miR‐30b Promotes spinal cord sensory function recovery via the Sema3A/NRP‐1/PlexinA1/RhoA/ROCK Pathway

Wang, Xin; Li, Bo; Wang, Zhijie; Wang, Fengyan; Liang, Jing; Chen, Chuanjie; Zhao, Lei; Zhou, Bo; Guo, Xiaoling; Ren, Liqun; Yuan, Xin; Chen, Xueming; Wang, Tianyi

doi:10.1111/jcmm.15591

Cited by 14 publications

(8 citation statements)

References 47 publications

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“…Interestingly, miR-30b was found to be significantly upregulated in hippocampal tissues of AD patients and rat models ( Li et al , 2020a ; Song et al , 2019 ), and in plasma samples of Parkinson’s disease patients ( Brennan et al , 2019 ), further supporting the fact that miRNA regulation can be differentially regulated based on the model, disease context, or even sample matrix. In vitro, similar to our study, inhibition of miR-30b resulted in a decrease in neurite length of rat primary sensory neurons ( Wang et al , 2020 ). miR-30d, which was downregulated upon exposure to COL and DOX in our study, was also downregulated in blood samples of acute ischemic stroke patients and in CSF samples of AD patients ( Brennan et al , 2019 ; Jiang et al , 2018 ).…”

Section: Resultssupporting

confidence: 89%

“…Inhibiting miR-30b was shown to decrease the neurite length, likely mediated by miR-30b targeting Sema3A/RhoA pathway, which is an important regulator for axonal growth ( Wang et al , 2020 )…”

Section: Resultsmentioning

confidence: 99%

“…We specifically focused on secreted biomarkers in vitro, since secreted factors would be most likely to translate to detection of miRNAs in fluids (serum, CSF, and urine) of animals or humans. Additionally, these miRNAs were previously shown to be altered in a variety of nonclinical systems, such as human neuroblastoma and neural progenitor cells, and nonclinical species including mice and rats under neurotoxic conditions ( Aranha et al , 2010 ; Beveridge et al , 2009 ; Feng et al , 2020 ; Jeyaseelan et al , 2008 ; Jian et al , 2019 ; Jin et al , 2021 ; Liu et al , 2015 ; Shen et al , 2020 ; Song et al , 2019 ; Wang and Jia, 2021 ; Wang et al , 2016 , 2020 ; Wei et al , 2015 ; Yang et al , 2021 ; Zhang et al , 2014 ; Zhao et al , 2017 , 2021 ; Zhong et al , 2020 ). This suggests a strong translation of effect across species and increases our confidence that these notable miRNAs may be predictive biomarkers of chemical-induced neurodegeneration in nonclinical safety studies and in humans.…”

Section: Discussionmentioning

confidence: 99%

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Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

You

Cohen

Pustovalova

et al. 2022

Toxicological Sciences

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Elucidation of predictive fluidic biochemical markers to detect and monitor chemical-induced neurodegeneration has been a major challenge due to a lack of understanding of molecular mechanisms driving altered neuronal morphology and function, as well as poor sensitivity in methods to quantify low-level biomarkers in bodily fluids. Here, we evaluated five neurotoxicants (acetaminophen [negative control], bisindolylmaleimide-1, colchicine, doxorubicin, paclitaxel, and rotenone) in human iPSC-derived neurons to profile secreted miRNAs at early and late stages of decline in neuronal cell morphology and viability. Based on evaluation of these morphological (neurite outgrowth parameters) and viability (ATP) changes, two concentrations of each chemical were selected for analysis in a human 754 miRNA panel: a low concentration with no/minimal effect on cell viability but a significant decrease in neurite outgrowth, and a high concentration with a significant decrease in both endpoints. A total of 39 miRNAs demonstrated significant changes (fold-change ≥1.5 or ≤ 0.67, p-value < 0.01) with at least one exposure. Further analyses of targets modulated by these miRNAs revealed 38 key mRNA targets with roles in neurological dysfunctions, and identified TGF-β signaling as a commonly enriched pathway. Of the 39 miRNAs, five miRNAs, three down-regulated (miR-20a, miR-30b, and miR-30d) and two up-regulated (miR-1243 and miR-1305), correlated well with morphological changes induced by multiple neurotoxicants and were notable based on their relationship to various neurodegenerative conditions and/or key pathways, such as TGF-β signaling. These data sets reveal miRNA candidates that warrant further evaluation as potential safety biomarkers of chemical-induced neurodegeneration.

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Section: Resultssupporting

confidence: 89%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

You

Cohen

Pustovalova

et al. 2022

Toxicological Sciences

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“…In vivo treatment with miR-30b agomir, following the results of the in vitro study, demonstrated that miR-30b agomir promoted axon growth by regulating the Sema3A/PlexinA1-NRP-1/RhoA pathway/ROCK. This also improved sensory conductive function after spinal cord dorsal column lesion [ 122 ].…”

Section: Mirnas For Neuronal Regeneration In Scimentioning

confidence: 99%

MiRNAs as Promising Translational Strategies for Neuronal Repair and Regeneration in Spinal Cord Injury

Silvestro

Mazzon

2022

Cells

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Spinal cord injury (SCI) represents a devastating injury to the central nervous system (CNS) that is responsible for impaired mobility and sensory function in SCI patients. The hallmarks of SCI include neuroinflammation, axonal degeneration, neuronal loss, and reactive gliosis. Current strategies, including stem cell transplantation, have not led to successful clinical therapy. MiRNAs are crucial for the differentiation of neural cell types during CNS development, as well as for pathological processes after neural injury including SCI. This makes them ideal candidates for therapy in this condition. Indeed, several studies have demonstrated the involvement of miRNAs that are expressed differently in CNS injury. In this context, the purpose of the review is to provide an overview of the pre-clinical evidence evaluating the use of miRNA therapy in SCI. Specifically, we have focused our attention on miRNAs that are widely associated with neuronal and axon regeneration. “MiRNA replacement therapy” aims to transfer miRNAs to diseased cells and improve targeting efficacy in the cells, and this new therapeutic tool could provide a promising technique to promote SCI repair and reduce functional deficits.

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“…Sema3A binds to the receptor complex containing PlexinA1 and Neuropilin-1 (NRP-1) and modulates the Rho/ROCK pathway [ 119 ]. Wang et al investigated whether miR-30b, which targets sema3A to promote retinal ganglion cell neurite growth [ 120 ], could exert primary sensory neuron neurite outgrowth after SCI [ 121 ]. They found that the up-regulation of miR-30b inhibited sema3A expression and RhoA/ROCK activity through the PlexinA1/NRP-1 co-receptor, promoting primary sensory neuron neurite outgrowth and spinal cord sensory conductive function recovery ( Table 2 and Figure 3 ).…”

Section: Rho/rock Pathway and Mirnas For Apoptosis/axon Regeneration In Scimentioning

confidence: 99%

Rho/ROCK Pathway and Noncoding RNAs: Implications in Ischemic Stroke and Spinal Cord Injury

Kimura

Horikoshi

Kuriyagawa

et al. 2021

IJMS

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Ischemic strokes (IS) and spinal cord injuries (SCI) are major causes of disability. RhoA is a small GTPase protein that activates a downstream effector, ROCK. The up-regulation of the RhoA/ROCK pathway contributes to neuronal apoptosis, neuroinflammation, blood-brain barrier dysfunction, astrogliosis, and axon growth inhibition in IS and SCI. Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), were previously considered to be non-functional. However, they have attracted much attention because they play an essential role in regulating gene expression in physiological and pathological conditions. There is growing evidence that ROCK inhibitors, such as fasudil and VX-210, can reduce injury in IS and SCI in animal models and clinical trials. Recently, it has been reported that miRNAs are decreased in IS and SCI, while lncRNAs are increased. Inhibiting the Rho/ROCK pathway with miRNAs alleviates apoptosis, neuroinflammation, oxidative stress, and axon growth inhibition in IS and SCI. Further studies are required to explore the significance of ncRNAs in IS and SCI and to establish new strategies for preventing and treating these devastating diseases.

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miR‐30b Promotes spinal cord sensory function recovery via the Sema3A/NRP‐1/PlexinA1/RhoA/ROCK Pathway

Abstract: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 14 publications

References 47 publications

Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

Profiling Secreted miRNA Biomarkers of Chemical-Induced Neurodegeneration in Human iPSC-Derived Neurons

MiRNAs as Promising Translational Strategies for Neuronal Repair and Regeneration in Spinal Cord Injury

Rho/ROCK Pathway and Noncoding RNAs: Implications in Ischemic Stroke and Spinal Cord Injury

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