scholarly journals Reversing Glial Scar Back To Neural Tissue Through NeuroD1-Mediated Astrocyte-To-Neuron Conversion

2018 ◽  
Author(s):  
Lei Zhang ◽  
Zhuofan Lei ◽  
Ziyuan Guo ◽  
Zifei Pei ◽  
Yuchen Chen ◽  
...  
Keyword(s):  
Glial Cells ◽  
Ectopic Expression ◽  
Neuronal Loss ◽  
Neural Tissue ◽  
Glial Scar ◽  
Reactive Astrocytes ◽  
Innovative Technology ◽  
Mouse Cortex ◽  
Injury Model ◽  
Neuronal Conversion

ABSTRACTNerve injury often causes neuronal loss and glial proliferation, disrupting the delicate balance between neurons and glial cells in the brain. Recently, we have developed an innovative technology to convert internal reactive glial cells into functional neurons inside the mouse brain. Here, we further demonstrate that such glia-to-neuron conversion can rebalance neuron-glia ratio and reverse glial scar back to neural tissue. Specifically, using a severe stab injury model in the mouse cortex, we demonstrated that ectopic expression of NeuroD1 in reactive astrocytes significantly reduced glial reactivity and transformed toxic A1 astrocytes into less harmful astrocytes before neuronal conversion. Importantly, astrocytes were not depleted after neuronal conversion but rather repopulated due to its intrinsic proliferation capability. Remarkably, converting reactive astrocytes into neurons also significantly reduced microglia-mediated neuroinflammation. Moreover, accompanying regeneration of new neurons together with repopulation of new astrocytes, blood-brain-barrier was restored and synaptic density was rescued in the injury sites. Together, these results demonstrate that glial scar can be reversed back to neural tissue through rebalancing neuron:glia ratio after glia-to-neuron conversion.

scholarly journals Comment on “Rapid and efficient in vivo astrocyte-to-neuron conversion with regional identity and connectivity?”

2020 ◽  
Author(s):  
Gong Chen ◽  
Wen Li ◽  
Zongqin Xiang ◽  
Liang Xu ◽  
Minhui Liu ◽  
...  
Keyword(s):  
Glial Cells ◽  
Viral Vectors ◽  
Ectopic Expression ◽  
Regional Identity ◽  
Neuronal Loss ◽  
Critical Factor ◽  
Dose Finding ◽  
Toxic Dose ◽  
Cell Conversion

ABSTRACTRegenerating functional new neurons in the adult mammalian central nervous system (CNS) has been proven to be very challenging due to the inability of neurons to divide and repopulate themselves after neuronal loss. In contrast, glial cells in the CNS can divide and repopulate themselves under injury or disease conditions. Therefore, many groups around the world have been able to utilize internal glial cells to directly convert them into neurons for neural repair. We have previously demonstrated that ectopic expression of NeuroD1 in dividing glial cells can directly convert reactive glial cells into neurons. However, Wang et al. recently posted an article in bioRxiv challenging the entire field of in vivo glia-to-neuron conversion after using one single highly toxic dose of AAV (2×1013 gc/ml, 1 μl) in the mouse cortex, producing artifacts that are very difficult to interpret. We present data here that reducing AAV dosage to safe level will avoid artifacts caused by toxic dosage. We also demonstrate with Aldh1l1-CreERT2 and Ai14 reporter mice that lineage-traced astrocytes can be successfully converted into NeuN+ neurons after infected by AAV5 GFAP::NeuroD1. Retroviral expression of NeuroD1 further confirms our previous findings that dividing glial cells can be converted into neurons. Together, the incidence of Wang et al. sends an alarming signal to the entire in vivo reprogramming field that the dosage of viral vectors is a critical factor to consider when designing proper experiments. For AAV, we recommend a relatively safe dose of 1×1010 - 1×1012 gc/ml (~1 μl) in the rodent brain for cell conversion experiments addressing basic science questions. For therapeutic purpose under injury or diseased conditions, AAV dosage needs to be adjusted through a series of dose finding experiments. Moreover, we recommend that the AAV results are further verified with retroviruses that mainly express transgenes in dividing glial cells in order to draw solid conclusions.

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 Reactive Astrocytes in Glial Scar Attract Olfactory Ensheathing Cells Migration by Secreted TNF-α in Spinal Cord Lesion of Rat

PLoS ONE ◽  
2009 ◽  
Vol 4 (12) ◽  
pp. e8141 ◽  
Author(s):  
Zhida Su ◽  
Yimin Yuan ◽  
Jingjing Chen ◽  
Li Cao ◽  
Yanling Zhu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Glial Scar ◽  
Spinal Cord Lesion ◽  
Reactive Astrocytes ◽  
Olfactory Ensheathing Cells ◽  
Tnf Α ◽  
Ensheathing Cells ◽  
Cord Lesion

scholarly journals Rapid, widespread, and longlasting induction of nestin contributes to the generation of glial scar tissue after CNS injury.

1995 ◽  
Vol 131 (2) ◽  
pp. 453-464 ◽  
Author(s):  
J Frisén ◽  
C B Johansson ◽  
C Török ◽  
M Risling ◽  
U Lendahl
Keyword(s):  
Spinal Cord ◽  
Scar Tissue ◽  
Central Canal ◽  
Glial Scar ◽  
Reactive Astrocytes ◽  
Spatiotemporal Pattern ◽  
Cns Injury ◽  
Neuronal Regeneration ◽  
Nestin Expression ◽  
The Central Nervous System

Neuronal regeneration does generally not occur in the central nervous system (CNS) after injury, which has been attributed to the generation of glial scar tissue. In this report we show that the composition of the glial scar after traumatic CNS injury in rat and mouse is more complex than previously assumed: expression of the intermediate filament nestin is induced in reactive astrocytes. Nestin induction occurs within 48 hours in the spinal cord both at the site of lesion and in degenerating tracts and lasts for at least 13 months. Nestin expression is induced with similar kinetics in the crushed optic nerve. In addition to the expression in reactive astrocytes, we also observed nestin induction within 48 hours after injury in cells close to the central canal in the spinal cord, while nestin expressing cells at later timepoints were found progressively further out from the central canal. This dynamic pattern of nestin induction after injury was mimicked by lacZ expressing cells in nestin promoter/lacZ transgenic mice, suggesting that defined nestin regulatory regions mediate the injury response. We discuss the possibility that the spatiotemporal pattern of nestin expression reflects a population of nestin positive cells, which proliferates and migrates from a region close to the central canal to the site of lesion in response to injury.

scholarly journals Reactive astrocyte-driven epileptogenesis is induced by microglia initially activated following status epilepticus

2019 ◽  
Author(s):  
Fumikazu Sano ◽  
Eiji Shigetomi ◽  
Youichi Shinozaki ◽  
Haruka Tsuzukiyama ◽  
Kozo Saito ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Glial Cells ◽  
Reactive Astrocytes ◽  
Pharmacological Intervention ◽  
Seizure Susceptibility ◽  
Drug Induced ◽  
Reactive Microglia ◽  
Sequential Activation ◽  
Animal Models Of Epilepsy ◽  
Increased Susceptibility

AbstractExtensive activation of glial cells during a latent period has been well documented in various animal models of epilepsy; however, it remains unknown whether such glial activation is capable of promoting epileptogenesis. Here, we show that temporally distinct activation profiles of microglia and astrocytes collaboratively contribute to epileptogenesis in a drug-induced status epilepticus model. We found that reactive microglia appear first, followed by reactive astrocytes and increased susceptibility to seizures. Pharmacological intervention against microglial activation reduces astrogliosis, aberrant astrocyte Ca2+ signaling, and seizure susceptibility. Reactive astrocytes exhibit larger Ca2+ signals mediated by IP3R2, whereas deletion of this type of Ca2+ signaling reduces seizure susceptibility after status epilepticus. Together, our findings indicate that the sequential activation of glial cells constitutes a cause of epileptogenesis after status epilepticus.

scholarly journals Rapamycin Preserves Neural Tissue, Promotes Schwann Cell Myelination and Reduces Glial Scar Formation After Hemi-Contusion Spinal Cord Injury in Mice

2021 ◽  
Vol 13 ◽  
Author(s):  
Junhao Liu ◽  
Ruoyao Li ◽  
Zucheng Huang ◽  
Junyu Lin ◽  
Wei Ji ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Schwann Cell ◽  
Motor Function ◽  
Neural Tissue ◽  
Glial Scar ◽  
Vehicle Group ◽  
Spinal Cord Tissue ◽  
Cord Injury

Protecting white matter is one of the key treatment strategies for spinal cord injury (SCI), including alleviation of myelin loss and promotion of remyelination. Rapamycin has been shown neuroprotective effects against SCI and cardiotoxic effects while enhancing autophagy. However, specific neuroprotection of rapamycin for the white matter after cervical SCI has not been reported. Therefore, we aim to evaluate the role of rapamycin in neuroprotection after hemi-contusion SCI in mice. Forty-six 8-week-old mice were randomly assigned into the rapamycin group (n = 16), vehicle group (n = 16), and sham group (n = 10). All mice of the rapamycin and vehicle groups received a unilateral contusion with 1.2-mm displacement at C5 followed by daily intraperitoneal injection of rapamycin or dimethyl sulfoxide solution (1.5 mg⋅kg–1⋅day–1). The behavioral assessment was conducted before the injury, 3 days and every 2 weeks post-injury (WPI). The autophagy-related proteins, the area of spared white matter, the number of oligodendrocytes (OLs) and axons were evaluated at 12 WPI, as well as the glial scar and the myelin sheaths formed by Schwann cells at the epicenter. The 1.2 mm contusion led to a consistent moderate–severe SCI in terms of motor function and tissue damage. Rapamycin administration promoted autophagy in spinal cord tissue after injury and reduced the glial scar at the epicenter. Additionally, rapamycin increased the number of OLs and improved motor function significantly than in the vehicle group. Furthermore, the rapamycin injection resulted in an increase of Schwann cell-mediated remyelination and weight loss. Our results suggest that rapamycin can enhance autophagy, promote Schwann cell myelination and motor function recovery by preserved neural tissue, and reduce glial scar after hemi-contusive cervical SCI, indicating a potential strategy for SCI treatment.

scholarly journals Role of laminin bioavailability in the astroglial permissivity for neuritic outgrowth

2002 ◽  
Vol 74 (4) ◽  
pp. 683-690 ◽  
Author(s):  
MARCIENNE TARDY
Keyword(s):  
Glial Fibrillary Acidic Protein ◽  
Neurite Outgrowth ◽  
Axonal Regeneration ◽  
Glial Scar ◽  
Reactive Astrocytes ◽  
Adult Brain ◽  
Morphological Response ◽  
Phenotypic Changes ◽  
Neuritic Outgrowth

The mechanisms involved in the failure of an adult brain to regenerate post-lesion remain poorly understood. The reactive gliosis which occurs after an injury to the CNS and leads to the glial scar has been considered as one of the major impediments to neurite outgrowth and axonal regeneration. A glial scar consists mainly of reactive, hypertrophic astrocytes. These reactive cells acquire new properties, leading to A non-permissive support for neurons. Astrogial reactivity is mainly characteriized by a high overexpression of the major component of the gliofilaments, the glial fibrillary acidic protein (GFAP). This GFAP overexpression is related to the astroglial morphological response to injury. We hypothesized that modulation of GFAP synthesis, reversing the hypertrophic phenotype, might also reverse the blockage of neuritic outgrowth observed after a lesion. In this article, we review findings of our group, confirming our hypothesis in a model of lesioned neuron-astrocyte cocultures. We demonstrate that permissivity for neuritic outgrowth is related to phenotypic changes induced in reactive astrocytes transfected by antisense GFAP-mRNA. We also found that this permissivity was related to a neuron-regulated extracellular laminin bioavailability.

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