MicroRNA Biomarkers in Cerebrospinal Fluid and Serum Reflect Injury Severity in Human Acute Traumatic Spinal Cord Injury

Tigchelaar, Seth; Gupta, Rishab; Shannon, Casey P.; Streijger, Femke; Sinha, Sunita; Flibotte, Stéphane; Rizzuto, Michael A.; Street, John; Paquette, Scott; Ailon, Tamir; Charest-Morin, Raphaële; Dea, Nicolas; Fisher, Charles G.; Dvorak, Marcel F.; Dhall, Sanjay S.; Mac-Thiong, Jean-Marc; Parent, Stefan; Bailey, Chris; Christie, Sean; Keuren‐Jensen, Kendall Van; Nislow, Corey; Kwon, Brian K.

doi:10.1089/neu.2018.6256

Cited by 51 publications

(41 citation statements)

References 61 publications

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“…In addition, the filtered known miRNAs were compared with recently reported miRNAs which can be used as biomarkers after SCI. 16,17,48 As shown in Figure 4, our novel results intersected with the reported results in 13 of the up-regulated (A) and 9 of the down-regulated miRNAs (B). Further comparing these miRNAs with the miRNAs in Table 3, we found that rno-miR-152-3p, rno-miR-130a-3p, and rno-miR-125b-5p belong to the top 10 up-regulated or down-regulated miRNAs.…”

Section: Resultssupporting

confidence: 89%

“…In human, miRNAs in cerebrospinal fluid and serum could also reflect injury severity in acute traumatic SCI. 17 However, up to now, there is no uniform standard for clinical evaluation of SCI based on “free circulation” miRNA spectrum. The reason may be that miRNA analysis from biological fluids is influenced by many pre-analysis variables, such as sample collection and processing methods, stability, and differences in serum and plasma coagulation processes.…”

Section: Introductionmentioning

confidence: 99%

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Identification of serum exosomal microRNAs in acute spinal cord injured rats

Ding

Chen

Wang

et al. 2019

Exp Biol Med (Maywood)

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It is important to find specific and easily detectable diagnostic markers in acute stage of spinal cord injury for guiding treatment and estimating prognosis. Although, microRNAs are attractive biomarkers, there is still no uniform standard for clinical evaluation of spinal cord injury based on “free circulation” miRNA spectrum. The reason may be that miRNA analysis from biological fluids is influenced by many pre-analysis variables. Exosome miRNAs are widely distributed in body fluids and have many advantages comparing with free miRNAs. The specific miRNAs in the central nervous system can be transported to the peripheral circulation and concentrated in exosomes. Therefore, we hypothesized that there might be some physiological changes associated with spinal cord injury in serum exosomal miRNAs. Using next-generation sequencing, miRNA profiles in serum exosomes of sham and acute spinal cord injury rats were analyzed, and integrative bioinformatics were used to analyze the function and regulation of putative target genes. The results showed that acute spinal cord injury can lead to changes in miRNA expression in the circulating exosomes. The changed miRNAs and their associated pathways may explain the pathology of acute spinal cord injury. More importantly, we determined serum exosomal miR-125b-5p, miR-152-3p, and miR-130a-3p are specific and easily detectable diagnostic markers in acute spinal cord injury. More interestingly, we also found some valuable known and novel miRNAs. Further bioinformatics analysis and functional research will be of great help to make clear their role in the pathological process of spinal cord injury and judging whether they can be used as diagnostic markers. Impact statement This research hypothesized that there might be some physiological changes associated with SCI in serum exosomal miRNAs. Using next-generation sequencing, miRNA profiles in serum exosomes of sham and acute SCI rats were analyzed, and integrative bioinformatics were used to analyze the function and regulation of putative target genes. The results showed that acute SCI can lead to changes in miRNA expression in the circulating exosomes. The changed miRNAs and their associated pathways may explain the pathology of acute SCI. More importantly, we determined serum exosomal miR-125b-5p, miR-152-3p, and miR-130a-3p are specific and easily detectable diagnostic markers in acute SCI.

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Section: Resultssupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Identification of serum exosomal microRNAs in acute spinal cord injured rats

Ding

Chen

Wang

et al. 2019

Exp Biol Med (Maywood)

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“…6 Based on these papers, we can conclude that the use of biomarkers on blood and cerebrospinal fluid (CSF) to predict neurological injury and severity remains on translational research since a specific array of biomarkers needs to be designed and tested before widespread clinical use. [7][8][9][10][11] Since the initial review on assessment tools for acute SCI was presented by Hadley et al 12 in 2002, the ASIA Impairment Scale (AIS, short form for ASIA International Standards for Neurological Classification of Spinal Cord Injury [ISNCSCI]) has been designated as the recommended evaluation tool to evaluate and classify initial neurological impairment on admission and provide information on improvement at follow-up. The AIS comprises 5 grades of neurological injury: grade A, complete neurological injury (no motor or sensory function at S4, S5 segment); grade B, no motor function but preserved sensory function below the neurological injury with preservation including S3 and S4; grade C, incomplete neurological injury (with the preserved motor function below the neurological levhttps://doi.org/10.14245/ns.2040366.183…”

Section: Clinical Assessment and Classification Of Scimentioning

confidence: 99%

Early Management of Spinal Cord Injury: WFNS Spine Committee Recommendations

et al. 2020

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“…The microRNAs (miRs) are small, non‐coding RNA molecules shown to play vital roles in the regulation of neurological disorders, including spinal cord injury due to their stability role in biological fluids, tissue specificity, as well as the protection effect between animal models and humans (Tigchelaar et al., 2019). It has been demonstrated that miRs including miR‐30c, miR‐372, and miR‐497 exert function on spinal cord I/R injury (Li, Liang, et al, 2018; Li, Lou, et al, 2018; Li, Yu, Tan, Zhang, & Ma, 2018; Wang et al., 2019; Xu, Wang, Zhang, & Zhuang, 2016).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐22‐3p alleviates spinal cord ischemia/reperfusion injury by modulating M2 macrophage polarization via IRF5

Fang

Yang

Pan

et al. 2020

Journal of Neurochemistry

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Cell death after spinal cord ischemia/reperfusion (I/R) can occur through necrosis, apoptosis, and autophagy, resulting in changes to the immune environment. However, the molecular mechanism of this immune regulation is not clear. Accumulating evidence indicates that microRNAs (miRs) play a crucial role in the pathogenesis of spinal cord I/R injury. Here, we hypothesized miR‐22‐3p may be involved in spinal cord I/R injury by interacting with interferon regulatory factor (IRF) 5. Rat models of spinal cord I/R injury were established by 12‐min occlusion of the aortic arch followed by 48‐hr reperfusion, with L4‐6 segments of spinal cord tissues collected. MiR‐22‐3p agomir, a lentivirus‐delivered siRNA specific for IRF5, or a lentivirus expressing wild‐type IRF5 was injected intrathecally to rats with I/R injury to evaluate the effects of miR‐22‐3p and IRF5 on hindlimb motor function. Macrophages isolated from rats were treated with miR‐22‐3p mimic or siRNA specific for IRF5 to evaluate their effects on macrophage polarization. The levels of IL‐1β and TNF‐α in spinal cord tissues were detected by ELISA. miR‐22‐3p was down‐regulated, whereas IRF5 was up‐regulated in rat spinal cord tissues following I/R. IRF5 was a target gene of miR‐22‐3p and could be negatively regulated by miR‐22‐3p. Silencing IRF5 or over‐expressing miR‐22‐3p relieved inflammation, elevated Tarlov score, and reduced the degree of severity of spinal cord I/R injury. Increased miR‐22‐3p facilitated M2 polarization of macrophages and inhibited inflammation in tissues by inhibiting IRF5, thereby attenuating spinal cord I/R injury. Taken together, these results demonstrate that increased miR‐22‐3p can inhibit the progression of spinal cord I/R injury by repressing IRF5 in macrophages, highlighting the discovery of a promising new target for spinal cord I/R injury treatment.

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MicroRNA Biomarkers in Cerebrospinal Fluid and Serum Reflect Injury Severity in Human Acute Traumatic Spinal Cord Injury

Cited by 51 publications

References 61 publications

Identification of serum exosomal microRNAs in acute spinal cord injured rats

Identification of serum exosomal microRNAs in acute spinal cord injured rats

Early Management of Spinal Cord Injury: WFNS Spine Committee Recommendations

MicroRNA‐22‐3p alleviates spinal cord ischemia/reperfusion injury by modulating M2 macrophage polarization via IRF5

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