scholarly journals Reactive Astrocytes Prevent Maladaptive Plasticity after Ischemic Stroke

2021 ◽  
pp. 102199
Author(s):  
Markus Aswendt ◽  
Ulrika Wilhelmsson ◽  
Frederique Wieters ◽  
Anna Stokowska ◽  
Felix Johannes Schmitt ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Reactive Astrocytes ◽  
Maladaptive Plasticity

scholarly journals Reactive astrocytes prevent maladaptive plasticity after ischemic stroke

2021 ◽  
Author(s):  
Markus Aswendt ◽  
Ulrika Wilhelmsson ◽  
Frederique Wieters ◽  
Anna Stokowska ◽  
Felix Johannes Schmitt ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Functional Connectivity ◽  
Neural Plasticity ◽  
Infarct Volume ◽  
Optimal Recovery ◽  
Reactive Astrocytes ◽  
Sensorimotor Function ◽  
Functional Connections ◽  
Maladaptive Plasticity

Restoration of functional connectivity is a major contributor to functional recovery after stroke. We investigated the role of reactive astrocytes in functional connectivity and recovery after photothrombotic stroke in mice with attenuated reactive gliosis (GFAP−/−Vim−/−). Infarct volume and longitudinal functional connectivity changes were determined by in vivo T2-weighted MRI and resting-state functional MRI. Sensorimotor function was assessed with behavioral tests, and glial and neural plasticity responses were quantified in the peri-infarct region. Four weeks after stroke, GFAP−/−Vim−/− mice showed impaired recovery of sensorimotor function and aberrant restoration of global neuronal connectivity. These mice also exhibited maladaptive plasticity responses, shown by higher number of lost and newly formed functional connections between primary and secondary targets of cortical stroke regions and increased peri-infarct expression of the axonal plasticity marker Gap43. We conclude that reactive astrocytes are required for optimal recovery-promoting plasticity responses after ischemic stroke.

scholarly journals The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke

2021 ◽  
Author(s):  
Yong-Ming Zhu ◽  
Liang Lin ◽  
Chao Wei ◽  
Yi Guo ◽  
Yuan Qin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Glucose Deprivation ◽  
Artery Occlusion ◽  
Glial Scar ◽  
Scar Formation ◽  
Reactive Astrocytes ◽  
Interacting Protein ◽  
Protein Levels ◽  
Endothelial Growth Factor ◽  
Cerebral Artery Occlusion

AbstractNecroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar. Graphical Abstract

scholarly journals Activation and Role of Astrocytes in Ischemic Stroke

2021 ◽  
Vol 15 ◽  
Author(s):  
Xin-Ya Shen ◽  
Zhen-Kun Gao ◽  
Yu Han ◽  
Mei Yuan ◽  
Yi-Sha Guo ◽  
...  
Keyword(s):  
Nervous System ◽  
Ischemic Stroke ◽  
Protective Role ◽  
Reactive Astrocytes ◽  
High Morbidity ◽  
Temporal Expression ◽  
The Central Nervous System ◽  
Controversial Topic ◽  
And Function

Ischemic stroke refers to the disorder of blood supply of local brain tissue caused by various reasons. It has high morbidity and mortality worldwide. Astrocytes are the most abundant glial cells in the central nervous system (CNS). They are responsible for the homeostasis, nutrition, and protection of the CNS and play an essential role in many nervous system diseases’ physiological and pathological processes. After stroke injury, astrocytes are activated and play a protective role through the heterogeneous and gradual changes of their gene expression, morphology, proliferation, and function, that is, reactive astrocytes. However, the position of reactive astrocytes has always been a controversial topic. Many studies have shown that reactive astrocytes are a double-edged sword with both beneficial and harmful effects. It is worth noting that their different spatial and temporal expression determines astrocytes’ various functions. Here, we comprehensively review the different roles and mechanisms of astrocytes after ischemic stroke. In addition, the intracellular mechanism of astrocyte activation has also been involved. More importantly, due to the complex cascade reaction and action mechanism after ischemic stroke, the role of astrocytes is still difficult to define. Still, there is no doubt that astrocytes are one of the critical factors mediating the deterioration or improvement of ischemic stroke.

scholarly journals Notch signaling regulates nucleocytoplasmic Olig2 translocation in reactive astrocytes differentiation after ischemic stroke

2013 ◽  
Vol 75 (3) ◽  
pp. 204-209 ◽  
Author(s):  
Takeshi Marumo ◽  
Yasushi Takagi ◽  
Kazue Muraki ◽  
Nobuo Hashimoto ◽  
Susumu Miyamoto ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Notch Signaling ◽  
Reactive Astrocytes

scholarly journals In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy

2019 ◽  
Author(s):  
Long-Jiao Ge ◽  
Fu-Han Yang ◽  
Jie Feng ◽  
Nan-Hui Chen ◽  
Min Jiang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Ischemic Stroke ◽  
High Efficiency ◽  
Ectopic Expression ◽  
Reactive Astrocytes ◽  
Neural Regeneration ◽  
Cortical Astrocyte ◽  
Cell Conversion ◽  
Human Primate

ABSTRACTStroke is a leading cause of death and disability but most of the clinical trials have failed in the past, despite our increasing understanding of the molecular and pathological mechanisms underlying stroke. While many signaling pathways have been identified in the aftermath of stroke, the majority of current approaches are focusing on neural protection rather than neuroregeneration. In this study, we report an in vivo neural regeneration approach to convert brain internal reactive astrocytes into neurons through ectopic expression of a neural transcription factor NeuroD1 in adult non-human primate (NHP) brains following ischemic stroke. We demonstrate that NeuroD1 AAV-based gene therapy can convert reactive astrocytes into neurons with high efficiency (90%), but astrocytes are never depleted in the NeuroD1-expressed areas, consistent with the proliferative capability of astrocytes. The NeuroD1-mediated in vivo astrocyte-to-neuron (AtN) conversion in monkey cortex following ischemic stroke increased local neuronal density, reduced reactive microglia, and surprisingly protected parvalbumin interneurons in the converted areas. The NeuroD1 gene therapy showed a broad time window, from 10 days to 30 days following ischemic stroke, in terms of exerting its neuroregenerative and neuroprotective effects. The cortical astrocyte-converted neurons also showed Tbr1+ cortical neuron identity, similar to our earlier findings in rodent animal models. Unexpectedly, NeuroD1 expression in converted neurons showed a significant decrease after 6 months of viral infection, suggesting a potential self-regulatory mechanism of NeuroD1 in adult mature neurons of NHPs. These results suggest that in vivo cell conversion through NeuroD1-based gene therapy may be an effective approach to regenerate new neurons in adult primate brains for tissue repair.

Abstract P728: Promoting Neuron Survival After Ischemic Stroke via Restoring Astrocytic Endoplasmic Reticulum Function and Glucose Metabolism

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Ruijia Liu ◽  
Shayan Jalali ◽  
Dandan Sun ◽  
Zhongling Zhang ◽  
Gulnaz Begum
Keyword(s):  
Endoplasmic Reticulum ◽  
Ischemic Stroke ◽  
Glucose Metabolism ◽  
Er Stress ◽  
Cortical Neurons ◽  
Reactive Astrocytes ◽  
Neuron Survival ◽  
Chaperone Protein ◽  
Er Chaperone ◽  
Specific Deletion

Stroke-induced reactive astrocytes exhibit abnormal functions and contribute to neurodegeneration. Thus, restoring normal homeostatic astrocyte functions is important for neuroprotection. Overstimulation of Na + /H + exchanger 1 (NHE1) activity after stroke triggers reactive astrocyte formation, which displays abnormal functions. We have shown that targeted deletion of Nhe1 in astrocytes leads to inhibition of reactive astrocytes, reduced infarct volume, and improved neurological function after ischemic stroke. In the present study, we investigated ischemic stroke-mediated endoplasmic reticulum (ER) stress and unfolded protein response (UPR) and its impact on cellular reparative functions. Astrocyte specific deletion of Nhe1 in Gfap-Cre ERT2+/- ;Nhe1 f/f mice ( Nhe1 Astro-KO) was induced by tamoxifen (Tam) treatment. Gfap-Cre ERT2- /- ;Nhe1 f/f mice treated with Tam served as wild-type (WT) controls. In transient middle cerebral artery occlusion (tMCAO) model, ischemic stroke triggered a significant increase in expression of ER stress marker proteins ATF4 and CHOP at 24 h reperfusion (Rp) in WT ischemic brains (p< 0.05), no such elevation was detected in Nhe1 Astro-KO ischemic brains. Immunocytochemical analysis revealed abundant ER chaperone protein GRP78 expression in non-ischemic cortical neurons (NeuN + ) of WT brains, but it was reduced by ~ 70% at 48 h Rp (p < 0.001). In contrast, Nhe1 Astro-KO brains preserved ER chaperone protein GRP78 in NeuN + cells in the ischemic cortex, and their adjacent GFAP + astrocytes showed ~40% increased GRP78 expression compared to WT. These polarized astrocytes with elevated GRP78 expression may provide neuroprotective support. Dysfunctional ER chaperone activity can affect glucose metabolism by decreasing glycolysis and mitochondrial respiration. Consistently, our bulk RNA-Seq analysis of reactive astrocytes shows that Nhe1 Astro-KO astrocytes exhibit significantly stimulated transcriptome profiles for glycolysis ( Hk2, Gpi, and Ldhb) and oxidative phosphorylation (complex I, IV and V). Together, our study demonstrates that restoring astrocytic ER chaperon function and glucose metabolism via specific deletion of Nhe1 promotes neuron survival after ischemic stroke.

scholarly journals Primate-specific response of astrocytes to stroke limits peripheral macrophage infiltration

2020 ◽  
Author(s):  
Anthony G. Boghdadi ◽  
Joshua Spurrier ◽  
Leon Teo ◽  
Mingfeng Li ◽  
Mario Skarica ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Brain Injuries ◽  
Reactive Astrocytes ◽  
Stroke Recovery ◽  
Specific Response ◽  
Inhibitory Protein ◽  
Brain Hemispheres ◽  
Marmoset Monkey

Reactive astrocytes play critical roles after brain injuries but their precise function in stroke is not well defined. Here, we utilized single nuclei transcriptomics to characterize astrocytes after ischemic stroke in nonhuman primate (NHP) marmoset monkey primary visual cortex. We identified 19 putative subtypes of astrocytes from injured and uninjured brain hemispheres and observed nearly complete segregation between stroke and control astrocyte clusters. We then screened for genes that might be limiting stroke recovery and discovered that one neurite-outgrowth inhibitory protein, NogoA, previously associated with oligodendrocytes but not astrocytes, was expressed in numerous reactive astrocyte subtypes. NogoA upregulation on reactive astrocytes was confirmed in vivo for NHP and human, but not observed to the same extent in rodent. Further in vivo and in vitro studies determined that NogoA mediated an anti-inflammatory response which limits deeper infiltration of peripheral macrophages from the lesion during the subacute post-stroke period. Specifically, these findings are relevant to the development of NogoA-targeting therapies shortly after ischemic stroke. Our findings have uncovered the complexity and species specificity of astrocyte responses, which need to be considered more when investigating novel therapeutics for brain injury.

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