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Acta Neurologica Belgica

, Volume 119, Issue 1, pp 21–27 | Cite as

MicroRNAs in contusion spinal cord injury: pathophysiology and clinical utility

  • Fang Li
  • Mou-Wang ZhouEmail author
Review article

Abstract

Spinal cord injury (SCI) in humans is a common central nervous system trauma. Pathophysiologically, SCI involves both primary and secondary damages. Therapeutically, targeting secondary damage including inflammation, neuropathic pain, apoptosis, demyelination, and glial reaction to promote functional benefits for SCI patients has long been considered a potential treatment strategy by neuroscientists and clinicians. As a type of small non-coding RNA, microRNAs (miRNAs) have been shown to play essential roles in the regulation of pathophysiologic processes of SCI and are considered to be an effective treatment method for SCI. Dysregulated expression of miRNAs is observed in SCI patients and animal models of SCI. Furthermore, miRNAs might also be used as biomarkers for diagnostic and prognostic purposes in SCI. Given contusion injury is the most clinically relevant type of SCI, this review mainly focuses on the role of miRNAs in the pathophysiology of contusion SCI and the putative utilization of miRNAs as diagnostic biomarkers and therapeutic targets for contusion SCI.

Keywords

MicroRNAs Spinal cord injury Review 

Introduction

Spinal cord injury (SCI), prevalent in young patients, is a common central nervous system (CNS) trauma with a high incidence, a high disability rate and a high mortality [1]. As estimated, there were approximately 2.5 million patients worldwide, and more than 130,000 patients being newly found annually [2]. To date, there is no effective treatment method for SCI, and although many therapies have been explored clinically, the efficacy of them is limited [3]. Therefore, it is necessary for neuroscientists and clinicians to explore new ways to treat SCI. At present, multiple studies indicate that many microRNAs (miRNAs) participate in pathophysiologic processes of SCI, with roles described in inflammatory, apoptosis, demyelination and so on [3, 4, 5]. MiRNAs are small non-coding RNAs, which mainly participate in regulating gene expression after transcription [6]. Recent reports show that expression of approximately 20–30% of human protein-coding genes is regulated by miRNAs [7]. These characteristics imply that miRNAs may be potential therapeutic targets for SCI. Given the fact that contusion injury is the most common type of SCI in clinical practice, we will mainly summarize the latest research advances of miRNAs in contusive spinal cord injury in this review.

MiRNAs in spinal cord

To better understand the changes in expression levels and the corresponding regulatory functions of miRNAs after contusion SCI, it is necessary to clarify how miRNAs work in normal spinal cord. Indeed, miRNAs are highly expressed in the mammalian CNS, including the spinal cord [8]. Previous reports suggest that approximately 77% of identified mature miRNAs are expressed in the adult rat spinal cord, and a large number of miRNAs are also found in the spinal cord of adult mouse [9, 10]. Furthermore, experimental data indicate that some miRNAs are specific to a given cell type [8]. For example, miR-124 and miR-128 are preferentially expressed in neurons, miR-23 is restricted to express in astrocytes, and miR-219 is specialized for oligodendrocytes [11, 12]. Moreover, miRNAs play important roles in every aspect of spinal cord function, involving in neural development, neurogenesis, glial differentiation and so on. For instance, experimental overexpression or inhibition of miR-219 has demonstrated its essential role in oligodendrocyte differentiation, whereas overexpression of miR-381 promotes cell proliferation of neurocytes via suppressed Hes1 expression [13, 14]. In addition to their role in the normal spinal cord, a great number of evidences indicate that miRNAs dysregulation is implicated in contusion SCI [15].

MiRNAs and contusion SCI

Altered miRNA profiles in contusion SCI

MiRNAs are attractive candidates as upstream regulators of SCI pathological progression due to miRNAs can regulate gene expression at the post-transcriptional level [16]. Recently, several publications described a large number of miRNAs were significantly dysregulated after contusion SCI [9, 17, 18, 19]. Liu et al. [9] published the first report on miRNA expression analysis after contusion SCI in rats. They examined miRNAs level at 4 h, and 1 and 7 days after injury by a microarray analysis and qRT-PCR. They detected 60 altered miRNAs and these miRNAs can be classified into three categories: 30 were increased, 16 were decreased, and 14 were increased at 4 h and then subsequently decreased at 1 and 7 days after contusion SCI. Another study by Strickland et al. [19] extended the time point of analysis to 14 days after contusion SCI in rats, the results showed that 36 miRNAs were obviously changed at 4 and 14 days post-injury. Among these, 4 were upregulated and 32 were downregulated. Similar results were observed in another report on contusion SCI in rats, 59 miRNAs were aberrant after injury, most of them downregulated at 7 days post-injury [18]. Interestingly, as the damage response progressed, the number of miRNAs that was downregulated gradually increased, whereas the number of upregulated miRNAs remained constant [18]. Furthermore, a contusion SCI in rats was induced in another recent study, microarray analysis revealed that nine miRNAs were upregulated and five miRNAs were downregulated at 1 day following injury, and three miRNAs were increased and five miRNAs were decreased at 3 days post-injury [17]. In addition, one publication using contusion SCI in mice identified ten altered miRNAs (five upregulated and five downregulated) after injury by miRNA-based array screening [20]. Specially, Li et al. investigated the levels of miR-21 in the serum of patients with contusion SCI. They found that the serum level of miR-21 immediately increased and peaked on day 7 post-SCI and then declined to the control level [21]. Besides, several studies reveal that the potential targets for these changed miRNAs by bioinformatics analysis include genes related to inflammation, oxidative stress, and apoptosis that are known to base the pathogenesis of contusion SCI [9, 18].

These data suggest that dysregulated miRNAs may contribute to the pathogenesis of contusion SCI and may be a novel class of therapeutic targets for treatment of contusion SCI. At present, although there have been no detailed and complete reports of abnormal expression profile analysis of miRNAs in contusion SCI patients, the above data from animal models of contusion SCI can largely reflect the conditions of SCI patients.

Inflammation and oxidative stress-linked miRNAs in contusion SCI

Inflammatory and oxidative stress participate in the pathophysiology of contusion SCI in humans and are also observed in animal models [18]. Biochemical disturbances accompany vascular and cellular alterations that are caused by contusion SCI which will initiate the inflammatory response and oxidative stress [22]. For contusion SCI, inflammation and oxidative stress caused deleterious effects, such as tissue further damage and excessive cell death [15]. More and more evidence suggests that miRNAs participate in inflammatory and oxidative stress following contusion SCI. Several studies have reported that miRNAs are involved in inflammation and oxidative stress after contusion SCI via targeting mRNAs of mediators linked to inflammatory response and oxidative stress [23, 24]. For example, miR-181a, miR-411, miR-99a, miR-486, and miR-384-5p, which are downregulated post-contusion SCI, target intercellular adhesion molecule 1 (ICAM-1), interleukin-\(1\upbeta\) (IL-\(1\upbeta\)) and tumor necrosis factor-\(\upalpha\) (TNF-\(\upalpha\)) [9, 25]. By contrast, miR-146a and miR-206, which target TNF receptor-associated factor 6 (TRAF6) and superoxide dismutase 1 (SOD-1), are upregulated after contusion SCI [9, 22].

A previous study using a contusion SCI model in mice found that miR-137 promoted the recovery of contusion SCI by degrading NEUROD4 to relieve the inflammation response and the progression of oxidative stress, thus promoting the recovery of contusion SCI [26]. Another study using serum samples from patients with contusion SCI analyzed the role of miR-137 on inflammatory response after injury. It found that miR-137 inhibited inflammatory response after contusion SCI via targeting of mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MK2). MK2 is a novel molecular target for anti-inflammatory molecule. The expression and activated level of MK2 is related to the pathology and processes of thousands of inflammatory diseases including SCI. In this study, researchers found that an elevated MK2 but a decreased miR-137 was expressed in serum specimens of patients with contusion SCI. Furthermore, they verified that MK2 was a direct target of miR-137 thorough a luciferase reporter assay. Even further, they elucidated that miR-137 could suppress the inflammatory response via negative regulation of MK2. Finally, through an animal model trial performed using mice, they demonstrated the protective effect of how miR-137 works on inflammatory response post-injury. All these findings revealed that miR-137 inhibited inflammatory response after contusion SCI via the targeting of MK2 [27]. The outcomes may provide a new target for treatment of contusion SCI .

Fu et al. found that miR-30a-5p was notably downregulated after contusion SCI in mice. Overexpression of miR-30a-5p significantly suppressed inflammatory responses as reflected by a decrease in the secretion of the cytokines TNF-\(\upalpha\), IL-1\(\upbeta\) and IL-10 triggered by SCI. Furthermore, introduction of miR-30a-5p strengthened the scavenging of oxygen free radicals accompanied by an increase in the expression of selenoprotein type N1(SEPN1), thioredoxin-like 1 (TXNL1) and glutathione peroxidase 1 (GPX1). More importantly, this study validated that Neurod 1 was a direct and functional target of miR-30a-5p by the dual luciferase reporter assay [4]. These findings indicate that miR-30a-5p ameliorates inflammatory responses and oxidative stress by targeting Neurod 1 and may be a treatment target for contusion SCI.

MiR-146a has been widely studied in the inflammatory response. High level of miR-146a was observed in animal models of contusion SCI [22, 23]. One study found that miR-146a upregulation after contusion SCI may be driven by pro-inflammatory cytokines, which in turn negatively regulate the pro-inflammatory cytokines by downregulating the expression of TRAF6 and IRAK1 [22]. But at present, publications about miR-146a in CNS are mostly focused on brain-related diseases, rarely in contusion SCI [28]. Thus, to better illustrate miR-146a may serve as a novel therapeutic target for SCI interventions, researchers need to do more in-depth research.

MiRNAs and astrogliosis in contusion SCI

Astrogliosis is an important hallmark of the cellular response to contusion SCI. It involves an early hypertrophy that is beneficial and the subsequent hyperplasia characterized by the formation of a dense glial scar that creates barriers to regeneration after contusion SCI [8, 29]. Increasing evidence supports that the process of astrogliosis is associated with miRNAs, which play a pivotal role in the shift from hypertrophy to hyperplasia [15]. Currently, we have retrieved several dysregulated miRNAs that are mainly related to astrogliosis after contusion SCI, including miR-21, miR-145, miR-146a and so on.

Most studies focus on miR-21. The expression of miR-21 increases in a time-dependent manner following contusion SCI. The miR-21 is highly expressed in astrocytes during astrogliosis post-injury and its role in astrogliosis has been studied in detail [30, 31]. Overexpression of miR-21 in astrocytes can reduce the hypertrophic response to injury, and inhibition of miR-21 function in astrocytes can exacerbate the hypertrophic phenotype following contusion SCI [19, 30]. One study revealed that miR-21 participated in the transition of astrocytic hypertrophy to hyperplasia after contusion SCI, and miR-21 was considered as a potential therapeutic target for manipulating astrogliosis and enhancing functional recovery in contusion SCI [30]. Another study showed that miR-21 could modulate astrocyte size through a novel mechanism of bone morphogenetic protein (BMP) signaling by binding to BMPR1a and BMPR1b. This may be beneficial in the study of the mechanism of miR-21 regulation and the manipulation of astrogliosis and the promotion of functional recovery after contusion SCI [32]. In addition, one experiment demonstrated that miR-21a-5p was significantly upregulated in the lesion core of spinal tissues after contusion SCI. Its results identified that miR-21-5p functions in an amplifying circuit to enhance TGF-\(\upbeta\) (transforming growth factors-\(\upbeta\), central pathological mediator of fibrotic diseases, were significantly upregulated in the lesion epicenter after SCI) signaling events in the activation of spinal fibroblasts and suggested that miR-21-5p might be a potential therapeutic target in the treatment of fibrotic scar formation after contusion SCI [33].

Additional miRNA involved in astrogliosis is miR-145. MiR-145 enriched in rat spinal astrocytes was downregulated at 1 week and 1 month after contusion SCI [34]. Overexpression of miR-145 could reduce the size and cell density of astrocytes at the lesion site by targeting glial fibrillary acidic protein (GFAP) and cell growth gene, MYC(c-myc), and downregulation of miR-145 could induce reactive astrogliosis after contusion SCI [34]. The findings reveal that miR-145 in astrocytes is a critical factor regulation astrogliosis following contusion SCI. MiR-146a is another miRNA for astrogliosis. MiR-146a is not only a regulator of inflammation but also a regulator of astrogliosis. MiR-146a works with miR-21 can drive astrocyte hyperplasia. Overexpression of miR-146a following contusion SCI can limit astrocyte reactivity [8, 15]. As reported, miR-125b is also involved in astrogliosis. MiR-125b appeared downregulated during the first week after contusion SCI, which would contribute to inhibit astrocyte proliferation and astrogliosis [18]. In addition, miR-17 may play a major role in the regulation of contusion SCI-induced reactive astrocyte. The formation of glial scar resulted from contusion SCI can be reduced by inhibiting miR-17 [35, 36].

MiRNAs and apoptosis in contusion SCI

Apoptosis, also called programed cell death, is an important hall mark of contusion SCI [15]. Apoptosis can affect all cell types in spinal cord, such as neurons, oligodendrocytes, and microglial cells [24, 37]. In recent years, multiple studies have suggested that miRNAs were involved in apoptosis after contusion SCI. Several miRNAs play roles in apoptosis via inhibition of the expression of pro-apoptotic and anti-apoptotic proteins [38, 39].

Among these miRNAs involved in apoptosis, miR-21 is one of the most dysregulated miRNAs after contusion SCI [24]. Suppression of miR-21 is demonstrated to cause apoptosis. MiR-21 reduced apoptosis by downregulating the Fas ligand gene, FASLG, and the phosphatase and tensin homolog gene, PTEN, both of which trigger apoptosis [17]. Like miR-21, miR-9 was significantly downregulated at the lesion site between days 1 and 7 after contusion SCI. It modulates apoptosis via directly regulating the monocyte chemotactic protein-induced protein 1 gene, MCPIP1, which is a known pro-apoptotic and macrophage-activating gene [40]. One study has shown that miR-223 is significantly increased at 1, 3, 7, and 14 days after contusion SCI. Antagomir-223 treatment post-injury resulted in obviously lowered apoptotic cells [41]. Liu et al. indicate that altered expression of miR-20a and miR-29b may cooperatively contribute to the neuronal apoptosis of contusion SCI through downregulating anti-apoptotic myeloid cell leukemia sequence-1 (Mcl-1) and upregulating pro-apoptotic BH3-only proteins [42]. Another recent study revealed the positive regulation functions of miR-137 in contusion SCI-induced apoptosis by downregulating calpain 2 and might provide an opportunity for development of novel therapies of contusion SCI [43].

MiRNAs and neuropathic pain in contusion SCI

Neuropathic pain is one of the common complications after contusion SCI, affecting up to 80% SCI patients [44, 45]. Emerging evidence has suggested that miRNAs play a significant role in regulating neuropathic pain following contusion SCI [15]. In 2018, Wang et al. discover potential genes and miRNAs related to SCI patients with neuropathic pain by bioinformatics method. They identified four targeted miRNAs, including miR-204-5p, miR-519d-3p, miR-20b-5p, and miR-6838-5p, which may be linked to neuropathic pain for SCI patients. At the same time, they suggest that these miRNAs may be potential biomarkers for the prediction of and potential targets for prevention and treatment of neuropathic pain after contusion SCI, but further studies are necessary for verifying the clinical applications of these findings [46]. Favereaux et al. identified that the intrathecal injection of miR-103 could significantly relieve neuropathic pain, and implied that miR-103 might be established as a strong candidate for the treatment of neuropathic pain after contusion SCI [47]. Similarly, intrathecal administration of miR-124 also prevents neuropathic pain following contusion SCI [48]. Many other miRNAs have been described to affect neuropathic pain after contusion SCI, for example, miR-103 and miR-195, which might modulate neuropathic pain at the lesion site following contusion SCI [15].

Although information on the roles of miRNAs in neuropathic pain after contusion SCI is very restricted, the preliminary data indicate that a promising role for the use of miRNAs as therapeutic agents for neuropathic pain relief after contusion SCI [8, 15, 49]. Furthermore, ongoing studies are required to further clarify miRNAs related to neuropathic pain caused by SCI.

MiRNAs and demyelination in contusion SCI

Demyelination is widespread after contusion SCI, and could be an important contributor to the loss of function due to secondary axonal loss [50]. Although there is spontaneous remyelination after contusion SCI, it is insufficient [29]. Moreover, many of the causes of demyelination following contusion SCI are unclear [50]. MiRNAs have been described to participate in the process of demyelination post injury [51].

Liu et al. shows that miR-219 might promote oligodendrocyte differentiation and attenuate demyelination in a cuprizone (CPZ)-induced demyelinated model by regulating the expression of monocarboxylate transporter 1 [51]. Wang et al. using in vivo targeted loss and gain of function studies demonstrate that deletion of miR-219 in mice leads to demyelination in the developing CNS and miR-219 is both necessary and sufficient for remyelination after demyelination [13]. However, at present, there is a lack of research about miR-219 in demyelination after contusion SCI. If miR-219 can be identified to play an important role in the injuried spinal cord, a potential therapy for remyelination may be found in upregulating its expression after contusion SCI [15].

Another miRNA, miR-210, has been implicated to involve in demyelination after contusion SCI. MiR-210 can inhibit the protein tyrosine phosphatase, non-receptor type 1 gene, PTPN1, and the ephrin-A3 gene, EFNA3, which have been shown to provide benefit for remyelination [52]. In addition to miR-210, miR-9 has been shown to play a role in demyelination after contusion SCI. Xu et al. reveal that reduction of miR-9 is needed at the acute stage of contusion SCI to allow for adequate axon regeneration and remyelination [40]. Further studies are needed to determine the contribution of miRNAs in demyelination and to evaluate their use as therapeutic tools in the contusion SCI.

MiRNA-controlled pathways in contusion SCI

One miRNA can have different targets, regulating single gene in several pathways or several genes in a single pathway [53]. The dysregulation of miRNAs probably affects a wide variety of molecular and cellular pathways in contusion SCI, including inflammation, oxidative stress, apoptosis, demyelination, glial scar formation and so on [29].

Several studies have reported in vivo research of miRNAs and their target pathways after contusion SCI. One study showed that miR-21 could regulate astrocyte size through a novel mechanism of bone morphogenetic protein (BMP) signaling by binding to BMPR1a and BMPR1b. This may be beneficial in the study of the mechanism of miR-21 regulation and the manipulation of gliosis and the promotion of functional recovery after contusion SCI [15]. Dai et al. revealed that miR-125b was downregulated in injured spinal cord, and overexpression of miR-125b promoted the repair and regeneration following contusion SCI through the regulation of the JAK/STAT pathway [54]. In addition, Zhu et al. demonstrated that overexpression of miR-494 activated AKT/mTOR signaling pathway via inhibiting PTEN expression in rat contusion SCI model. Their findings suggested that miR-494 harbored the protective effect after SCI by modulating PTEN/AKT/mTOR pathway in rats and it is a potential candidate for SCI therapeutics [3]. Interestingly, another study exhibited that miR-17 was able to target PTEN and stimulate the PI3K/Akt/mTOR pathway. The formation of glial scar that resulted from contusion SCI can be reduced either by inhibiting miR-17 or by overexpressing PTEN [36]. Besides, one study indicated that miR-199b attenuated contusion SCI at least partly through \(\hbox {IKK}\beta\)–NF–\(\upkappa \hbox {B}\) signaling pathway and affecting the function of microglia. The findings suggest that miR-199b may be employed as therapeutic for contusion SCI [55].

MiRNAs as potential biomarkers of contusion SCI

Evidence has emerged that miRNAs in biofluids (CSF and blood) might be a very good candidate to be biomarker of contusion SCI because they are very stable in fluids, are tissue specific, and have phylogenetic relationship [56]. There are already some reports using miRNA as biomarkers in some pathologies, such as Alzheimer, epilepsy, brain injury, and many others [57, 58]. Therefore, they have attracted huge attention because of their pivotal role in human disease, and have been suggested as promising new therapeutic targets.

MiRNAs may serve as biomarkers when their expression changes [23]. For instance, in a recent study on mouse contusion SCI models with the different contusive compressing power worked on spinal cord, the expression levels of miR-9*, miR-219 and miR-384-5p in the serum were significantly upregulated relative to the severity of contusion SCI within 12 h after injury [59]. These miRNAs may be hopeful candidates as biomarkers to evaluate the severity of contusion SCI before a neurological exam. Another study provides a comprehensive description of the changes that occur across miRNAs during the early post-injury phase of acute SCI. The miRNAs detected in porcine serum increased globally in an injury severity-dependent manner and provides promising targets for markers of injury severity in contusion SCI [60]. In addition, one study exhibited that the serum levels of miR-21 at different time points have different changes after contusion SCI and serum miR-21 levels have significantly correlated with degree of injury in contusion SCI patients [21]. These findings might provide reference for diagnosis and treatment, and contribute to the identification of selective and temporal drug-targeted therapy after contusion SCI. However, further studies should be done in clinical trials to provide credible evidence.

Prospects for a miRNA-based treatment for contusion SCI

Effective therapy for contusion SCI patients is lacking. In recent years, the discovery of drastically altered miRNA expression after contusion SCI offers opportunities for potential therapeutic interventions [61]. There are already some studies that demonstrated the promising use of some miRNAs after contusion SCI. Theoretic principles of miRNAs treatment for contusion SCI could be either to overexpress “good” miRNAs, or to reduce “bad” miRNAs [23]. Lin et al. demonstrated that miR-409 was downregulated after contusion SCI and overexpression of miR-409 could promote the recovery of contusion SCI [62]. Jee et al. exhibited that reduction of miR-20a expression effectively induced definitive motor neuron survival and neurogenesis, and contusion SCI animals showed improved functional deficit [63].

Although the possibility of using miRNAs as therapeutic reagents has drawn high attention after contusion SCI, the limited use of miRNAs as a therapeutic tool is the identification of a signature of miRNAs during pathology, their mechanism of action, delivery of miRNAs, and their active form in vivo [56]. In addition, in 2018, Kleaveland et al. described that several types of non-coding RNAs (ncRNAs), such as miR-7 and miR-671, can collaborate to establish a sophisticated regulatory network to regulate brain function in mice [64]. Although similar research has not been seen in contusion SCI, it reminds us that future ideal therapy based on miRNAs should focus on the regulatory network of ncRNAs. Once all the above information is available, miRNAs could have a brilliant future and have the potential to be novel therapeutic reagents for contusion SCI patients.

Conclusions

In this review, we discuss the role of miRNAs in the pathophysiology and clinical potential applications of contusion SCI. However, miRNAs function and their relationships with contusion SCI remain to be fully elucidated, and some problems remain to be solved. Recent studies have considerably expanded the number of miRNAs with potential roles in contusion SCI, and improved our understanding of their targets. A crucial test for clinical translation will be the proof of whether a miRNA-based treatment can improve outcomes of contusion SCI. Due to most existing studies on the role of miRNAs in contusion SCI are conducted on animals, these data cannot be easily applied to humans. Therefore, more research is mandated in humans, as we believe that miRNAs may provide new hope for better treatment of patients with contusion SCIs in the future. Further study of miRNAs will improve our understanding pathophysiological mechanisms of contusion SCI and lead to new diagnostic and treatment methods.

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant number 81261120563).

Author contributions

FL conceived the content and wrote the critical review. MZ provided the ideas and supervised the work. Both authors read and approved the final version of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This review does not require ethical approval at our institution.

Informed consent

This review does not have information that could identify the subject. According to the rules of Acta Neurologica Belgian, informed consent is not required.

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Copyright information

© Belgian Neurological Society 2019

Authors and Affiliations

  1. 1.Department of Rehabilitation MedicinePeking University Third HospitalBeijingPeople’s Republic of China

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