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.     

MicroRNAs in human diseases

The discovery of microRNAs (miRNAs), a new class of negative regulator that represses gene expression by pairing with their target messenger RNAs (mRNAs), has revealed a natural pathway for controlling gene expression. There are hundreds of miRNAs encoded in the human genome and thousands of target mRNAs, which illustrates the important regulatory roles of miRNAs in cell developmental, differentiation, proliferation and apoptosis pathways. In this scenario, it is not surprising that deregulated miRNAs have been involved in the pathogenesis of many human diseases. The recent development of technologies and compounds to identify and modulate miRNAs has opened new avenues for diagnosis, prognosis and therapeutic applications. Here, we summarize most of the recent patents related to the detection and profiling of miRNAs from pathological samples and to miRNA modulators used as new therapies for disease, including cancer and viral infections, as well as methods for their delivery.     

MiRNA‐145‐5p prevents differentiation of oligodendrocyte progenitor cells by regulating expression of myelin gene regulatory factor

The roles of specific microRNAs (miRNA) in oligodendrocyte (OL) differentiation have been studied in depth. However, miRNAs in OL precursors and oligodendrocyte progenitor cells (OPCs) have been less extensively investigated. MiR‐145‐5p is highly expressed in OPCs relative to differentiating OLs, suggesting this miRNA may serve a function specifically in OPCs. Knockdown of miR‐145‐5p in primary OPCs led to spontaneous differentiation, as evidenced by an increased proportion of MAG⁺ cells, increased cell ramification, and upregulation of multiple myelin genes including MYRF, TPPP, and MAG, and OL cell cycle exit marker Cdkn1c. Supporting this transition to a differentiating state, proliferation was reduced in miR‐145‐5p knockdown OPCs. Further, knockdown of miR‐145‐5p in differentiating OLs showed enhanced differentiation, with increased branching, myelin membrane production, and myelin gene expression. We identified several OL‐specific genes targeted by miR‐145‐5p that exhibited upregulation with miR‐145‐5p knockdown, including myelin gene regulatory factor (MYRF), that could be regulating the prodifferentiation phenotype in both miR‐145 knockdown OPCs and OLs. Indeed, spontaneous differentiation with knockdown of miR‐145‐5p was fully rescued by concurrent knockdown of MYRF. However, proliferation rate was only partially rescued with MYRF knockdown, and overexpression of miR‐145‐5p in OPCs increased proliferation rate without affecting expression of already lowly expressed differentiation genes. Taken together, these data suggest that in OPCs miR‐145‐5p both prevents differentiation at least in part by preventing expression of MYRF and promotes proliferation via as‐yet‐unidentified mechanisms. These findings clarify the need for differential regulation of miR‐145‐5p between OPCs and OLs and may have further implications in demyelinating diseases such as multiple sclerosis where miR‐145‐5p is dysregulated.     

MicroRNA: Key regulators of oligodendrocyte development and pathobiology

MicroRNAs (miRNAs or miRs) are a group of small non-coding RNAs that function through binding to messenger RNA (mRNA) targets and downregulating gene expression. miRNAs have been shown to regulate many cellular functions including proliferation, differentiation, development and apoptosis. Recently, evidence has grown which shows the involvement of miRs in oligodendrocyte (OL) specification and development. In particular, miRs-138, -219, -338, and -9 have been classified as key regulators of OL development, acting at various points in the OL lineage and influencing precursor cell transit into mature myelinating OLs. Many studies have emerged which link miRNAs with OL and myelin pathology in various central nervous system (CNS) diseases including multiple sclerosis (MS), ischemic stroke, spinal cord injury, and adult-onset autosomal dominant leukodystrophy (ADLD).     

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.     

胰腺相关microRNAs研究进展

miRNAs是一类长约21-25nt的内源性的小非编码RNA(small noncoding RNA),它在基因的转录后调控中发挥着重要的作用。miRNAs可以通过与靶基因的mRNA的3'端UTR区完全或部分互补,进而降解该目的mRNA或阻止其翻译成相关蛋白,下调靶基因表达,以此参与个体发育、细胞分化、细胞增殖以及疾病发生过程中的基因表达调控。本文简要介绍miRNAs在胰腺发育、β细胞功能以及胰腺相关疾病中的研究进展。     

The Function of MicroRNAs in Renal Development and Pathophysiology

MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that modulate diverse biological processes predominantly by translation inhibition or induction of mRNA degradation. They are important regulatory elements involved in renal physiology and pathology. Dysregulation of miRNAs disrupts early kidney development, renal progenitor cell differentiation and the maintenance of mature nephrons. miRNAs are also reported to participate in various renal diseases, including chronic kidney disease, acute kidney injury, allograft acute rejection and renal cell carcinoma. Differentially regulated miRNAs may represent innovative biomarkers for diagnosis and prognosis. Therefore, determining the roles of miRNAs in different types of renal diseases will help to clarify the pathogenesis and facilitate the development of novel therapies.     

New advances of microRNAs in the pathogenesis of rheumatoid arthritis,with a focus on the crosstalk between DNA methylation and the microRNA machinery

Rheumatoid arthritis (RA) is a symmetrical polyarticular disease of unknown aetiology that affects primarily the articular cartilage and bone. Characteristic features of RA pathogenesis are persistent inflammation, synovium hyperplasia and cartilage erosion accompanied by joint swelling and joint destruction. Several lines of evidence have showed a crucial role of activated fibroblast-like synoviocytes (FLS) in the pathogenesis of RA. MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding RNAs with about 21 nucleotides in length and have been detected in a variety of sources, including tissues, serum, and other body fluids, such as saliva. In light of key roles of miRNAs in the regulation of gene expression, miRNAs influence a wide range of physiological and pathological processes. For example, miRNAs are evident in various malignant and nonmalignant diseases, and accumulating evidence also shows that miRNAs have important roles in the pathogenesis of RA. It has been demonstrated that miRNAs can be aberrantly expressed even in the different stages of RA progression, allowing miRNAs to help understand the pathogenesis of the disease, to act as important biomarkers, and to monitor the disease severity and the effects of drug treatment. In addition, miRNAs are emerging as potential targets for new therapeutic strategies of this kind of autoimmune disorders. The ultimate goal is the identification of miRNA targets that could be manipulated through specific therapies, aiming at activation or inhibition of specific miRNAs responsible for the RA development. In this review, the importance of miRNAs in the pathogenesis of RA is discussed systematically, with particular emphasis on the role of the crosstalk between DNA methylation and the microRNA machinery.     

Thinking about RNA? MicroRNAs in the brain

MicroRNAs (miRNAs) are a recently discovered class of small RNA molecules implicated in a wide range of diverse gene regulatory mechanisms. Interestingly, numerous miRNAs are expressed in a spatially and temporally controlled manner in the nervous system. This suggests that gene regulation networks based on miRNA activities may be particularly relevant in neurons. Recent studies show the involvement of RNA-mediated gene silencing in neurogenesis, neural differentiation, synaptic plasticity, and neurologic and psychiatric diseases. This review focuses on the roles of miRNAs in the gene regulation of the nervous system.     

The small RNA expression profile of the developing murine urinary and reproductive systems

microRNAs (miRNAs) are small non-coding RNAs with fundamental roles in the regulation of gene expression. miRNAs assemble with Argonaute (Ago) proteins to miRNA-protein complexes (miRNPs), which interact with distinct binding sites on mRNAs and regulate gene expression. Specific miRNAs are key regulators of tissue and organ development and it has been shown in mammals that miRNAs are also involved in the pathogenesis of many diseases including cancer. Here, we have characterized the miRNA expression profile of the developing murine genitourinary system. Using a computational approach, we have identified several miRNAs that are specific for the analyzed tissues or the developmental stage. Our comprehensive miRNA expression atlas of the developing genitourinary system forms an invaluable basis for further functional in vivo studies.     

MicroRNAs: Emerging roles in adipogenesis and obesity

Obesity is a serious health problem worldwide associated with an increased risk of life-threatening diseases such as type 2 diabetes, atherosclerosis, and certain types of cancer. Understanding the molecular basis of adipogenesis and fat cell development in obesity is essential to identify new biomarkers and therapeutic targets for the development of anti-obesity drugs. Recent computational and experimental studies have shown that microRNAs (miRNAs) appear to play regulatory roles in many biological processes associated with obesity, including adipocyte differentiation and lipid metabolism. In addition, many miRNAs are dysregulated in metabolic tissues from obese animals and humans, which potentially contributes to the pathogenesis of obesity-associated complications. The discovery of circulating miRNAs has highlighted their potential as both endocrine signaling molecules and disease markers. The potential of miRNA based therapeutics targeting obesity is highlighted as well as recommendations for future research which could lead to a breakthrough in the treatment of obesity.     

特异性miRNA调节机理研究进展

MicroRNA(miRNA)是一类新鉴定的非蛋白质编码小RNA,它们在多种生物学过程中发挥重要作用。最新研究表明许多miRNA表达受RNA编辑、差别加工和组织特异性增强子调节而呈现时间和空间特异性,而且基于miRNA调节设计分子药物的前景很好。深入理解miRNA调节的机理有助于揭示一些疾病的发病机理,发现干预治疗的新分子靶标,以及最终建立有效的基因疗法。因此,本文将对miRNA调节机理的最新研究进行综述。