LncRNA Xist Contributes to Endogenous Neurological Repair After Chronic Compressive Spinal Cord Injury by Promoting Angiogenesis Through the miR-32-5p/Notch-1 Axis

Cheng, Xing; Xu, Jianhua; Yu, Zhengran; Xu, Jiadai; Long, Houqing

doi:10.3389/fcell.2020.00744

Cited by 30 publications

(37 citation statements)

References 50 publications

(61 reference statements)

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“…DAPT solution (1 μg/μL) was prepared by dissolving DAPT powder (MCE, United States) in 0.01 M phosphate-buffered saline (PBS) containing 5% dimethyl sulfoxide. The DAPT solution (1 mg/kg per rat) and a negative control were intraperitoneally injected using a microinjection syringe ( Cheng et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Pathophysiological Changes and the Role of Notch-1 Activation After Decompression in a Compressive Spinal Cord Injury Rat Model

Cheng

et al. 2021

Front. Neurosci.

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Surgical decompression is the primary treatment for cervical spondylotic myelopathy (CSM) patients with compressive spinal cord injury (CSCI). However, the prognosis of patients with CSCI varies, and the pathophysiological changes following decompression remain poor. This study aimed to investigate the pathophysiological changes and the role of Notch-1 activation after decompression in a rat CSCI model. Surgical decompression was conducted at 1 week post-injury (wpi). DAPT was intraperitoneally injected to down-regulate Notch-1 expression. Basso, Beattie, and Bresnahan scores and an inclined plane test were used to evaluate the motor function recovery. Hematoxylin and eosin staining was performed to assess pathophysiological changes, while hypoxia-inducible factor 1 alpha, vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), matrix metalloproteinase (MMP)-9, MMP-2, Notch-1, and Hes-1 expression in the spinal cord were examined by immunohistochemical analysis or quantitative PCR. The results show that early decompression can partially promote motor function recovery. Improvements in structural and cellular damage and hypoxic levels were also observed in the decompressed spinal cord. Moreover, decompression resulted in increased VEGF and vWF expression, but decreased MMP-9 and MMP-2 expression at 3 wpi. Expression levels of Notch-1 and its downstream gene Hes-1 were increased after decompression, and the inhibition of Notch-1 significantly reduced the decompression-induced motor function recovery. This exploratory study revealed preliminary pathophysiological changes in the compressed and decompressed rat spinal cord. Furthermore, we confirmed that early surgical decompression partially promotes motor function recovery may via activation of the Notch-1 signaling pathway after CSCI. These results could provide new insights for the development of drug therapy to enhance recovery following surgery.

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Section: Methodsmentioning

confidence: 99%

Pathophysiological Changes and the Role of Notch-1 Activation After Decompression in a Compressive Spinal Cord Injury Rat Model

Cheng

et al. 2021

Front. Neurosci.

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“…[18] Our previous study showed that 4 weeks of chronic compression led to a severe ischaemia-hypoxia environment, as demonstrated by increased HIF-1α expression, [25] and signi cantly decreased microvascular density, as demonstrated by micro-CT and immunohistochemistry data. [39,49] Thus, the increased T2WI hyperintensity in our study was more likely to represent transient ischaemia upon exion. We assume that the CCSCI models, whose spinal cord circulation was already compromised, suffered more perfusion decrease upon exion than sham mice.…”

Section: Discussionmentioning

confidence: 67%

Neurophysiological and Spinal Cord Perfusion Changes at Dynamic Neck Positions in a Compressive Spinal Cord Injury Rat Model

Yu¹,

Cheng²,

Chen³

et al. 2021

Preprint

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Background: Cervical spondylotic myelopathy (CSM) is a degenerative condition of the spine that caused by static and dynamic compression of the spinal cord. However, the pathophysiological changes at dynamic neck positions remain poor. This study investigated the interplay between neurophysiological and haemodynamic responses at dynamic neck positions in a chronic compressive spinal cord injury (CCSCI) rat model. Methods: Behavioural tests including Basso, Beattie, and Bresnahan scores and an inclined plane test were used to evaluate the motor function recovery. Combined examination of dynamic motor and somatosensory evoked potentials (DMEPs and DSSEPs, respectively) was performed regularly to evaluate the dynamic motor and sensory conduction of the cervical cord. At 4 weeks post-injury (wpi), dynamic magnetic resonance imaging (MRI) and dynamic laser Doppler flowmetry (LDF) were used to demonstrate the interstructure and spinal cord blood flow (SCBF) at the compression site at dynamic neck positions. Hematoxylin and eosin (HE) staining was performed to assess the cords' pathological changes.Results: Behavioural tests and combined DMEPs and DSSEPs examination showed that spinal cord neurological function and dynamic neural conduction deteriorated gradually within a 4-week compression period. The DMEPs were mainly deteriorated upon flexion, while DSSEPs were upon all neck positions after the compression. At 4 wpi, dynamic MRI showed increased T2-weighted image (T2WI) signal intensities. Also, dynamic LDF demonstrated decreased SCBF at the spinal cord compression site. Both of them altered especially upon cervical flexion. The dynamic change in SCBF was significantly correlated with the change in DMEP amplitude upon flexion. Conclusions: This exploratory study revealed that changes in axonal conduction in the motor and somatosensory tracts of the spinal cord were significantly related to chronic compression time and neck position. Furthermore, spinal cord ischaemia may be intimately related to motor conduction dysfunction upon flexion in CCSCI models. These results indicated the potential for therapies targeting dynamic spinal cord perfusion to prevent progression and functional loss in CSM.

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“…In LPS-induced SCI (Spinal cord injury) microglia cells and lncRNA Xist, which interacts with miR-27a to mediate the downstream target gene of Smurf1 expression, alleviated the apoptosis and inflammatory injury of microglia cells after SCI through activating miR-27a/Smurf1 axis ( Zhao Q. et al, 2020 ). These signaling pathways, which include lncRNA Xist/miR-494/PTEN/PI3K/AKT signaling pathway ( Gu et al, 2017 ), lncRNA Xist/miR-142-5p/PDCD4 signaling pathway ( Tang et al, 2020 ), lncRNA Xist/miR-217/TLR4 signaling pathway ( Jin et al, 2019 ), lncRNA Xist/miR-32-5p/Notch-1 signaling pathway ( Cheng X. et al, 2020 ), and lncRNA Xist/miR-15a-5p/CUL3signaling pathway ( Xu et al, 2019 ), participated in the SCI, acute kidney injury, and nephropathy procession. Cheng and Wang (2020) identified that lncRNA Xist could act as a ceRNA to sponge miR-212-3p and miR-122-5p to facilitate kidney transplant acute kidney injury progression via regulating the expression of ASF1A, BRWD1, and PFKFB2 using GEO database assay.…”

Section: The Role Of Lncrna Xist In Non-cancer Diseasesmentioning

confidence: 99%

Biological Function of Long Non-coding RNA (LncRNA) Xist

Wang

Min

Guo

et al. 2021

Front. Cell Dev. Biol.

125

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Long non-coding RNAs (lncRNAs) regulate gene expression in a variety of ways at epigenetic, chromatin remodeling, transcriptional, and translational levels. Accumulating evidence suggests that lncRNA X-inactive specific transcript (lncRNA Xist) serves as an important regulator of cell growth and development. Despites its original roles in X-chromosome dosage compensation, lncRNA Xist also participates in the development of tumor and other human diseases by functioning as a competing endogenous RNA (ceRNA). In this review, we comprehensively summarized recent progress in understanding the cellular functions of lncRNA Xist in mammalian cells and discussed current knowledge regarding the ceRNA network of lncRNA Xist in various diseases. Long non-coding RNAs (lncRNAs) are transcripts that are more than 200 nt in length and without an apparent protein-coding capacity (Furlan and Rougeulle, 2016; Maduro et al., 2016). These RNAs are believed to be transcribed by the approximately 98–99% non-coding regions of the human genome (Derrien et al., 2012; Fu, 2014; Montalbano et al., 2017; Slack and Chinnaiyan, 2019), as well as a large variety of genomic regions, such as exonic, tronic, and intergenic regions. Hence, lncRNAs are also divided into eight categories: Intergenic lncRNAs, Intronic lncRNAs, Enhancer lncRNAs, Promoter lncRNAs, Natural antisense/sense lncRNAs, Small nucleolar RNA-ended lncRNAs (sno-lncRNAs), Bidirectional lncRNAs, and non-poly(A) lncRNAs (Ma et al., 2013; Devaux et al., 2015; St Laurent et al., 2015; Chen, 2016; Quinn and Chang, 2016; Richard and Eichhorn, 2018; Connerty et al., 2020). A range of evidence has suggested that lncRNAs function as key regulators in crucial cellular functions, including proliferation, differentiation, apoptosis, migration, and invasion, by regulating the expression level of target genes via epigenomic, transcriptional, or post-transcriptional approaches (Cao et al., 2018). Moreover, lncRNAs detected in body fluids were also believed to serve as potential biomarkers for the diagnosis, prognosis, and monitoring of disease progression, and act as novel and potential drug targets for therapeutic exploitation in human disease (Jiang W. et al., 2018; Zhou et al., 2019a). Long non-coding RNA X-inactive specific transcript (lncRNA Xist) are a set of 15,000–20,000 nt sequences localized in the X chromosome inactivation center (XIC) of chromosome Xq13.2 (Brown et al., 1992; Debrand et al., 1998; Kay, 1998; Lee et al., 2013; da Rocha and Heard, 2017; Yang Z. et al., 2018; Brockdorff, 2019). Previous studies have indicated that lncRNA Xist regulate X chromosome inactivation (XCI), resulting in the inheritable silencing of one of the X-chromosomes during female cell development. Also, it serves a vital regulatory function in the whole spectrum of human disease (notably cancer) and can be used as a novel diagnostic and prognostic biomarker and as a potential therapeutic target for human disease in the clinic (Liu et al., 2018b; Deng et al., 2019; Dinescu et al., 2019; Mutzel and Schulz, 2020; Patrat et al., 2020; Wang et al., 2020a). In particular, lncRNA Xist have been demonstrated to be involved in the development of multiple types of tumors including brain tumor, Leukemia, lung cancer, breast cancer, and liver cancer, with the prominent examples outlined in Table 1. It was also believed that lncRNA Xist (Chaligne and Heard, 2014; Yang Z. et al., 2018) contributed to other diseases, such as pulmonary fibrosis, inflammation, neuropathic pain, cardiomyocyte hypertrophy, and osteoarthritis chondrocytes, and more specific details can be found in Table 2. This review summarizes the current knowledge on the regulatory mechanisms of lncRNA Xist on both chromosome dosage compensation and pathogenesis (especially cancer) processes, with a focus on the regulatory network of lncRNA Xist in human disease.

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LncRNA Xist Contributes to Endogenous Neurological Repair After Chronic Compressive Spinal Cord Injury by Promoting Angiogenesis Through the miR-32-5p/Notch-1 Axis

Cited by 30 publications

References 50 publications

Pathophysiological Changes and the Role of Notch-1 Activation After Decompression in a Compressive Spinal Cord Injury Rat Model

Pathophysiological Changes and the Role of Notch-1 Activation After Decompression in a Compressive Spinal Cord Injury Rat Model

Neurophysiological and Spinal Cord Perfusion Changes at Dynamic Neck Positions in a Compressive Spinal Cord Injury Rat Model

Biological Function of Long Non-coding RNA (LncRNA) Xist

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