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miR-210 in ischaemic stroke: biomarker potential, challenges and future perspectives

European Journal of Medical Research volume 29, Article number: 432 (2024) Cite this article

Abstract

Ischaemic stroke, a leading cause of global morbidity and mortality, necessitates effective biomarkers for enhanced diagnostic and prognostic stratification. MicroRNAs (miRNAs), particularly miR-210, have emerged as promising candidates due to their intricate regulatory roles in cellular responses to hypoxia and neuroprotective effects. This study explores the potential of miR-210 as a biomarker for ischaemic stroke, considering its expression patterns, regulatory functions and diagnostic/prognostic implications. A literature search was conducted on PubMed, Scopus, Google Scholar and Web of Science to identify studies focusing on miR-210 in ischaemic stroke. Inclusion criteria comprised reports on miR-210 expression in ischaemic stroke patients, excluding non-English studies, reviews, commentaries and conference abstracts lacking primary data. Studies investigating miR-210 levels in ischaemic stroke patients revealed significant alterations in expression patterns compared to healthy controls. Diagnostic potential was explored, indicating miR-210’s sensitivity and specificity in distinguishing ischaemic stroke from other neurological conditions. Prognostic value was evident through associations with infarct size, functional outcomes and long-term survival. Challenges included variability in miR-210 levels, limited diagnostic specificity, absence of standardised assays and concerns regarding cost-effectiveness and accessibility. While miR-210 holds promise as an ischaemic stroke biomarker, challenges must be addressed for its successful integration into clinical practice. Standardised reference ranges, validation studies in diverse populations and collaborative efforts for assay standardisation are crucial. Despite challenges, miR-210’s diagnostic and prognostic potential, particularly in predicting therapeutic responses, suggests a significant role in advancing ischaemic stroke management.

Background

Every year, 15 million people worldwide experience a stroke. Of these, 5 million people die from strokes, and another 5 million sustain lasting disabilities [1]. Studies have shown that ischaemic stroke is responsible for 80% of all strokes, while 15% of all strokes are accounted for by haemorrhagic stroke, and the other 5% are due to unknown aetiology [1, 2]. Ischaemic stroke is often due to decreased cerebral blood flow [3]. Because neurons are deprived of oxygen and energy during an ischaemic stroke, their regular metabolic substrates cease to function in seconds and show evidence of structural damage in as little as 2 min [3]. Following ischaemia, energy-dependent systems within the cell malfunction and neurons cannot maintain their regular transmembrane ionic gradient [2]. This leads to an imbalance between ions and water, which in turn causes necrotic cell death and apoptosis [1, 2].

In recent years, hundreds of genes have been linked to the pathogenesis of stroke, but only a small number have been proven to have a complete impact on the disease’s susceptibility [4]. Furthermore, many studies have been done on the impact of microRNAs (miRNAs) on stroke because earlier studies showed that the expression of miRNAs was associated with the prognosis of this condition [4, 5]. MiRNAs are a novel family of short, single-stranded, non-protein coding regulatory RNA molecules, including ~ 20–24 nucleotides highly conserved through evolution [2, 5, 6]. They control gene expression by recognising binding sites in the 3′ untranslated region (3′ UTR) of mRNA targets to post-transcriptionally control biological processes [5, 6]. It has been shown that at least one conserved miRNA-binding site is found in more than 60% of human protein-coding genes, and most protein-coding genes are partially controlled by miRNAs, with potentially profound biological implications [5].

miRNAs have been implicated in the control of various diseases and normal physiological cellular processes, such as differentiation, neuronal development, proliferation, synaptic plasticity, hematopoiesis, metabolism, apoptosis, immune function, migration and post-stroke immune depression, neurodegenerative diseases and tumorigenesis in association with ischaemic stroke [6, 7]. MiRNAs play a very significant role in diverse biological and pathological processes in several neurological disorders, and due to their function in regulating gene expression, they offer promise as potential disease biomarkers and therapeutic targets for ischaemic stroke [8,9,10].

miRNA-210 belongs to a group of miRNAs known as hypoxiamiRs, which are upregulated by the state of hypoxia in cells and tissues [11,12,13,14]. miRNA-210 is the master hypoxia-induced miRNA and one of the most predominant hypoxiamiRs activated by hypoxia-inducible factor 1 (HIF-1alpha) [13]. Interestingly, it is involved in both acute and chronic ischaemia and, therefore, has been proposed as a potential novel regulatory biomarker for ischaemic stroke [13]. It is also noteworthy that, during the process of the occurrence, development and nerve repair in ischaemic stroke, miR-210 participates in various cellular processes such as regulation of cell proliferation and cell cycle, inhibition of apoptosis by downregulating the expression of Caspase 8 to improve the survival of stem cells, induction of angiogenesis, promotion of nerve regeneration via the inhibition of neuronal apoptosis, promotion of glycolysis, as well as inhibition of mitochondrial metabolism [15,16,17]. This review explores the roles of miR-210 as a biomarker in ischaemic stroke.

Methodology

To explore the roles of miR-210 as a biomarker in ischaemic stroke, a search of PubMed, Scopus, Google Scholar and Web of Science was conducted to gather studies focused on miR-210’s expression patterns, regulatory functions and potential implications in ischaemic stroke. The search strategy employed a range of keywords such as “miR-210”, “ischemic stroke”, “miR-210 expression”, “regulatory functions” and related terms (see Table 1).

Table 1 Methodology
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Included studies reported on miR-210 expression levels in the context of ischaemic stroke. No time limits were put on the literature search. Studies published in languages other than English were excluded. Reviews, commentaries and conference abstracts without primary data were excluded to focus on original studies.

In synthesising the findings, a narrative approach was adopted to identify common themes and patterns across the selected studies. The goal was to establish connections between miR-210 expression, its regulatory functions, and the potential implications of ischaemic stroke. This narrative synthesis provided a cohesive overview of the collected evidence.

miR-210: biogenesis and response to hypoxic conditions

miR-210 belongs to a family called the micro-RNAs (mi-RNA), which in turn is one of several entities domiciled under a heterogenous superfamily regarded as non-coding RNAs (ncRNA) [17] (see Fig. 1). This supergroup also includes other RNA subtypes such as transfer RNA (tRNA), ribosomal RNA, small nuclear RNA, small nucleolar RNA, etc. [17]. Despite becoming a subject of much discourse in recent years, mi-RNAs had initially been a black hole of knowledge until their discovery in 1993 by Victor Ambros and his team [18]. While conducting a genetic screen to evaluate defects in the development of Caenorhabditis elegans, they found that lin-4—a gene that represses lin-14 involved in the L2 phase of larval development—generates double RNAs which are 22 and 61 nucleotides long [19]. The 22-nucleotide-long RNA discovered is now regarded as the first known member of small RNAs, otherwise called micro-RNAs, and they are known to play crucial physiological roles from cell proliferation to apoptosis [19, 20]. Today, at least 2000 miRNAs are recognised in the human genome (miRBase Release 19) [21].

Fig. 1
figure 1

Overview of miR-210 biogenesis and its response to hypoxic conditions. The biogenesis of miR-210 starts with the transcription of the pri-miRNA by RNA Polymerase II. The prior-miRNA is then processed in the nucleus by Drosha into a precursor miRNA (pre-miRNA) with a stem-loop structure. Under hypoxic conditions, Hypoxia Inducible Factor (HIF)α, primarily HIF1α, binds to hypoxia response elements in the promoter region of the miR-210 gene, leading to its increased expression. The mature miR-210 participates in various hypoxic responses, including angiogenesis, stem cell maintenance and metabolic adaptation. The structure of immature miR-210 is depicted to illustrate its processing and function

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As stated above, miRNAs contain about 19–24 nucleotides and function as post-transcriptional regulators of gene regulation through a process that utilises a base pair between an RNA-induced silencing complex (RISC) and the miRNA and 3′-UTR of the mRNA [22]. miRNAs are single-stranded and originate from endogenous hairpin-like transcripts [23]. Their biogenesis originates from a source—called the primary miRNA transcript (pri-miRNA)—which holds thousands of nucleotides and stem-loop structures [23]. RNA Polymerase II is responsible for the initial transcription of the pri-miRNA, but the follow-up step is handled by Drosha (a nuclear RNAse III-type protein) in the nucleus and involves the processing of the pri-miRNA as mentioned earlier into precursor miRNAs (pre-miRNAs) which are approximately 70 nucleotides long and contain an imperfect stem-loop structure [24]. Subsequently, the newly formed pre-miRNA is transported into the cytoplasm by the action of Exportin-5 (a RAN-GTP-based nucleus-to-cytoplasm cargo transporter) where it is split by RNAse III Dicer to form a miRNA pair, one of which is broken down or sometimes persists as a complementary strand. At the same time, the other survives as the mature miRNA that joins the earlier mentioned RISC following the recruitment of Argonaute 2 (Ago)—an essential part of RISC—by the action of the transactivating response RNA-binding protein (TRBP) [25, 26]. In essence, the fate of the miRNA duplex formed by the action of RNAse III Dicer is determined by the action of the RISC complex as it will choose the RNA strand with the least thermodynamic stability [27]. miR-210 is found within the intron of a non-coding gene on chromosome 11. While knowledge gaps remain in the biogenesis of this specific mi-RNA, its mature form seems to be formed from the AK123483 transcript, which serves as the pri-miR-210 [28].

Hypoxia is a condition of tissue oxygen deprivation that may stem from physiological or pathological conditions [29]. Hypoxia Inducible Factor (HIF) is a heterodimer of bHLH-PAS proteins that, through a transcriptional mechanism, regulates the mechanism by which cells respond to oxygen deprivation through the recruitment of genes that control cellular events including but not limited to proliferation, angiogenesis, apoptosis [15]. The heterodimer comprises a volatile HIFα subunit and a stable HIFβ (ARNT1) subunit-containing hypoxia response elements that bind to DNA [30]. The majority of the cellular response to hypoxia is controlled by the oxygen-sensitive HIFα primarily through two of its three known isoforms, namely HIF1α and HIF2α [29]. When tissues have enough oxygen, the fate of HIFα is to be degraded following its hydroxylation by prolyl-4-hydroxylases in a reaction overseen by E3 ubiquitin ligase. However, in hypoxic cellular states, diminished prolyl-4-hydroxylase allows HIFα to form a heterodimer with HIFβ, triggering a downstream cascade of hypoxia response events [30, 31].

It has been discovered that miRNAs are regulated by hypoxia, and mir-210 is the leading and most consistently hypoxia-induced miRNA [32,33,34]. The mechanism by which this occurs, as suggested by Crosby et al., stems largely from the induction of miR-210 by HIF1α binding to its hypoxic response element [35]. Hypoxia is a feature of several pathological conditions, and a number of them, including malignancies, atherosclerosis, myocardial infarction and diabetic heart failure, are states in which miR-210 contributes to cellular hypoxic response [36,37,38,39].

Both acute and chronic ischaemic stroke are conditions in which hypoxia is prevalent, creating the right conditions for the expression of miR-210, which has been discovered to play important roles not just in evaluation but in determining the prognosis of the condition [40]. It has been found that miR-210 can target transcripts under hypoxic conditions to create an avenue for angiogenesis, the persistence of stem cells and the encouragement of glycolysis [41]. The inhibition of miR-210 has been associated with a tendency to increase ischaemic damage in muscular and vascular tissues [40,41,42].

Studies have attempted to proffer explanations for the security offered by miR-210 in hypoxic states—the recruitment of genes that control oxidative phosphorylation, which leads to the generation of reactive oxygen species, in part, contributes to its work [43, 44]. While the mechanisms by which it operates remain, as yet, not fully elucidated, its functionality is both situation- and time-reliant as over-expression and even under-expression might yield neuroprotective effects as demonstrated by a study in perinatal hypoxic–ischaemic encephalopathy, which showed that inhibiting miR-210 leads to a shrinkage of areas of cellular death in the brain [45]. This contrasts with most other findings that identified increased miR-210 expression in hypoxic states. In stimulating angiogenesis, which is often required for the adaptation to hypoxia, miR-210 promotes cell migration and capillary formation under the influence of vascular endothelial growth factor (VEGF) by blocking the ephrin-A3, a tyrosine kinase ligand-receptor [46]. Furthermore, its targeting of Notch expression facilitates angiogenesis after ischaemia [47].

Current evidence on expression levels of miR-210 in ischaemic stroke

There is a shortage of reliable biomarkers for ischaemic stroke [8]. Serum concentrations of miR-210 have, therefore, been investigated as possible diagnostic and/or prognostic markers for ischaemic stroke. Using samples acquired from 52 ischaemic stroke patients and their healthy counterparts at five time points: upon admission, 24 and 48 h after admission, upon discharge and 3 months later. Serum levels of miR‐210 were analysed using real-time RT‐PCR and ELISA. MiR‐210 was found to be significantly lower in stroke patients compared to the control group, and it was also found that there was a significant difference between the mean of miR‐210 at the time of admission and 3 months after stroke, depicting a significant increase [12].

Studies expressed that the lower expression of miR‐210 could increase PGE2 expression [48, 49]. The lower expression of miR‐210 may be associated with deactivating the PI3K/Akt pathway, which mediates neuroprotective effects, and the arrested signalling could promote unrestricted stroke [49]. Moreover, miR‐210 downregulation is associated with the elevated expression of the p53 tumour suppressor gene within the DNA repair process, which modifies stroke severity [16]. Consistent with the findings of Rahmati et al., several previous reports show that miR‐210 is reduced in the serum of stroke patients compared to controls [50,51,52]. Other studies have also identified that miR‐210 was a powerful diagnostic marker [16, 50].

A study by Tian et al. on the expression levels of miR-210, miR-137 and miR-153 in acute cerebral infarction revealed that levels of miR-210 in the observation group were significantly lower than those in the control group. The 1-year survival of the low-expression group of miR-210 is significantly lower than that of the high-expression group, making miR-210 a good prognostic marker [53].

Diagnostic potential of miR-210

The evaluation of miR-210 as a regulatory diagnostic biomarker for ischaemic stroke has been a topic of significant interest (see Fig. 2). Li et al. [54] examined the expression of miR-210 in ischaemic stroke patients and its association with clinical outcomes. The study found that elevated levels of miR-210 were significantly associated with larger infarct size and poorer functional outcomes in ischaemic stroke patients. However, the study was limited by a small sample size and the lack of long-term follow-up data, which may have affected the robustness of the results. Similarly, Zeng et al. [55] measured the blood levels of miR-210 in 112 stroke patients and 60 healthy controls. They found that miR-210 was significantly decreased in stroke patients, especially at 7 and 14 days after stroke onset. They also showed that the cut-off point of miR-210 for diagnosis was 0.505 with 88.3% sensitivity and that miR-210 level was positively correlated with good outcome and negatively correlated with infarct volume. Furthermore, a study by Yin et al. [54] investigated the potential utility of miR-210 in differentiating ischaemic stroke from other stroke subtypes, such as haemorrhagic stroke. The study reported that miR-210 had good discriminatory power in distinguishing ischaemic stroke from haemorrhagic stroke, with high sensitivity and specificity. However, the study was limited by potential selection bias and lacked validation in an independent cohort, raising concerns about the findings’ reliability and generalisability.

Fig. 2
figure 2

Overview of miR-210 as a diagnostic biomarker for ischaemic stroke. Elevated miR-210 levels are associated with larger infarct size and poorer outcomes in ischaemic stroke patients. miR-210 also effectively differentiates ischaemic from haemorrhagic stroke with high sensitivity and specificity

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Several original studies have investigated the sensitivity of miR-210 as a biomarker for ischaemic stroke. For example, a study by Zeng et al. [56] found that miR-210 levels were significantly elevated in patients with acute ischaemic stroke compared to healthy controls and patients with other neurological conditions. The sensitivity of miR-210 as a biomarker for ischaemic stroke was reported to be 85%, indicating its potential to identify patients with the condition accurately. These findings suggest that miR-210 exhibits high sensitivity in detecting ischaemic stroke, making it a valuable biomarker for early diagnosis. In addition to sensitivity, the specificity of miR-210 as a biomarker for ischaemic stroke is also crucial in distinguishing it from other conditions that may present with similar symptoms. One study by Ma et al. [57] investigated the specificity of miR-210 by comparing its levels in patients with ischaemic stroke and those with haemorrhagic stroke. The study’s results demonstrated that miR-210 was significantly elevated in the ischaemic stroke group compared to the haemorrhagic stroke group, indicating its specificity in differentiating between the two types of strokes. These findings suggest that miR-210 exhibits high specificity in identifying ischaemic stroke and can potentially be a reliable diagnostic biomarker.

Prognostic value of miR-210 in ischaemic stroke

In a study by Huang et al., the inhibition of miR-210 through miR-210-LNA not only significantly reduced brain damage and improved behavioural deficits in the acute phase of ischaemic stroke, but also crucially mitigated the post-ischaemic inflammation response [57] (see Fig. 3). This implies that miR-210’s impact extends beyond the immediate aftermath of stroke, influencing the inflammatory environment with potential long-term consequences. Similarly, Tian et al.’s 1-year study revealed a significant survival difference between low-expression and high-expression groups of miR-210 in patients with acute cerebral infarction [53]. This extended time frame provides evidence supporting the notion that miR-210 levels may be indicative of long-term outcomes, emphasising its potential as a prognostic marker.

Fig. 3
figure 3

miR-210’s prognostic value in ischaemic stroke. Inhibiting miR-210 reduced brain damage, improved behavioural deficits and mitigated post-ischaemic inflammation, suggesting a role beyond immediate stroke effects. miR-210 levels significantly impact long-term survival in acute cerebral infarction patients, indicating its potential as a prognostic marker. Additionally, miR-210 promotes angiogenesis through VEGF and Notch signalling pathways, enhancing recovery in ischaemia/reperfusion models. miR-210’s correlation with brain-derived neurotrophic factor (BDNF) and its role in improving neurobehavior and microvessel density support its use as a prognostic biomarker. Elevated miR-210 levels correlate with reduced damage and better outcomes, while its dynamic expression suggests value in monitoring recovery and therapeutic responses. Ref. [11, 12, 46, 53, 57,58,59,60,61,62]

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In their study, Jeyaseelan et al. observed a temporal upregulation and subsequent downregulation of brain miR-210 levels in transient ischaemic stroke rats [58]. This dynamic pattern suggests a role of miR-210 in stroke recovery, where varying expression levels influence different phases of the recovery process. Highlighting a prolonged increase in post-stroke brain cortex miR-210 levels over 7 days, Lou et al. indicate a lasting influence on stroke recovery, emphasising the need for a comprehensive understanding of miR-210’s role in short-term and long-term outcomes [46]. Furthermore, Chan et al. demonstrated that miR-210 upregulation induced pro-apoptotic gene caspase-3 expression, contributing to endothelial cell apoptosis [59]. Conversely, Chio et al. reported antiapoptotic effects of miR-210 overexpression in specific cell types under oxygen–glucose deprivation or hypoxia [60, 61]. This duality shows the context-dependent nature of miR-210’s impact on apoptosis, adding complexity to its role in stroke pathology. The broad spectrum of effects exhibited by miR-210, such as preventing apoptosis, targeting multiple transcripts involved in cellular responses to hypoxia, protecting stem-cell survivance, terminating mitochondrial metabolism, promoting glycolysis and inducing angiogenesis [12], suggests a crucial role in shaping the cellular environment post-stroke, either contributing to recovery or exacerbating damage.

MiR-210 exhibits a multifaceted role, promoting angiogenesis through the vascular endothelial growth factor (VEGF) signalling pathway and activating the Notch signalling pathway in response to hypoxia, potentially enhancing angiogenesis after cerebral ischaemia [11]. Evidence suggests that overexpression of miR-210 leads to increased focal angiogenesis and improved functional recovery in ischaemia/reperfusion models [11, 13]. Conversely, lower expression of miR-210 may be linked to the deactivation of the PI3K/Akt pathway, which mediates neuroprotective effects. The consequently arrested signalling could potentially contribute to unrestricted stroke. Additionally, the downregulation of miR-210 is associated with elevated expression of the p53 tumour suppressor gene in the DNA repair process, potentially influencing the modification of stroke severity [12].

Zeng et al., in their investigation of the relationship between brain-derived neurotrophic factor (BDNF) and microRNAs (miRNAs) in ischaemic stroke among humans, examined circulating miRNA profiles in patients affected by ischaemic stroke [53]. Silico analysis revealed that hypoxia-related miR-210 is a target of the BDNF gene. The study documented significant advancements in long-term outcomes for stroke therapy by delivering lentivirus-mediated miR-210 to the ischaemic brains of mice. Overexpression of miR-210 increased microvessel density and the number of neuronal progenitor cells within the brains of ischaemic mice [8, 53]. This augmentation contributed to an improvement in the neurobehaviour of ischaemic mice. Furthermore, the upregulated mature-BDNF/pro-BDNF ratio highlighted that miR-210 holds promise as a therapeutic avenue for ischaemic stroke. The ongoing research progress elucidating the role of BDNF in neural plasticity, neural protection and neurogenesis presents crucial information for shaping new strategies in poststroke rehabilitation. BDNF’s regulatory role in poststroke kinematic learning and rehabilitation adds a layer of significance, indicating that as stroke patients recover, the rise in BDNF levels contributes to nerve protection [8, 53]. This intricate interplay between miR-210, BDNF and poststroke recovery mechanisms offers promising insights for the development of targeted therapeutic interventions in ischaemic stroke.

The proposition of miR-210 as a potential circulating biomarker for the diagnosis and prognosis of ischaemic stroke stems from its intricate involvement in adjusting hypoxia-associated pathways under both physiological and pathological conditions [12]. The collective evidence underscores the substantial potential of miR-210 for prognostic stratification in ischaemic stroke. Elevated miR-210 levels during the acute phase of ischaemic stroke not only align with reduced brain damage and improved behavioural deficits but also impact the post-ischaemic inflammatory response [62]. The observed dynamic expression pattern of miR-210 over time in transient ischaemic stroke rats and its prolonged elevation in the post-stroke brain cortex accentuate its nuanced role in stroke recovery, suggesting that monitoring miR-210 levels could provide insights into the evolving nature of outcomes [63].

Furthermore, the significant survival difference between low and high miR-210 expression groups in patients with acute cerebral infarction emphasises its potential as a prognostic indicator for long-term outcomes [53]. The association between miR-210 and brain-derived neurotrophic factor (BDNF), particularly the improved mature-BDNF/pro-BDNF ratio and enhanced microvessel density in the ischaemic brain, strengthens the case for miR-210 as a key player in prognostic stratification. This suggests its utility in predicting outcomes and guiding potential therapeutic interventions [8, 53]. In the study by Zeng et al., miRNA-210 was explored as a potential blood biomarker for acute cerebral ischaemia due to its role as a master and pleiotropic hypoxia-miRNA [54]. The study measured miRNA-210 levels in blood samples from stroke patients and healthy controls, revealing a significant decrease in miR-210 in stroke patients, especially at 7 and 14 days post-stroke onset. Notably, miR-210 levels in blood from stroke patients were significantly higher than those in blood from individuals who had never had a stroke. These findings suggest that blood miR-210 in acute ischaemic stroke patients could be valuable in diagnosing and prognosing stroke, as well as predicting the response of stroke patients to therapy. Zeng et al. further proposed that blood miR-210 can reflect changes in the brain, making it a potential monitoring tool for the time, dose and effect of drug administration in stroke management [54]. The stability of blood-circulating miRNA, demonstrated in both in vitro and in vivo experiments, enhances its potential utility.

The correlations observed between miR-210 expression levels and various facets of stroke recovery position it as a promising candidate for prognostic stratification in ischaemic stroke, with the added value of serving as a diagnostic and prognostic tool, as well as predicting the response of stroke patients to therapy [50].

Challenges in proposing miR-210 as an ischaemic stroke biomarker

Proposing miR-210 as a potential biomarker for ischaemic stroke represents a promising avenue in the quest for more effective and minimally invasive diagnostic tools. However, this proposition has its challenges, and a thorough examination of these challenges is essential for a comprehensive understanding of miR-210’s role in clinical applications. One prominent challenge lies in the variability of miR-210 levels, which introduces complexity to its potential use as a universal biomarker [64]. The observed differences across diverse patient groups, influenced by variables such as age, sex and comorbidities, raise concerns about the reliability of miR-210 [44, 65, 66]. The variability in expression levels reflects the heterogeneity within patient populations, and understanding these nuances becomes paramount in harnessing the true potential of miR-210. Addressing the challenge of variability demands understanding the factors influencing miR-210 levels. Age-related variations, gender-specific differences, and the influence of comorbidities must be explored to comprehensively understand miR-210’s expression patterns. Comprehensive research efforts are crucial to disentangle the relationships between miR-210 and these factors, shedding light on its reliability and applicability across diverse populations.

The limited diagnostic specificity of miR-210 poses another critical challenge in its potential role as a biomarker for ischaemic stroke [12]. This challenge is particularly pronounced when attempting to distinguish ischaemic stroke from other neurological conditions, such as transient ischaemic attacks or migraines. The constraints faced by miR-210 in achieving diagnostic specificity underline the necessity for rigorous investigation and validation of its performance in various clinical scenarios [12].

The absence of standardised diagnostic assays for miR-210 detection presents a significant challenge in its journey towards becoming a reliable biomarker for ischaemic stroke [50]. This challenge shows the pressing need for uniform and consistent methods to detect miR-210, as the current lack of standardised diagnostic assays introduces the potential for inconsistencies, thereby limiting its clinical utility. The challenge of lacking standardised diagnostic assays emphasises the critical role of methodological consistency in realising the full potential of miR-210. The absence of uniformity in detection methods raises concerns about the reliability and comparability of findings across different studies. This lack of standardisation hampers the ability to draw meaningful conclusions from research efforts and impedes the integration of miR-210 into clinical practice.

Challenges related to cost-effectiveness and accessibility arise in the context of miR-210 assays [67]. Compared to traditional diagnostic methods, concerns about associated costs and the requirement for specialised laboratory facilities may hinder the widespread implementation of miR-210 assays, particularly in resource-limited settings [67]. Addressing this challenge necessitates health economic studies to evaluate the overall cost-effectiveness of miR-210 testing. Additionally, exploring the development of affordable point-of-care assays could enhance accessibility and utility in various healthcare settings.

Future prospects for proposing miR-210 as an ischaemic stroke biomarker

As the exploration of miR-210 as a potential biomarker for ischaemic stroke progresses, several promising prospects emerge, each poised to contribute significantly to its clinical integration. The impact of demographic and clinical variables on miR-210 levels necessitates the establishment of standardised reference ranges. An approach involves researching potential confounding factors and quantifying their impact on miR-210 expression. Establishing standardised reference ranges is pivotal to mitigating variability challenges, allowing for a more accurate interpretation of miR-210 levels in the clinical context. Moreover, the proposed use of miR-210 as a biomarker shows the need for comprehensive and diverse research populations. A universal biomarker should demonstrate consistent patterns across different demographic and clinical subgroups. Therefore, large-scale, multicenter studies are essential to validate the robustness of miR-210 as a biomarker for ischaemic stroke. These studies should encompass a broad spectrum of patient demographics and clinical characteristics to ensure the generalisability of findings.

Validation studies play a pivotal role in this process, especially when considering the complexity of neurological disorders. Large-scale, multicenter studies become imperative to assess the diagnostic performance of miR-210 rigorously. These studies should encompass diverse patient populations, including individuals with different neurological conditions, to comprehensively evaluate miR-210’s specificity. Comparative analyses with established biomarkers for ischaemic stroke can further enhance the understanding of its unique diagnostic value. Moreover, the challenge of diagnostic specificity emphasises the importance of a tailored and context-specific approach. Different neurological conditions may present overlapping symptoms, making the need for a nuanced understanding of miR-210’s performance in diverse clinical scenarios even more crucial. Diagnostic specificity is not a one-size-fits-all attribute, and miR-210’s potential must be assessed within the specific clinical context of ischaemic stroke and its differentiating features.

Addressing this challenge requires concerted efforts to develop and implement standardised diagnostic assays for miR-210. Standardisation ensures that the methods used for miR-210 detection are consistent across different laboratories and research settings, enhancing the reproducibility and reliability of results. This standardisation is essential to establish a robust foundation for miR-210 as a biomarker, enabling clinicians and researchers to interpret and apply the findings in various clinical scenarios confidently. Future endeavours should prioritise the refinement of diagnostic assays, incorporating rigorous validation processes to ensure their accuracy and consistency. Collaboration between researchers, clinicians and diagnostic assay developers becomes paramount to establishing consensus on standardised methods for miR-210 detection. The focus should extend beyond mere detection and include quantifying and interpreting miR-210 levels, ensuring that the assays provide clinically relevant information.

Limitations and strengths of review

The review has limitations that need consideration. The absence of long-term follow-up data in the existing literature restricts the study’s ability to draw sustained conclusions about the enduring impact of miR-210 on ischaemic stroke outcomes. Additionally, there may be a degree of selection bias in certain included studies, potentially limiting the representativeness of the findings across the spectrum of ischaemic stroke patients. Including non-English language studies introduces language bias, potentially overlooking pertinent contributions in other languages. On the flip side, the study boasts several strengths. The comprehensive literature review draws from multiple databases, ensuring a thorough exploration of miR-210’s role in ischaemic stroke. The inclusivity of studies featuring diverse patient demographics and clinical characteristics enhances the study’s robustness and broad applicability. The multifaceted analysis of miR-210’s diagnostic potential, prognostic value and challenges in its biomarker proposal provides a holistic understanding. Furthermore, the study serves as a guidepost for future research by identifying critical areas for improvement, including the need for standardised assays, demographic-specific reference ranges and large-scale multicenter studies, steering the trajectory of future investigations in this domain.

Conclusion

The exploration of miR-210 as a potential biomarker for ischaemic stroke holds significant promise, yet it has its challenges. Ischaemic stroke, a major global health concern, necessitates effective diagnostic tools, and miR-210, as a hypoxia-inducible microRNA, presents a compelling candidate. However, several challenges must be carefully considered before miR-210 can be confidently proposed as a universal biomarker for ischaemic stroke.

The roles of miR-210 in diverse cellular processes, ranging from angiogenesis to apoptosis, highlight its potential as a key player in the pathophysiology of ischaemic stroke. Its responsiveness to hypoxic conditions and its involvement in acute and chronic ischaemia positions miR-210 as a versatile and dynamic candidate for further exploration. The current evidence on miR-210’s expression levels in ischaemic stroke patients provides insights into its diagnostic and prognostic potential. While studies indicate associations between miR-210 levels and factors such as infarct size, functional outcomes and long-term survival, challenges arise in variability, diagnostic specificity and the lack of standardised diagnostic assays.

Variability in miR-210 levels across diverse patient groups introduces complexities, raising concerns about its reliability as a universal biomarker. The challenge of diagnostic specificity, particularly in distinguishing ischaemic stroke from other neurological conditions, underscores the need for rigorous investigation and validation in various clinical scenarios. The absence of standardised diagnostic assays poses a significant hurdle, emphasising the importance of methodological consistency for the clinical utility of miR-210. Furthermore, cost-effectiveness and accessibility issues may limit the widespread implementation of miR-210 assays, especially in resource-limited settings.

To address these challenges, future research should focus on establishing standardised reference ranges for miR-210, considering demographic and clinical variables. Large-scale, multicenter studies are essential to validate its diagnostic performance across diverse populations and neurological conditions. Collaboration between researchers, clinicians and diagnostic assay developers becomes crucial for developing and implementing standardised diagnostic assays. In navigating the prospects of miR-210 as an ischaemic stroke biomarker, it is imperative to prioritise comprehensive research, methodological standardisation and collaborative efforts. The potential benefits of miR-210 as a diagnostic and prognostic tool in ischaemic stroke underscore its significance, making it a promising avenue for continued exploration and refinement. Despite the challenges, the pursuit of miR-210 as a biomarker for ischaemic stroke represents a valuable contribution to advancing our understanding of this complex neurological condition.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

miR-210:

MicroRNA-210

HIF-1α:

Hypoxia-inducible factor 1 alpha

3′ UTR:

3′ Untranslated region

mRNA:

Messenger RNA

ncRNA:

Non-coding RNA

tRNA:

Transfer RNA

rRNA:

Ribosomal RNA

pri-miRNA:

Primary microRNA

pre-miRNA:

Precursor microRNA

RISC:

RNA-induced silencing complex

Ago:

Argonaute

TRBP:

Transactivating response RNA-binding protein

BDNF:

Brain-derived neurotrophic factor

VEGF:

Vascular endothelial growth factor

ELISA:

Enzyme-linked immunosorbent assay

PI3K/Akt:

Phosphoinositide 3-kinase/protein kinase B

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Authors and Affiliations

  1. Department of Medicine, Ladoke Akintola University of Technology, Ogbomoso, Nigeria

    Nicholas Aderinto & Opabode Muntaqim Obasanjo

  2. Department of Medicine and Surgery, University of Ilorin, Ilorin, Nigeria

    Gbolahan Olatunji & Emmanuel Kokori

  3. Department of Neurosurgery, Trivandrum Medical College, Thiruvananthapuram, Kerala, India

    Vivek Sanker

  4. Department of Medicine and Surgery, Obafemi Awolowo University Teaching Hospital, Ife, Nigeria

    Ismaila Ajayi Yusuf & Oluwatobiloba Oluwatomisin Apampa

  5. Department of Medicine and Surgery, Bowen University Teaching Hospital, Iwo, Nigeria

    Temiloluwa Oluwakorede Adefusi

  6. Federal Medical Centre Bida, Niger, Nigeria

    Emmanuel Egbunu

  7. College of Health Sciences, Benue State University, Benue, Nigeria

    John Ehi Aboje

  8. Siberian State Medical University, Tomsk, Russia

    Ikponmwosa Jude Ogieuhi

  9. Faculty of Medicine, Sumy State University, Sumy, Ukraine

    Wireko Andrew Awuah

  10. Department of Medicine and Surgery, Ladoke Akintola University of Technology, Ogbomoso, Nigeria

    Nicholas Aderinto

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Contributions

NA conceptualised the study; All authors were involved in the literature review; GO and EK extracted the data from the reviewed studies; all authors wrote the final and first drafts. All authors read and approved the final manuscript.

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Aderinto, N., Olatunji, G., Kokori, E. et al. miR-210 in ischaemic stroke: biomarker potential, challenges and future perspectives. Eur J Med Res 29, 432 (2024). https://doi.org/10.1186/s40001-024-02029-6

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European Journal of Medical Research

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