Overexpressed ski efficiently promotes neurorestoration, increases neuronal regeneration, and reduces astrogliosis after traumatic brain injury

Zhai, Yu; Ye, Shiyang; Wang, Qiushi; Xiong, Ranhua; Fu, Sheng-Yu; Du, Hao; Xu, Ya‐Wei; Peng, Yan; Huang, Zhizhong; Yang, Nan; Zhao, Yan; Ning, Yuping; Li, Ping; Zhou, Yuan‐Guo

doi:10.1038/s41434-022-00320-x

Cited by 9 publications

(9 citation statements)

References 90 publications

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“…In addition, glial limitans borders, which are mainly formed by reactive astrocytes, inhibit axon regeneration and restrict neuroplasticity (Rhodes & Fawcett, 2004; Wanner et al, 2008). Thus, reducing astrogliosis through cell cycle inhibition improves axonal regeneration and functional recovery after TBI (Di Giovanni et al, 2005; Zhai et al, 2022). Of note, Sox2 controls the proliferation/self‐renewal of stem cells and glial cells under both normal physiological and pathological conditions through its target genes regulatory network (Barone et al, 2021; Mercurio, Serra, & Nicolis, 2019; Zhang, Zhu, et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Specific knockout of Sox2 in astrocytes reduces reactive astrocyte formation and promotes recovery after early postnatal traumatic brain injury in mouse cortex

Liu

Hong

Gong

et al. 2022

Glia

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In response to central nervous system (CNS) injury, astrocytes go through a series of alterations, referred to as reactive astrogliosis, ranging from changes in gene expression and cell hypertrophy to permanent astrocyte borders around stromal cell scars in CNS lesions. The mechanisms underlying injury-induced reactive astrocytes in the adult CNS have been extensively studied. However, little is known about injuryinduced reactive astrocytes during early postnatal development. Astrocytes in the mouse cortex are mainly produced through local proliferation during the first 2 weeks after birth. Here we show that Sox2, a transcription factor critical for stem cells and brain development, is expressed in the early postnatal astrocytes and its expression level was increased in reactive astrocytes after traumatic brain injury (TBI) at postnatal day (P) 7 in the cortex. Using a tamoxifen-induced hGFAP-CreERT2; Sox2 flox/flox ; Rosa-tdT mouse model, we found that specific knockout of Sox2 in astrocytes greatly inhibited the proliferation of reactive astrocytes, the formation of glia limitans borders and subsequently promoted the tissue recovery after postnatal TBI at P7 in the cortex. In addition, we found that injury-induced glia limitans borders were still formed at P2 in the wild-type mouse cortex, and knockout of Sox2 in astrocytes inhibited the reactivity of both astrocytes and microglia. Together, these findings provide evidence that Sox2 is essential for the reactivity of astrocytes in response to the cortical TBI during the early postnatal period and suggest that Sox2-dependent astrocyte reactivity is a potential target for therapeutic treatment after TBI.

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Section: Discussionmentioning

confidence: 99%

Specific knockout of Sox2 in astrocytes reduces reactive astrocyte formation and promotes recovery after early postnatal traumatic brain injury in mouse cortex

Liu

Hong

Gong

et al. 2022

Glia

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“…A total of 4 μL of Adeno-PAD4 (Ad-PAD4) or Adeno-EGFP (Ad-con) was injected stereotactically into two sites of the right cortex (1.5 mm caudal and 1.5 mm rostral from lesion epicenter) at a dose of 2 μL, respectively, 24 h before mice subjected to CCI. The injections were performed with a 5 μL Hamilton syringe (Hamilton Company, USA) at a flow rate of 0.5 μL/min through the hole at a depth of 1.0 mm ( 33 , 34 ). After the injection, the needle was held for 10 min before retraction, and the scalp was stitched.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice

et al. 2023

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IntroductionIncreased neutrophil extracellular trap (NET) formation has been reported to be associated with cerebrovascular dysfunction and neurological deficits in traumatic brain injury (TBI). However, the biological function and underlying mechanisms of NETs in TBI-induced neuronal cell death are not yet fully understood.MethodsFirst, brain tissue and peripheral blood samples of TBI patients were collected, and NETs infiltration in TBI patients was detected by immunofluorescence staining and Western blot. Then, a controlled cortical impact device was used to model brain trauma in mice, and Anti-Ly6G, DNase, and CL-amidine were given to reduce the formation of neutrophilic or NETs in TBI mice to evaluate neuronal death and neurological function. Finally, the pathway changes of neuronal pyroptosis induced by NETs after TBI were investigated by administration of peptidylarginine deiminase 4 (a key enzyme of NET formation) adenovirus and inositol-requiring enzyme-1 alpha (IRE1α) inhibitors in TBI mice.ResultsWe detected that both peripheral circulating biomarkers of NETs and local NETs infiltration in the brain tissue were significantly increased and had positive correlations with worse intracranial pressure (ICP) and neurological dysfunction in TBI patients. Furthermore, the depletion of neutrophils effectively reduced the formation of NET in mice subjected to TBI. we found that degradation of NETs or inhibition of NET formation significantly inhibited nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 1 (NLRP1) inflammasome-mediated neuronal pyroptosis after TBI, whereas these inhibitory effects were abolished by cyclic GMP-AMP (cGAMP), an activator of stimulating Interferon genes (STING). Moreover, overexpression of PAD4 in the cortex by adenoviruses could aggravate NLRP1-mediated neuronal pyroptosis and neurological deficits after TBI, whereas these pro-pyroptotic effects were rescued in mice also receiving STING antagonists. Finally, IRE1α activation was significantly upregulated after TBI, and NET formation or STING activation was found to promote this process. Notably, IRE1α inhibitor administration significantly abrogated NETs-induced NLRP1 inflammasome-mediated neuronal pyroptosis in TBI mice.DiscussionOur findings indicated that NETs could contribute to TBI-induced neurological deficits and neuronal death by promoting NLRP1-mediated neuronal pyroptosis. Suppression of the STING/ IRE1α signaling pathway can ameliorate NETs-induced neuronal pyroptotic death after TBI.

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“…Reduced neurological deficits and brain water content; Multiple HBO sessions/ day were more protective than a single session Gene therapy FPI 112 Rat (#) 20 min post-TBI; VEGF-ZFP Functional recovery; reduced apoptosis; increased microvascular density and diameter CCI 114 Juvenile rat (# & $) 7 days post-TBI; human GR Improved spatial learning and memory CCI 115 Mouse (#) Soon after TBI; ski Reduced lesion volume and astrogliosis; Improved neurological recovery; promoted neurogenesis Weight-drop 113 Rat (#) 15 min post-TBI; IGF-1 Reduced oxidative stress & cognitive deficits Dietary adaptation CCI 57 Rat (#) Pre-and post-TBI 30% CR Improved spatial learning and memory Reduced lesion volume; upregulation of BDNF expression CCI 65 Juvenile rat (#) Post-TBI KD for 7 days Reduced cortical contusion volume at PND35 and PND45, but not PND17 and PND65…”

Section: Hyperbaric Oxygenmentioning

confidence: 99%

Non-pharmacological interventions for traumatic brain injury

Davis,

Arruri,

Joshi

et al. 2024

J Cereb Blood Flow Metab

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Heterogeneity and variability of symptoms due to the type, site, age, sex, and severity of injury make each case of traumatic brain injury (TBI) unique. Considering this, a universal treatment strategy may not be fruitful in managing outcomes after TBI. Most of the pharmacological therapies for TBI aim at modifying a particular pathway or molecular process in the sequelae of secondary injury rather than a holistic approach. On the other hand, non-pharmacological interventions such as hypothermia, hyperbaric oxygen, preconditioning with dietary adaptations, exercise, environmental enrichment, deep brain stimulation, decompressive craniectomy, probiotic use, gene therapy, music therapy, and stem cell therapy can promote healing by modulating multiple neuroprotective mechanisms. In this review, we discussed the major non-pharmacological interventions that are being tested in animal models of TBI as well as in clinical trials. We evaluated the functional outcomes of various interventions with an emphasis on the links between molecular mechanisms and outcomes after TBI.

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Overexpressed ski efficiently promotes neurorestoration, increases neuronal regeneration, and reduces astrogliosis after traumatic brain injury

Cited by 9 publications

References 90 publications

Specific knockout of Sox2 in astrocytes reduces reactive astrocyte formation and promotes recovery after early postnatal traumatic brain injury in mouse cortex

Specific knockout of Sox2 in astrocytes reduces reactive astrocyte formation and promotes recovery after early postnatal traumatic brain injury in mouse cortex

Inhibition of neutrophil extracellular trap formation attenuates NLRP1-dependent neuronal pyroptosis via STING/IRE1α pathway after traumatic brain injury in mice

Non-pharmacological interventions for traumatic brain injury

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