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Articles de revues sur le sujet "Reprogramming, stroke, reactive astrocytes, motor cortex"
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Williamson, Michael R., Cathleen Joy A. Fuertes, Michael R. Drew et Theresa A. Jones. « Abstract P734 : Reactive Astrocytes Facilitate Vascular Repair and Remodeling After Stroke ». Stroke 52, Suppl_1 (mars 2021). http://dx.doi.org/10.1161/str.52.suppl_1.p734.
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Astrocytes and blood vessels interact closely in the neurovascular unit. After stroke, reactive astrocytes surrounding the infarct undergo structural and functional changes. Simultaneously, considerable plasticity of vascular structure occurs, including formation and elimination of microvascular segments, and is associated with restoration of blood flow and behavioral recovery. Reactive astrocytes have established protective functions soon after injury, but less is known about how they influence later reparative processes, which include vascular remodeling. Here we investigated whether reactive astrocytes support vascular remodeling in a mouse model of stroke. Analysis of gene expression data from reactive astrocytes during the first week after stroke showed substantial upregulation of genes and pathways implicated in regulating vascular and basement membrane remodeling. With repeated in vivo 2-photon imaging, we found that astrocytes contacted new vascular segments formed in peri-infarct cortex after photothrombotic infarcts, suggesting close interactions between reactive astrocytes and new blood vessels. Next, we used GFAP-thymidine kinase (TK) transgenic mice to chemogenetically ablate proliferating peri-infarct astrocytes after stroke (N=8 GFAP-TK; N=8 wildtype mice). Astrocyte ablation following photothrombotic stroke in motor cortex caused dysfunctional vascular repair and remodeling characterized by reduced vascular density, diminished endothelial cell proliferation, prolonged blood flow deficits, and sparse coverage of vessels by glycocalyx, basement membrane, and pericytes. Moreover, peri-infarct vascular permeability was exacerbated in GFAP-TK mice, and this increased permeability was correlated with heightened cell death in the subacute phase after stroke. Tests of forelimb use asymmetry and locomotor coordination both showed worsened recovery in GFAP-TK mice. In contrast to the effects of peri-infarct astrocyte ablation, vascular structure was unaffected by adeno-associated virus-mediated ablation of astrocytes in the otherwise intact brain. Our findings implicate reactive astrocytes as crucial cellular mediators of functionally important vascular repair and remodeling after stroke.
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Chen, Meifan, Laura Ingle, Erik J. Plautz, Xiangmei Kong, Rui Tang, Neil Ghosh, Megan K. Romprey, William K. Fenske et Mark P. Goldberg. « LZK-dependent stimulation of astrocyte reactivity promotes corticospinal axon sprouting ». Frontiers in Cellular Neuroscience 16 (15 septembre 2022). http://dx.doi.org/10.3389/fncel.2022.969261.
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Injury to the adult mammalian central nervous system induces compensatory plasticity of spared axons—referred to as collateral axon sprouting—that can facilitate neural recovery. The contribution of reactive astrocytes to axon sprouting remains elusive. Here, we sought to investigate the role of axon degeneration-reactive astrocytes in the regulation of collateral axon sprouting that occurs in the mouse spinal cord after unilateral photothrombotic stroke of the primary motor cortex. We identified astrocytic leucine zipper-bearing kinase (LZK) as a positive regulator of astrocyte reactivity to corticospinal axon degeneration. Remarkably, genetic stimulation of astrocyte reactivity, via LZK overexpression in adult astrocytes, enhanced corticospinal axon sprouting. LZK promoted the production of astrocyte-derived ciliary neurotrophic factor (CNTF) that likely enhanced axon growth in mice with astrocytic LZK overexpression after injury. Our finding that LZK-dependent stimulation of astrocyte reactivity promotes corticospinal axon sprouting highlights the potential of engineering astrocytes to support injury-induced axon plasticity for neural repair.
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Orczykowski, Mary E., Eli Shobin, Samantha M. Calderazzo, Brian C. Kramer, Farzad Mortazavi, Douglas L. Rosene et Tara L. Moore. « Abstract WP112 : Residual Damage is Reduced Following Human Umbilical Tissue Derived Cell Infusion in a Non-human Primate Model of Cortical Injury ». Stroke 48, suppl_1 (février 2017). http://dx.doi.org/10.1161/str.48.suppl_1.wp112.
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Introduction: Stroke is the leading cause of long-term disability in the United States due to impairments that endure after brain injury. While studies in rodent models have evaluated numerous neurorestorative treatments following stroke, none have received FDA approval. We evaluated a therapy using human umbilical tissue-derived cells (hUTC) as a potential neurorestorative treatment in our non-human primate model of cortical injury limited to the hand area of primary motor cortex. Given treatment 24 hours after injury, hUTC treated monkeys showed a significantly greater degree of recovery of fine motor function compared to vehicle treated controls (Moore et al., 2013). To explore the effect of hUTC, histopathological markers of inflammation and oxidative stress were assessed. Hypothesis: Treatment with hUTC will enhance the recruitment of glia to the injury and reduce the cascade of inflammation and oxidative stress. Methods: Using immunohistochemistry, activated microglia (LN3), reactive astrocytes (GFAP), oxidative damage (4HNE), and accumulated hemosiderin (Perls’ Prussian Blue) were quantified in ipsilesional primary motor cortex and underlying white matter. Microglia were counted using unbiased stereology. A Sholl Analysis was performed on traced perilesional astrocytes. The area of oxidative damage and hemosiderin was assessed using densitometry. Results: Compared to vehicle controls, density of activated microglia in the hUTC treated group approached a significant increase in the perilesional gray and white matter (p=0.070; p=0.092). Astrocytes exhibited more complex processes in treated monkeys (p=0.042). Staining for 4HNE was significantly reduced in white matter underlying the lesion in treated monkeys (p=0.033). Lastly, both the area and intensity of Perls’ staining for hemosiderin was significantly reduced in the perilesional area of treated monkeys (p=0.045; p=0.001). Conclusions: Treatment with hUTC resulted in increased activation of microglia and complexity of reactive astrocyte processes as well as reduced post-lesion oxidative damage and hemosiderin deposition. This suggests the hUTC treatment enhanced recovery, in part, by recruitment of glial cells that limited the damage following cortical injury.
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Srinageshwar, Bhairavi, Melissa Andrews, Clayton Malkowski, Alexa Toth, Justin Stadler, Bethany MacDonald, Raegan Schalau et al. « Abstract TP254 : Reduction Of Behavior Deficits Following Delivery Of Sox2 To Stroke Rats Using Mixed-Surface PAMAM Dendrimer Nanomolecules ». Stroke 53, Suppl_1 (février 2022). http://dx.doi.org/10.1161/str.53.suppl_1.tp254.
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A major drawback of current stroke treatment strategies (such as the use of tPA) includes time sensitivity to achieve maximum therapeutic efficacy. Alternative treatments include less time-sensitive approaches and utilize in vivo reprogramming of resident reactive astrocytes to repopulate the lost neurons in sufficient numbers. In this study, we tested whether a transcription factor, hSOX2, when expressed under a glial cell-specific GFAP promoter, could sufficiently reprogram astrocytes in and around the infarct to enhance their differentiation into neurons. To achieve delivery of the hSOX2 gene, we utilize PAMAM dendrimers, which are nanomolecules with a well-established capacity of delivering drugs/ large biomolecules to the brain across the BBB and confer intrinsic anti-inflammatory properties. Dendrimers are comprised of an interior dendritic structure with modifiable sizes, and an exterior surface with functional surface groups. The G4 PAMAM dendrimers used in this study has 10% of the surface covered with amine groups and 90% of the surface covered with hydroxyl groups (G4-90/10). These dendrimers are less toxic and readily form complexes with plasmids up to 14 kb in size (dendriplex) and successfully deliver cargo in vitro and in vivo . Four days following stroke inductions in Sprague Dawley rats via MCAo, the hSOX2 dendriplex was injected into the ipsilateral corpus callosum. A battery of behavior tests, such as cylinder and ladder tasks, were used to assess motor abilities of the treated and untreated stroked and sham-operated control rats. Moreover, the animals underwent In vivo Imaging System to confirm the presence of dendriplex in the brain. Five weeks following the injections, the brains were collected and processed, using immunohistochemistry, to detect the complex and measure the amount of hSOX2 gene expression. The size of the brain infarct was measured using the conventional H&E staining. Our results indicated that the dendrimers were able to deliver the hSOX2 gene to the stroke brain and this significantly reduced motor deficits, relative to untreated stroked rats. These results indicated that PAMAM dendrimers effectively deliver genes into the brain and that the hSOX2 gene can successfully reduce motor deficits following stroke.
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Qian, Jian Y., Michael Chopp, Yi Li, Yisheng Cui, Cynthia Roberts et Zhongwu Liu. « Abstract W P92 : Attenuated GFAP/Vimentin Retards Motor Behavioral Recovery and Axonal Remodeling and Up-regulates Axonal Growth-Inhibiting Molecules in Mice After Stroke ». Stroke 46, suppl_1 (février 2015). http://dx.doi.org/10.1161/str.46.suppl_1.wp92.
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To investigate whether reactive astrocytes contribute to neurological recovery, we compared behavioral outcome, axonal remodeling of the corticospinal tract (CST) and the levels of axonal growth-inhibiting/promoting molecules in the central nervous systems (CNS) between wild-type (WT) and glial fibrillary acidic protein/vimentin double knockout (GFAP-/-Vim-/-) mice subjected to Rose Bengal induced cerebral cortical photothrombotic stroke in the right forelimb motor area. Both foot-fault test and single pellet reaching test were performed prior to stroke and at 3 days after stroke and weekly thereafter, to monitor functional deficit and recovery. Biotinylated dextran amine (BDA) was injected into the left motor cortex to label the CST axons anterogradely. Compared with WT mice, the motor functional recovery and BDA-positive CST axonal length in the denervated side of the cervical gray matter were significantly reduced in GFAP-/-Vim-/-mice (n=10/group, P<0.01). Western blot data (prior to and on 3, 7 or 14 days after stroke, n=6/group) showed that in GFAP-/-Vim-/- mice, axonal growth-inhibiting molecules, Nogo R and neurocan, were up-regulated time-dependently in the CNS compared with WT mice (P<0.01). However, no increase was detected in the expressions of Nogo A and Oligodendrocyte myelin glycoprotein (P>0.05). There was no difference in the levels of axonal growth-promoting molecules (Myelin-Associated Glycoprotein and phosphor-ERK) between GFAP-/-Vim-/-mice and WT littermates (p>0.05). Our results suggest that attenuated astrocytic reactivity impairs or delays neurological recovery by reducing CST axonal remodeling in the denervated spinal cord and increasing some axonal growth-inhibiting molecules in CNS. Manipulation of astrocytic reactivity post stroke may represent a therapeutic target for neurorestorative strategies.
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Demel, Stacie L., Kyle B. Walsh, Daniel Woo et Agnes Luo. « Abstract TP230 : A Novel Mouse Model Of IVH Reveals Local, But Not Global Inflammation, And No Cognitive Impairment Over Multiple Time Points ». Stroke 54, Suppl_1 (février 2023). http://dx.doi.org/10.1161/str.54.suppl_1.tp230.
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Background: Intracerebral hemorrhage is the most severe stroke subtype, and extension of blood into the ventricles (IVH) is associated with increased morbidity and mortality. The mechanisms that contribute to poor clinical outcomes are unclear. We set out to establish a novel IVH mouse model for the purpose of measuring motor and cognitive function in acute and chronic stages. Methods: Mice underwent either an autologous blood (40ul; IVH) or normal saline (40 ul; SHAM) injection into a lateral ventricle. Motor function was tested in an open field automated locomotion test at 3- and 7-days post-surgery, and weekly thereafter until 90 days after injection. Anxiety-like behavior was measured using Elevated Plus Maze at 14, 30- and 120-days post injection, and cognitive function was tested using Barnes Maze 30 days post injection. Neuroinflammation was assessed utilizing Iba1+ for activated microglia and GFAP+ immunoreactivity for reactive astrocytes. Adult neurogenesis was assessed at the subventricular and subgranular zones using tamoxifen treated nestin-creER-Ai9-tdTomato mice that were harvested at 30 days post injection. Results: MRI revealed blood in the ventricles up to 7 days post injection; confirmed via histology. Hydrocephalus occurred in the IVH, but not SHAM group (p = 0.04). There was no difference in cognitive function or anxiety-like behavior at any time point post injection. At 30 days, mild astrocyte reactivity was noted near the lateral ventricular wall in the IVH, but not SHAM group. There was no difference in reactive astrocytes between the IVH and SHAM groups in the hippocampus or cortex or newly born immature neurons. Conclusion: While global neuroinflammation was not detected in our novel mouse model of pure IVH, local inflammation continued out to 30 days post IVH. This long-term activation was not accompanied by cognitive deficits, suggesting that the model does not emulate clinical findings, but supports study of local inflammation after IVH.
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Yew, Wai Ping, Natalia D. Djukic, Jaya S. P. Jayaseelan, Richard J. Woodman, Hakan Muyderman et Neil R. Sims. « Differential effects of the cell cycle inhibitor, olomoucine, on functional recovery and on responses of peri-infarct microglia and astrocytes following photothrombotic stroke in rats ». Journal of Neuroinflammation 18, no 1 (31 juillet 2021). http://dx.doi.org/10.1186/s12974-021-02208-w.
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Abstract Background Following stroke, changes in neuronal connectivity in tissue surrounding the infarct play an important role in both spontaneous recovery of neurological function and in treatment-induced improvements in function. Microglia and astrocytes influence this process through direct interactions with the neurons and as major determinants of the local tissue environment. Subpopulations of peri-infarct glia proliferate early after stroke providing a possible target to modify recovery. Treatment with cell cycle inhibitors can reduce infarct volume and improve functional recovery. However, it is not known whether these inhibitors can influence neurological function or alter the responses of peri-infarct glia without reducing infarction. The present study aimed to address these issues by testing the effects of the cell cycle inhibitor, olomoucine, on recovery and peri-infarct changes following photothrombotic stroke. Methods Stroke was induced by photothrombosis in the forelimb sensorimotor cortex in Sprague-Dawley rats. Olomoucine was administered at 1 h and 24 h after stroke induction. Forelimb function was monitored up to 29 days. The effects of olomoucine on glial cell responses in peri-infarct tissue were evaluated using immunohistochemistry and Western blotting. Results Olomoucine treatment did not significantly affect maximal infarct volume. Recovery of the affected forelimb on a placing test was impaired in olomoucine-treated rats, whereas recovery in a skilled reaching test was substantially improved. Olomoucine treatment produced small changes in aspects of Iba1 immunolabelling and in the number of CD68-positive cells in cerebral cortex but did not selectively modify responses in peri-infarct tissue. The content of the astrocytic protein, vimentin, was reduced by 30% in the region of the lesion in olomoucine-treated rats. Conclusions Olomoucine treatment modified functional recovery in the absence of significant changes in infarct volume. The effects on recovery were markedly test dependent, adding to evidence that skilled tasks requiring specific training and general measures of motor function can be differentially modified by some interventions. The altered recovery was not associated with specific changes in key responses of peri-infarct microglia, even though these cells were considered a likely target for early olomoucine treatment. Changes detected in peri-infarct reactive astrogliosis could contribute to the altered patterns of functional recovery.
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Pessina, Monica A., Bethany G. Bowley, Maria Medalla, Douglas L. Rosene et Tara L. Moore. « Abstract P811 : Oral Curcumin Treatment Facilitates Recovery of Function in a Rhesus Monkey Model of Cortical Injury ». Stroke 52, Suppl_1 (mars 2021). http://dx.doi.org/10.1161/str.52.suppl_1.p811.
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Curcumin is a primary component of the spice turmeric, and is a potent anti-inflammatory and anti-oxidant compound. In rodent models of brain damage from stroke or trauma, curcumin acts primarily on microglia and astrocytes to inhibit pro-inflammatory signaling pathways and to reduce inflammation and levels of reactive oxygen species (ROS). Further, rats with cortical injury treated with curcumin have smaller lesions and fewer neurological impairments than those treated with vehicle. However, it is not clear whether curcumin exerts the same biological effect in primate brains as in rodent brains, and the effects of curcumin have not yet been extensively tested in monkey models of brain injury. Data from our laboratory has demonstrated that curcumin enhances spatial working memory and motor function in normal aging rhesus monkeys given daily doses of dietary curcumin over two years. The question remains as to whether chronic dietary curcumin can enhance neuroprotection and dampen or ameliorate functional motor deficits after cortical injury. Thus, we administered curcumin to adult, male rhesus monkeys daily for two weeks prior to and 12 weeks following induced cortical injury to the hand-representation of primary motor cortex (M1). Monkeys given daily treatment with oral doses of curcumin, but not those given vehicle, demonstrated significantly enhanced recovery of function in terms of time to retrieve a food reward on our hand dexterity task (HDT). In addition, treated monkeys returned to pre-injury finger-thumb grasp patterns on the HDT, while monkeys that received vehicle developed a compensatory whole hand grasp pattern and never returned to pre-injury grasp. These findings provide evidence that the anti-inflammatory compound, curcumin, is an effective treatment for facilitating recovery of function following cortical injury. Studies investigating the effect of curcumin on the microglia and astrocytes in the brains from these monkeys will provide evidence of the role of curcumin in reducing inflammation and ROS following injury.
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Colitti, Nina, Franck Desmoulin, Alice Le Friec, Wafae Labriji, Lorenne Robert, Amandine Michaux, Fabrice Conchou, Carla Cirillo et Isabelle Loubinoux. « Long-Term Intranasal Nerve Growth Factor Treatment Favors Neuron Formation in de novo Brain Tissue ». Frontiers in Cellular Neuroscience 16 (19 juillet 2022). http://dx.doi.org/10.3389/fncel.2022.871532.
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ObjectiveTo date, no safe and effective pharmacological treatment has been clinically validated for improving post-stroke neurogenesis. Growth factors are good candidates but low safety has limited their application in the clinic. An additional restraint is the delivery route. Intranasal delivery presents many advantages.Materials and MethodsA brain lesion was induced in twenty-four rats. Nerve growth factor (NGF) 5 μg/kg/day or vehicle was given intranasally from day 10 post-lesion for two periods of five weeks, separated by a two-week wash out period with no treatment. Lesion volume and atrophy were identified by magnetic resonance imaging (MRI). Anxiety and sensorimotor recovery were measured by behavior tests. Neurogenesis, angiogenesis and inflammation were evaluated by histology at 12 weeks.ResultsRemarkable neurogenesis occurred and was visible at the second and third months after the insult. Tissue reconstruction was clearly detected by T2 weighted MRI at 8 and 12 weeks post-lesion and confirmed by histology. In the new tissue (8.1% of the lesion in the NGF group vs. 2.4%, in the control group at 12 weeks), NGF significantly increased the percentage of mature neurons (19% vs. 7%). Angiogenesis and inflammation were not different in the two groups. Sensorimotor recovery was neither improved nor hampered by NGF during the first period of treatment, but NGF treatment limited motor recovery in the second period.InterpretationThe first five-week period of treatment was very well tolerated. This study is the first presenting the effects of a long treatment with NGF and has shown an important tissue regeneration rate at 8 and 12 weeks post-injury. NGF may have increased neuronal differentiation and survival and favored neurogenesis and neuron survival through subventricular zone (SVZ) neurogenesis or reprogramming of reactive astrocytes. For the first time, we evidenced a MRI biomarker of neurogenesis and tissue reconstruction with T2 and diffusion weighted imaging.
Thèses sur le sujet "Reprogramming, stroke, reactive astrocytes, motor cortex"
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M, Salluzzo, Martins Mendez M, Alia C, Cangi D, Götz M, Cremisi F et Caleo M. « Direct reprogrammin of reactive astrocytes into neurons in mouse motor cortex after stroke ». Doctoral thesis, 2021. http://hdl.handle.net/2158/1254079.
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In this thesis, I tested the effect of using “reprogramming” transcription factors to directly convert reactive astrocytes into new neurons after a focal cortical ischemic injury in the primary motor cortex. Direct reprogramming of endogenous astrocytes in the mouse motor cortex is capable to produce a new neuronal population that acquire a motor identity, integrate in the host tissue and support the recovery of function of the affected forelimb.