MicroRNAs: Novel Regulators of Oligodendrocyte Differentiation and Potential Therapeutic Targets in Demyelination-Related Diseases

MicroRNAs (miRNAs or miRs) are a class of endogenous small non-coding RNAs that consist of about 22 nucleotides and play critical roles in various biological processes, including cell proliferation, differentiation, apoptosis, and tumorigenesis. In recent years, some specific miRNA, such as miR-219, miR-138, miR-9, miR-23, and miR-19b were found to participate in the regulation of oligodendrocyte (OL) differentiation and myelin maintenance, as well as in the pathogenesis of demyelination-related diseases (e.g., multiple sclerosis, ischemic stroke, and leukodystrophy). These miRNAs control their target mRNA or regulate the protein levels of some signaling pathways, and participate in OL differentiation and the pathogenesis of demyelination-related diseases. During pathologic processes, the expression levels of specific miRNAs are dynamically altered. Therefore, miRNAs act as diagnostic and prognostic indicators of defects in OL differentiation and demyelination-related diseases, and they can provide potential targets for therapeutic drug development.     

Search for signatures in miRNAs associated with cancer

Since the first discovery in the early 1990''s, the predicted and validated population of microRNAs (miRNAs or miRs) has grown significantly. These small (~22 nucleotides long) regulators of gene expression have been implicated and associated with several genes in the cancer pathway as well. Globally, the identification and verification of microRNAs as biomarkers for cancer cell types has been the area of thrust for most miRNA biologists. However, there has been a noticeable vacuum when it comes to identifying a common signature or trademark that could be used to demarcate a miR to be associated with the development or suppression of cancer. To answer these queries, we report an in silico study involving the identification of global signatures in experimentally validated microRNAs which have been associated with cancer. This study has thrown light on the presence of significant common signatures, viz., - sequential and hybridization, which may distinguish a miR to be associated with cancer. Based on our analysis, we suggest the utility of such signatures in the design and development of algorithms for prediction of miRs involved in the cancer pathway.     

Specification and maintenance of oligodendrocyte precursor cells from neural progenitor cells: involvement of microRNA-7a

The generation of myelinating cells from multipotential neural stem cells in the CNS requires the initiation of specific gene expression programs in oligodendrocytes (OLs). We reasoned that microRNAs (miRNAs) could play an important role in this process by regulating genes crucial for OL development. Here we identified miR-7a as one of the highly enriched miRNAs in oligodendrocyte precursor cells (OPCs), overexpression of which in either neural progenitor cells (NPCs) or embryonic mouse cortex promoted the generation of OL lineage cells. Blocking the function of miR-7a in differentiating NPCs led to a reduction in OL number and an expansion of neuronal populations simultaneously. We also found that overexpression of this miRNA in purified OPC cultures promoted cell proliferation and inhibited further maturation. In addition, miR-7a might exert the effects just mentioned partially by directly repressing proneuronal differentiation factors including Pax6 and NeuroD4, or proOL genes involved in oligodendrocyte maturation. These results suggest that miRNA pathway is essential in determining cell fate commitment for OLs and thus providing a new strategy for modulating this process in OL loss diseases.     

Correlated miR-mRNA Expression Signatures of Mouse Hematopoietic Stem and Progenitor Cell Subsets Predict “Stemness” and “Myeloid” Interaction Networks

Several individual miRNAs (miRs) have been implicated as potent regulators of important processes during normal and malignant hematopoiesis. In addition, many miRs have been shown to fine-tune intricate molecular networks, in concert with other regulatory elements. In order to study hematopoietic networks as a whole, we first created a map of global miR expression during early murine hematopoiesis. Next, we determined the copy number per cell for each miR in each of the examined stem and progenitor cell types. As data is emerging indicating that miRs function robustly mainly when they are expressed above a certain threshold (∼100 copies per cell), our database provides a resource for determining which miRs are expressed at a potentially functional level in each cell type. Finally, we combine our miR expression map with matched mRNA expression data and external prediction algorithms, using a Bayesian modeling approach to create a global landscape of predicted miR-mRNA interactions within each of these hematopoietic stem and progenitor cell subsets. This approach implicates several interaction networks comprising a “stemness” signature in the most primitive hematopoietic stem cell (HSC) populations, as well as “myeloid” patterns associated with two branches of myeloid development.     

The microRNA-17~92 cluster: Still a miRacle?

MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression by binding to target mRNAs, leading to translational repression or degradation. The polycistronic microRNA cluster comprises seven mature microRNAs (miR-17-5p and – 3p, miR-18a, miR-19a and b, miR-20a and miR-92a) and has initially been linked to tumorigenesis. Meanwhile, additional functions have been assigned to the cluster such as the regulation of hematopoiesis and immune functions. Recently, loss-off-function studies revealed a critically role of the miR-17~92 cluster in heart and lung development and the individual miRNAs encoded by the cluster such as miR-17 and miR-92a were shown to control lung development and postnatal neovascularization, respectively. The present article summarizes the functions of the miR-17~92 cluster in health and disease and discusses the specific contribution and the targets of the individual miRNAs encoded by the cluster.     

GSK3 and miRNA in neural tissue: From brain development to neurodegenerative diseases

MicroRNAs (miRs) are small RNAs modulating gene expression and creating intricate regulatory networks that are dysregulated in many pathological states, including neurodegenerative disorders. In silico analyses denote a multifunctional kinase glycogen synthase kinase-3 (GSK3) as a putative target of numerous miRs identified in neural tissue. GSK3 is engaged in almost all aspects of neuronal development and functioning. Moreover, there is an autoregulatory feedback between GSK3 and miRNAs as the kinase can influence biogenesis of miRs. Members of the miR-GSK3 axes might thus represent convenient therapeutic targets in neuropathologies that display its abnormal regulation. This review summarizes the present knowledge about direct interactions of GSK3 and miRs in brain, and their putative roles in pathogenesis of neurodegenerative and neuropsychiatric disorders. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.     

Dysregulation in microRNA Expression Is Associated with Alterations in Immune Functions in Combat Veterans with Post-Traumatic Stress Disorder

While the immunological dysfunction in combat Veterans with post-traumatic stress disorder (PTSD) has been well documented, the precise mechanisms remain unclear. The current study evaluated the role of microRNA (miR) in immunological dysfunction associated with PTSD. The presence of peripheral blood mononuclear cells (PBMC) and various lymphocyte subsets in blood collected from PTSD patients were analyzed. Our studies demonstrated that the numbers of both PBMC and various lymphocyte subsets increased significantly in PTSD patients. When T cells were further analyzed, the percentage of Th1 cells and Th17 cells increased, regulatory T cells(Tregs) decreased, while Th2 cells remained unaltered in PTSD patients. These data correlated with increased plasma levels of IFN-γ and IL-17 while IL-4 showed no significant change. The increase in PBMC counts, Th1 and Th17 cells seen in PTSD patients correlated with the clinical scores. High-throughput analysis of PBMCs for 1163 miRs showed that the expression of a significant number of miRs was altered in PTSD patients. Pathway analysis of dysregulated miRs seen in PTSD patients revealed relationship between selected miRNAs and genes that showed direct/indirect role in immunological signaling pathways consistent with the immunological changes seen in these patients. Of interest was the down-regulation of miR-125a in PTSD, which specifically targeted IFN-γ production. Together, the current study demonstrates for the first time that PTSD was associated with significant alterations in miRNAs, which may promote pro-inflammatory cytokine profile. Such epigenetic events may provide useful tools to identify potential biomarkers for diagnosis, and facilitate therapy of PTSD.     

Regulation of tumor angiogenesis by microRNAs: State of the art

MicroRNAs (miRNAs, miRs) are small (21–25 nucleotides) endogenous and noncoding RNAs involved in many cellular processes such as apoptosis, development, proliferation, and differentiation via binding to the 3′-untranslated region of the target mRNA and inhibiting its translation. Angiogenesis is a hallmark of cancer, which provides oxygen and nutrition for tumor growth while removing deposits and wastes from the tumor microenvironment. There are many angiogenesis stimulators, among which vascular endothelial growth factor (VEGF) is the most well known. VEGF has three tyrosine kinase receptors, which, following VEGF binding, initiate proliferation, invasion, migration, and angiogenesis of endothelial cells in the tumor environment. One of the tumor microenvironment conditions that induce angiogenesis through increasing VEGF and its receptors expression is hypoxia. Several miRNAs have been identified that affect different targets in the tumor angiogenesis pathway. Most of these miRNAs affect VEGF and its tyrosine kinase receptors expression downstream of the hypoxia-inducible Factor 1 (HIF-1). This review focuses on tumor angiogenesis regulation by miRNAs and the mechanism underlying this regulation.     

Plasma miR-122 and miR-3149 Potentially Novel Biomarkers for Acute Coronary Syndrome

ObjectiveWe evaluated the potentiality of plasma microRNAs (miRNAs, or miRs) that were considered as novel biomarkers for acute coronary syndrome (ACS), including acute myocardial infarction (AMI) and unstable angina (UA).ConclusionPlasma miR-122, -140-3p, -720, -2861, and -3149 were associated with and potentially novel biomarkers for ACS.     

The latest progress on miR‐374 and its functional implications in physiological and pathological processes

Non‐coding RNAs (ncRNAs) have been emerging players in cell development, differentiation, proliferation and apoptosis. Based on their differences in length and structure, they are subdivided into several categories including long non‐coding RNAs (lncRNAs >200nt), stable non‐coding RNAs (60‐300nt), microRNAs (miRs or miRNAs, 18‐24nt), circular RNAs, piwi‐interacting RNAs (26‐31nt) and small interfering RNAs (about 21nt). Therein, miRNAs not only directly regulate gene expression through pairing of nucleotide bases between the miRNA sequence and a specific mRNA that leads to the translational repression or degradation of the target mRNA, but also indirectly affect the function of downstream genes through interactions with lncRNAs and circRNAs. The latest studies have highlighted their importance in physiological and pathological processes. MiR‐374 family member are located at the X‐chromosome inactivation center. In recent years, numerous researches have uncovered that miR‐374 family members play an indispensable regulatory role, such as in reproductive disorders, cell growth and differentiation, calcium handling in the kidney, various cancers and epilepsy. In this review, we mainly focus on the role of miR‐374 family members in multiple physiological and pathological processes. More specifically, we also summarize their promising potential as novel prognostic biomarkers and therapeutic targets from bench to bedside.     

PGC-Enriched miRNAs Control Germ Cell Development

Non-coding microRNAs (miRNAs) regulate the translation of target messenger RNAs (mRNAs) involved in the growth and development of a variety of cells, including primordial germ cells (PGCs) which play an essential role in germ cell development. However, the target mRNAs and the regulatory networks influenced by miRNAs in PGCs remain unclear. Here, we demonstrate a novel miRNAs control PGC development through targeting mRNAs involved in various cellular pathways. We reveal the PGC-enriched expression patterns of nine miRNAs, including miR-10b, -18a, -93, -106b, -126-3p, -127, -181a, -181b, and -301, using miRNA expression analysis along with mRNA microarray analysis in PGCs, embryonic gonads, and postnatal testes. These miRNAs are highly expressed in PGCs, as demonstrated by Northern blotting, miRNA in situ hybridization assay, and miRNA qPCR analysis. This integrative study utilizing mRNA microarray analysis and miRNA target prediction demonstrates the regulatory networks through which these miRNAs regulate their potential target genes during PGC development. The elucidated networks of miRNAs disclose a coordinated molecular mechanism by which these miRNAs regulate distinct cellular pathways in PGCs that determine germ cell development.     

Natural flavonoids exhibit potent anticancer activity by targeting microRNAs in cancer: A signature step hinting towards clinical perfection

Cancer prevalence and its rate of incidence are constantly rising since the past few decades. Owing to the toxicity of present-day antineoplastic drugs, it is imperative to explore safer and more effective molecules to combat and/or prevent this dreaded disease. Flavonoids, a class of polyphenols, have exhibited multifaceted implications against several diseases including cancer, without showing significant toxicity towards the normal cells. Shredded pieces of evidence suggest that flavonoids can enhance drug sensitivity and suppress proliferation, metastasis, and angiogenesis of cancer cells by modulating several oncogenic or oncosuppressor microRNAs (miRNAs, miRs). They play pivotal roles in regulation of various biological and pathological processes, including various cancers. In the present review, the structure, chemistry and miR targeting efficacy of quercetin, luteolin, silibinin, genistein, epigallocatechin gallate, and cyanidin against several cancer types are comprehensively discussed. miRs are considered as next-generation medicine of recent times, and their targeting by naturally occurring flavonoids in cancer cells could be deemed as a signature step. We anticipate that our compilations related to miRNA-mediated regulation of cancer cells by flavonoids might catapult the clinical investigations and affirmation in the future.     

Circulating microRNAs in Sera Correlate with Soluble Biomarkers of Immune Activation but Do Not Predict Mortality in ART Treated Individuals with HIV-1 Infection: A Case Control Study

Introduction

The use of anti-retroviral therapy (ART) has dramatically reduced HIV-1 associated morbidity and mortality. However, HIV-1 infected individuals have increased rates of morbidity and mortality compared to the non-HIV-1 infected population and this appears to be related to end-organ diseases collectively referred to as Serious Non-AIDS Events (SNAEs). Circulating miRNAs are reported as promising biomarkers for a number of human disease conditions including those that constitute SNAEs. Our study sought to investigate the potential of selected miRNAs in predicting mortality in HIV-1 infected ART treated individuals.

Materials and Methods

A set of miRNAs was chosen based on published associations with human disease conditions that constitute SNAEs. This case: control study compared 126 cases (individuals who died whilst on therapy), and 247 matched controls (individuals who remained alive). Cases and controls were ART treated participants of two pivotal HIV-1 trials. The relative abundance of each miRNA in serum was measured, by RTqPCR. Associations with mortality (all-cause, cardiovascular and malignancy) were assessed by logistic regression analysis. Correlations between miRNAs and CD4+ T cell count, hs-CRP, IL-6 and D-dimer were also assessed.

Results

None of the selected miRNAs was associated with all-cause, cardiovascular or malignancy mortality. The levels of three miRNAs (miRs -21, -122 and -200a) correlated with IL-6 while miR-21 also correlated with D-dimer. Additionally, the abundance of miRs -31, -150 and -223, correlated with baseline CD4+ T cell count while the same three miRNAs plus miR-145 correlated with nadir CD4+ T cell count.

Discussion

No associations with mortality were found with any circulating miRNA studied. These results cast doubt onto the effectiveness of circulating miRNA as early predictors of mortality or the major underlying diseases that contribute to mortality in participants treated for HIV-1 infection.     

MicroRNA function and neurotrophin BDNF

MicroRNAs (miRs), endogenous small RNAs, regulate gene expression through repression of translational activity after binding to target mRNAs. miRs are involved in various cellular processes including differentiation, metabolism, and apoptosis. Furthermore, possible involvement of miRs in neuronal function have been proposed. For example, miR-132 is closely related to neuronal outgrowth while miR-134 plays a role in postsynaptic regulation, suggesting that brain-specific miRs are critical for synaptic plasticity. On the other hand, numerous studies indicate that BDNF (brain-derived neurotrophic factor), one of the neurotrophins, is essential for a variety of neuronal aspects such as cell differentiation, survival, and synaptic plasticity in the central nervous system (CNS). Interestingly, recent studies, including ours, suggest that BDNF exerts its beneficial effects on CNS neurons via up-regulation of miR-132. Here, we present a broad overview of the current knowledge concerning the association between neurotrophins and various miRs.     

Coronary Artery-Bypass-Graft Surgery Increases the Plasma Concentration of Exosomes Carrying a Cargo of Cardiac MicroRNAs: An Example of Exosome Trafficking Out of the Human Heart with Potential for Cardiac Biomarker Discovery

IntroductionExosome nanoparticles carry a composite cargo, including microRNAs (miRs). Cultured cardiovascular cells release miR-containing exosomes. The exosomal trafficking of miRNAs from the heart is largely unexplored. Working on clinical samples from coronary-artery by-pass graft (CABG) surgery, we investigated if: 1) exosomes containing cardiac miRs and hence putatively released by cardiac cells increase in the circulation after surgery; 2) circulating exosomes and exosomal cardiac miRs correlate with cardiac troponin (cTn), the current “gold standard” surrogate biomarker of myocardial damage.ConclusionsThe plasma concentrations of exosomes and their cargo of cardiac miRs increased in patients undergoing CABG and were positively correlated with hs-cTnI. These data provide evidence that CABG induces the trafficking of exosomes from the heart to the peripheral circulation. Future studies are necessary to investigate the potential of circulating exosomes as clinical biomarkers in cardiac patients.