OR: 3.74; 95% CI: 1.45-9.61; P < 0.01) and better patient-reported outcome (OR: 1.02; 95% CI: 1.00-1.04; P < 0.05). In conclusion, stroke patients had limited prior knowledge of SCT, yet attitudes were positive among the majority after receiving standardized and neutral information. Gender and degree of stroke recovery may influence attitudes to SCT, indicating a need for targeted information to improve knowledge about SCT.
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| 4. |
- Andsberg, Gunnar, et al.
(författare)
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Upregulation of p75 neurotrophin receptor after stroke in mice does not contribute to differential vulnerability of striatal neurons
- 2001
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 169:2, s. 351-363
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Tidskriftsartikel (refereegranskat)abstract
- The survival of different neuron types and the expression of the p75 neurotrophin receptor (p75(NTR)) after focal cerebral ischemia were studied in the mouse striatum using immunocytochemical and histochemical techniques and stereological procedures. As assessed at 1 week after 30 min of middle cerebral artery occlusion, the order of vulnerability was projection neurons > parvalbumin-expressing interneurons > nitric oxide synthase-containing interneurons > cholinergic interneurons. Within the ischemic lesion, projection neurons were almost completely lost whereas cholinergic interneurons were spared. Calretinin-immunoreactive interneurons also seemed resistant to the insult. Expression of p75(NTR) was induced in cholinergic interneurons within the lesioned area, raising the possibility of a protective action. However, the number of cholinergic interneurons was unaffected in p75(NTR) knockout mice subjected to the same ischemic insult. These quantitative data demonstrate that striatal neurons in the mouse are differentially susceptible to ischemic damage and argue against a significant role of p75(NTR) for the high resistance of cholinergic interneurons.
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| 5. |
- Bengzon, Johan, et al.
(författare)
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Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures
- 1997
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Ingår i: Proceedings of the National Academy of Sciences. - 1091-6490. ; 94:19, s. 10432-10437
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal apoptosis was observed in the rat dentate gyrus in two experimental models of human limbic epilepsy. Five hours after one hippocampal kindling stimulation, a marked increase of in situ terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling (TUNEL) of fragmented DNA was observed in nuclei located within and on the hilar border of the granule cell layer and in the polymorphic region. Forty kindling stimulations with 5-min interval produced higher numbers of labeled nuclei compared with one stimulation. The increase of TUNEL-positive nuclei was prevented by the protein synthesis inhibitor cycloheximide but not affected by the N-methyl-D-aspartate receptor antagonist MK-801. Kainic acid-induced seizures lead to a pattern of labeling in the hippocampal formation identical to that evoked by kindling. A large proportion of cells displaying TUNEL-positive nuclei was double-labeled by the neuron-specific antigen NeuN, demonstrating the neuronal identity of apoptotic cells. Either 1 or 40 kindling stimulations also gave rise to a marked increase of the number of cells double-labeled with the mitotic marker bromodeoxyuridine and NeuN in the subgranular zone and on the hilar border of the dentate granule cell layer. The present data show that single and intermittent, brief seizures induce both apoptotic death and proliferation of dentate gyrus neurons. We hypothesize that these processes, occurring early during epileptogenesis, are primary events in the development of hippocampal pathology in animals and possibly also in patients suffering from temporal lobe epilepsy.
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| 6. |
- Boltze, Johannes, et al.
(författare)
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New Mechanistic Insights, Novel Treatment Paradigms, and Clinical Progress in Cerebrovascular Diseases
- 2021
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- The past decade has brought tremendous progress in diagnostic and therapeutic options for cerebrovascular diseases as exemplified by the advent of thrombectomy in ischemic stroke, benefitting a steeply increasing number of stroke patients and potentially paving the way for a renaissance of neuroprotectants. Progress in basic science has been equally impressive. Based on a deeper understanding of pathomechanisms underlying cerebrovascular diseases, new therapeutic targets have been identified and novel treatment strategies such as pre- and post-conditioning methods were developed. Moreover, translationally relevant aspects are increasingly recognized in basic science studies, which is believed to increase their predictive value and the relevance of obtained findings for clinical application.This review reports key results from some of the most remarkable and encouraging achievements in neurovascular research that have been reported at the 10th International Symposium on Neuroprotection and Neurorepair. Basic science topics discussed herein focus on aspects such as neuroinflammation, extracellular vesicles, and the role of sex and age on stroke recovery. Translational reports highlighted endovascular techniques and targeted delivery methods, neurorehabilitation, advanced functional testing approaches for experimental studies, pre-and post-conditioning approaches as well as novel imaging and treatment strategies. Beyond ischemic stroke, particular emphasis was given on activities in the fields of traumatic brain injury and cerebral hemorrhage in which promising preclinical and clinical results have been reported. Although the number of neutral outcomes in clinical trials is still remarkably high when targeting cerebrovascular diseases, we begin to evidence stepwise but continuous progress towards novel treatment options. Advances in preclinical and translational research as reported herein are believed to have formed a solid foundation for this progress. © Copyright © 2021 Boltze, Aronowski, Badaut, Buckwalter, Caleo, Chopp, Dave, Didwischus, Dijkhuizen, Doeppner, Dreier, Fouad, Gelderblom, Gertz, Golubczyk, Gregson, Hamel, Hanley, Härtig, Hummel, Ikhsan, Janowski, Jolkkonen, Karuppagounder, Keep, Koerte, Kokaia, Li, Liu, Lizasoain, Ludewig, Metz, Montagne, Obenaus, Palumbo, Pearl, Perez-Pinzon, Planas, Plesnila, Raval, Rueger, Sansing, Sohrabji, Stagg, Stetler, Stowe, Sun, Taguchi, Tanter, Vay, Vemuganti, Vivien, Walczak, Wang, Xiong and Zille.
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| 7. |
- Collin, Tove, et al.
(författare)
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Quantitative analysis of the generation of different striatal neuronal subtypes in the adult brain following excitotoxic injury.
- 2005
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Ingår i: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 195:1, s. 71-80
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Tidskriftsartikel (refereegranskat)abstract
- Recent findings in adult rodents have provided evidence for the formation of new striatal neurons from subventricular zone (SVZ) precursors following stroke. Little is known about which factors determine the magnitude of striatal neurogenesis in the damaged brain. Here we studied striatal neurogenesis following an excitotoxic lesion to the adult rat striatum induced by intrastriatal quinolinic acid (QA) infusion. New cells were labeled with the thymidine-analogue 5-bromo-2'-deoxyuridine (BrdU) and their identity was determined immunocytochemically with various phenotypic markers. The unilateral lesion gave rise to increased cell proliferation mainly in the ipsilateral SVZ. At 2 weeks following the insult, there was a pronounced increase of the number of new neurons co-expressing BrdU and a marker of migrating neuroblasts, doublecortin, in the ipsilateral striatum, particularly its non-damaged medial parts. About 80% of the new neurons survived up to 6 weeks, when they expressed the mature neuronal marker NeuN and were preferentially located in the outer parts of the damaged area. Lesion-generated neurons expressed phenotypic markers of striatal medium spiny neurons (DARPP-32) and intemeurons (parvalbumin or neuropeptide Y). The magnitude of neurogenesis correlated to the size of the striatal damage. Our data show for the first time that an excitotoxic lesion to the striatum can trigger the formation of new striatal neurons with phenotypes of both projection neurons and interneurons.
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| 8. |
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| 9. |
- De La Rosa-Prieto, Carlos, et al.
(författare)
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Stroke alters behavior of human skin-derived neural progenitors after transplantation adjacent to neurogenic area in rat brain
- 2017
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Ingår i: Stem Cell Research and Therapy. - : Springer Science and Business Media LLC. - 1757-6512. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Intracerebral transplantation of human induced pluripotent stem cells (iPSCs) can ameliorate behavioral deficits in animal models of stroke. How the ischemic lesion affects the survival of the transplanted cells, their proliferation, migration, differentiation, and function is only partly understood. Methods: Here we have assessed the influence of the stroke-induced injury on grafts of human skin iPSCs-derived long-term neuroepithelial-like stem cells using transplantation into the rostral migratory stream (RMS), adjacent to the neurogenic subventricular zone, in adult rats as a model system. Results: We show that the occurrence of an ischemic lesion, induced by middle cerebral artery occlusion, in the striatum close to the transplant does not alter the survival, proliferation, or generation of neuroblasts or mature neurons or astrocytes from the grafted progenitors. In contrast, the migration and axonal projection patterns of the transplanted cells are markedly influenced. In the intact brain, the grafted cells send many fibers to the main olfactory bulb through the RMS and a few of them migrate in the same direction, reaching the first one third of this pathway. In the stroke-injured brain, on the other hand, the grafted cells only migrate toward the ischemic lesion and virtually no axonal outgrowth is observed in the RMS. Conclusions: Our findings indicate that signals released from the stroke-injured area regulate the migration of and fiber outgrowth from grafted human skin-derived neural progenitors and overcome the influence on these cellular properties exerted by the neurogenic area/RMS in the intact brain.
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| 10. |
- Delavaran, Hossein, et al.
(författare)
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Proximity of brain infarcts to regions of endogenous neurogenesis and involvement of striatum in ischaemic stroke.
- 2012
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Clinical stroke trials with stem cell-based approaches aiming for trophic actions, modulation of inflammation and neuroprotection are ongoing. However, experimental studies also suggest that neuronal replacement by grafted neural stem cells (NSCs) and possibly by endogenous NSCs from the subventricular zone (SVZ) may restore function in the stroke-damaged striatum. To evaluate the potential clinical impact of these findings, we analyzed the spatial relationship of infarcts to the SVZ and the proportion of individuals with striatal lesions in a consecutive series of ischaemic stroke patients. METHODS: Patients aged 20-75 years with first-ever ischaemic stroke underwent DW-MRI of the brain within 4 days after stroke onset. We analyzed location, size, number of acute focal ischaemic abnormalities and their spatial relationship to the SVZ. Stroke severity was assessed using NIH Stroke Scale (NIHSS). RESULTS: Of 108 included patients, the distance from the nearest margin of the infarct(s) to the SVZ was ≤2 mm in 51/102 patients with visible ischaemic lesions on DW-MRI. Twenty-four patients had involvement of striatum. Eight of these had predominantly striatal lesions, that is >50% of the total ischaemic lesion volume was located in caudate nucleus and/or putamen. These 8 patients had a median NIHSS of 3. CONCLUSIONS: Many stroke patients have infarcts located close to the SVZ, providing some supportive evidence that optimized endogenous neurogenesis may have therapeutic potential. However, predominantly striatal infarcts are rare and tend to give mild neurological deficits, indicating that striatum should not be the primary target for neuronal replacement efforts in humans.
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