Cells

2023

Jump to: 2022, 2021

15 pages, 2582 KiB

Open AccessArticle

Circulating miR-451a Expression May Predict Recurrence in Atrial Fibrillation Patients after Catheter Pulmonary Vein Ablation

by Ricardo Lage, María Cebro-Márquez, Marta E. Vilar-Sánchez, Laila González-Melchor, Javier García-Seara, José Luis Martínez-Sande, Xesús Alberte Fernández-López, Alana Aragón-Herrera, María Amparo Martínez-Monzonís, José Ramón González-Juanatey, Moisés Rodríguez-Mañero and Isabel Moscoso

Cells 2023, 12(4), 638; https://doi.org/10.3390/cells12040638 - 16 Feb 2023

Cited by 4 | Viewed by 2366

Abstract

Atrial fibrillation is the most prevalent tachyarrhythmia in clinical practice, with very high cardiovascular morbidity and mortality with a high-cost impact in health systems. Currently, it is one of the main causes of stroke and subsequent heart failure and sudden death. miRNAs mediate [...] Read more.

Atrial fibrillation is the most prevalent tachyarrhythmia in clinical practice, with very high cardiovascular morbidity and mortality with a high-cost impact in health systems. Currently, it is one of the main causes of stroke and subsequent heart failure and sudden death. miRNAs mediate in several processes involved in cardiovascular disease, including fibrosis and electrical and structural remodeling. Several studies suggest a key role of miRNAs in the course and maintenance of atrial fibrillation. In our study, we aimed to identify the differential expression of circulating miRNAs and their predictive value as biomarkers of recurrence in atrial fibrillation patients undergoing catheter pulmonary vein ablation. To this effect, 42 atrial fibrillation patients were recruited for catheter ablation. We measured the expression of 84 miRNAs in non-recurrent and recurrent groups (45.2%), both in plasma from peripheral and left atrium blood. Expression analysis showed that miRNA-451a is downregulated in recurrent patients. Receiver operating characteristic curve analysis showed that miR-451a in left atrium plasma could predict atrial fibrillation recurrence after pulmonary vein isolation. In addition, atrial fibrillation recurrence is positively associated with the increment of scar percentage. Our data suggest that miRNA-451a expression plays an important role in AF recurrence by controlling fibrosis and progression. Full article

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2022

Jump to: 2023, 2021

31 pages, 5830 KiB

Open AccessArticle

Extracellular Vesicle-Mediated miR-150-3p Delivery in Joint Homeostasis: A Potential Treatment for Osteoarthritis?

by Huan Wang, Jun Shu, Chengfei Zhang, Yang Wang, Rongxing Shi, Fan Yang and Xuezhang Tang

Cells 2022, 11(17), 2766; https://doi.org/10.3390/cells11172766 - 5 Sep 2022

Cited by 8 | Viewed by 2740

Abstract

Background: The disruption of joint homeostasis is a critical event during the process of joint injury in osteoarthritis (OA). As regulatory molecules, microRNAs (miRNAs) can be released from secretory cells and delivered to recipient cells through extracellular vesicles (EVs), thereby playing an important [...] Read more.

Background: The disruption of joint homeostasis is a critical event during the process of joint injury in osteoarthritis (OA). As regulatory molecules, microRNAs (miRNAs) can be released from secretory cells and delivered to recipient cells through extracellular vesicles (EVs), thereby playing an important role in regulating joint homeostasis. We hypothesized that the fibroblast-like synoviocytes (FLSs) in healthy joints could release EVs enriched in miRNAs that can maintain joint homeostasis by regulating the signal transduction pathways in the joints, whereby the articular cartilage (AC) is protected from degeneration, and OA progression is delayed. Methods: Via high-throughput sequencing and qPCR, we found that miR-150-3p was enriched in the circulating EVs in healthy rats. Next, we established an in vitro cell model in which chondrocytes were cultured with (i) FLSs transfected with miR-150-3p mimics or (ii) EVs released by FLSs (FLS–EVs) inside the healthy synovial membrane (SM). The transportation mechanism from FLSs to chondrocytes was studied using the EV inhibitor GW4869, and the FLSs were transfected with a miR-150-3p mimic or inhibitor. To assess the therapeutic effect of miR-150-3p-carrying EVs (EVs-150) in vivo, healthy FLS-derived EVs (H-FLS–EVs) were injected into the tail vein of rats with OA at various stages of the pathogenesis and evaluated for the progression of OA. Results: The chondrocytes could uptake fluorescent-labeled miR-150-3p mimics and FLS–EVs, and GW4869 suppressed this uptake. The overexpression of miR-150-3p could significantly reduce the concentrations of pro-inflammatory cytokines in the cell culture medium and the expression of the miR-150-3p target T cell receptor-interacting molecule 14 (Trim14), as well as the innate immune-related factors, including nuclear factor kappa B (NF-κB) and interferon-β (IFN-β). Similarly to the in vitro findings, the miR-150-3p level in the serum EVs was significantly upregulated among the EV-treated rats. In the AC of the OA rat model injected with H-FLS–EVs, the joint degeneration was suppressed, and Type II collagen (COLII) and aggrecan (ACAN) were significantly upregulated, whereas the innate immune-related factors Trim14, NF-κB, and IFN-β were downregulated compared with the levels in the untreated OA rats. Notably, the suppression of joint degeneration was more significant when H-FLS–EVs were administered at the early stages of OA rather than the late stages. Conclusion: H-FLS–EVs protect chondrocyte function and maintain joint homeostasis by modulating the innate immune response by suppressing the Trim14/NF-κB/IFNβ axis. These effects are achieved through the EV-mediated transport of miR-150-3p from the FLSs to the chondrocytes. Our findings show that EV-mediated miR-150-3p can be used to suppress OA, thus providing a novel therapeutic strategy. Additionally, the EV-mediated miR-150-3p transport may also serve as a potential biomarker in the diagnosis, treatment, and prognosis of OA. Full article

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16 pages, 1730 KiB

Open AccessReview

Dynamin-Independent Mechanisms of Endocytosis and Receptor Trafficking

by Chayanika Gundu, Vijay Kumar Arruri, Poonam Yadav, Umashanker Navik, Ashutosh Kumar, Veda Sudhir Amalkar, Ajit Vikram and Ravinder Reddy Gaddam

Cells 2022, 11(16), 2557; https://doi.org/10.3390/cells11162557 - 17 Aug 2022

Cited by 11 | Viewed by 4679

Abstract

Endocytosis is a fundamental mechanism by which cells perform housekeeping functions. It occurs via a variety of mechanisms and involves many regulatory proteins. The GTPase dynamin acts as a “molecular scissor” to form endocytic vesicles and is a critical regulator among the proteins [...] Read more.

Endocytosis is a fundamental mechanism by which cells perform housekeeping functions. It occurs via a variety of mechanisms and involves many regulatory proteins. The GTPase dynamin acts as a “molecular scissor” to form endocytic vesicles and is a critical regulator among the proteins involved in endocytosis. Some GTPases (e.g., Cdc42, arf6, RhoA), membrane proteins (e.g., flotillins, tetraspanins), and secondary messengers (e.g., calcium) mediate dynamin-independent endocytosis. These pathways may be convergent, as multiple pathways exist in a single cell. However, what determines the specific path of endocytosis is complex and challenging to comprehend. This review summarizes the mechanisms of dynamin-independent endocytosis, the involvement of microRNAs, and factors that contribute to the cellular decision about the specific route of endocytosis. Full article

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20 pages, 3544 KiB

Open AccessFeature PaperArticle

miR-324-5p and miR-30c-2-3p Alter Renal Mineralocorticoid Receptor Signaling under Hypertonicity

by Thi An Vu, Ingrid Lema, Imene Hani, Lydie Cheval, Laura Atger-Lallier, Vilayvane Souvannarath, Julie Perrot, Mélanie Souvanheuane, Yannick Marie, Sylvie Fabrega, Anne Blanchard, Jérôme Bouligand, Peter Kamenickỷ, Gilles Crambert, Laetitia Martinerie, Marc Lombès and Say Viengchareun

Cells 2022, 11(9), 1377; https://doi.org/10.3390/cells11091377 - 19 Apr 2022

Cited by 5 | Viewed by 2750

Abstract

The Mineralocorticoid Receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron, but mechanisms regulating MR expression are still poorly understood. We previously showed that RNA Binding Proteins (RBPs) regulate MR expression at the post-transcriptional level in response to variations of [...] Read more.

The Mineralocorticoid Receptor (MR) mediates the sodium-retaining action of aldosterone in the distal nephron, but mechanisms regulating MR expression are still poorly understood. We previously showed that RNA Binding Proteins (RBPs) regulate MR expression at the post-transcriptional level in response to variations of extracellular tonicity. Herein, we highlight a novel regulatory mechanism involving the recruitment of microRNAs (miRNAs) under hypertonicity. RT-qPCR validated miRNAs candidates identified by high throughput screening approaches and transfection of a luciferase reporter construct together with miRNAs Mimics or Inhibitors demonstrated their functional interaction with target transcripts. Overexpression strategies using Mimics or lentivirus revealed the impact on MR expression and signaling in renal KC3AC1 cells. miR-324-5p and miR-30c-2-3p expression are increased under hypertonicity in KC3AC1 cells. These miRNAs directly affect Nr3c2 (MR) transcript stability, act with Tis11b to destabilize MR transcript but also repress Elavl1 (HuR) transcript, which enhances MR expression and signaling. Overexpression of miR-324-5p and miR-30c-2-3p alter MR expression and signaling in KC3AC1 cells with blunted responses in terms of aldosterone-regulated genes expression. We also confirm that their expression is increased by hypertonicity in vivo in the kidneys of mice treated with furosemide. These findings may have major implications for the pathogenesis of renal dysfunctions, sodium retention, and mineralocorticoid resistance. Full article

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27 pages, 4378 KiB

Open AccessArticle

Dissecting miRNA–Gene Networks to Map Clinical Utility Roads of Pharmacogenomics-Guided Therapeutic Decisions in Cardiovascular Precision Medicine

by Fani Chatzopoulou, Konstantinos A. Kyritsis, Christos I. Papagiannopoulos, Eleftheria Galatou, Nikolaos Mittas, Nikoleta F. Theodoroula, Andreas S. Papazoglou, Efstratios Karagiannidis, Maria Chatzidimitriou, Anna Papa, Georgios Sianos, Lefteris Angelis, Dimitrios Chatzidimitriou and Ioannis S. Vizirianakis

Cells 2022, 11(4), 607; https://doi.org/10.3390/cells11040607 - 10 Feb 2022

Cited by 12 | Viewed by 3587

Abstract

MicroRNAs (miRNAs) create systems networks and gene-expression circuits through molecular signaling and cell interactions that contribute to health imbalance and the emergence of cardiovascular disorders (CVDs). Because the clinical phenotypes of CVD patients present a diversity in their pathophysiology and heterogeneity at the [...] Read more.

MicroRNAs (miRNAs) create systems networks and gene-expression circuits through molecular signaling and cell interactions that contribute to health imbalance and the emergence of cardiovascular disorders (CVDs). Because the clinical phenotypes of CVD patients present a diversity in their pathophysiology and heterogeneity at the molecular level, it is essential to establish genomic signatures to delineate multifactorial correlations, and to unveil the variability seen in therapeutic intervention outcomes. The clinically validated miRNA biomarkers, along with the relevant SNPs identified, have to be suitably implemented in the clinical setting in order to enhance patient stratification capacity, to contribute to a better understanding of the underlying pathophysiological mechanisms, to guide the selection of innovative therapeutic schemes, and to identify innovative drugs and delivery systems. In this article, the miRNA–gene networks and the genomic signatures resulting from the SNPs will be analyzed as a method of highlighting specific gene-signaling circuits as sources of molecular knowledge which is relevant to CVDs. In concordance with this concept, and as a case study, the design of the clinical trial GESS (NCT03150680) is referenced. The latter is presented in a manner to provide a direction for the improvement of the implementation of pharmacogenomics and precision cardiovascular medicine trials. Full article

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4 pages, 211 KiB

Open AccessEditorial

The Enticing Path of miR Therapeutics: Difficult but Not without Prospects

by Ajit Vikram

Cells 2022, 11(3), 418; https://doi.org/10.3390/cells11030418 - 26 Jan 2022

Cited by 1 | Viewed by 2033

Abstract

MicroRNAs (miRs) are short non-coding RNAs that regulate the translation and stability of mRNAs to fine-tune gene expression [...] Full article

2021

Jump to: 2023, 2022

17 pages, 4092 KiB

Open AccessArticle

miR-511 Deficiency Protects Mice from Experimental Colitis by Reducing TLR3 and TLR4 Responses via WD Repeat and FYVE-Domain-Containing Protein 1

by Shafaque Rahman, Jolien Vandewalle, Patricia H. P. van Hamersveld, Caroline Verseijden, Olaf Welting, Aldo Jongejan, Pierina Casanova, Sybren L. Meijer, Claude Libert, Theodorus B. M. Hakvoort, Wouter J. de Jonge and Sigrid E. M. Heinsbroek

Cells 2022, 11(1), 58; https://doi.org/10.3390/cells11010058 - 25 Dec 2021

Cited by 5 | Viewed by 3599

Abstract

Antimicrobial responses play an important role in maintaining intestinal heath. Recently we reported that miR-511 may regulate TLR4 responses leading to enhanced intestinal inflammation. However, the exact mechanism remained unclear. In this study we investigated the effect of miR-511 deficiency on anti-microbial responses [...] Read more.

Antimicrobial responses play an important role in maintaining intestinal heath. Recently we reported that miR-511 may regulate TLR4 responses leading to enhanced intestinal inflammation. However, the exact mechanism remained unclear. In this study we investigated the effect of miR-511 deficiency on anti-microbial responses and DSS-induced intestinal inflammation. miR-511-deficient mice were protected from DSS-induced colitis as shown by significantly lower disease activity index, weight loss and histology scores in the miR-511-deficient group. Furthermore, reduced inflammatory cytokine responses were observed in colons of miR-511 deficient mice. In vitro studies with bone marrow-derived M2 macrophages showed reduced TLR3 and TLR4 responses in miR-511-deficient macrophages compared to WT macrophages. Subsequent RNA sequencing revealed Wdfy1 as the potential miR-511 target. WDFY1 deficiency is related to impaired TLR3/TLR4 immune responses and the expression was downregulated in miR-511-deficient macrophages and colons. Together, this study shows that miR-511 is involved in the regulation of intestinal inflammation through downstream regulation of TLR3 and TLR4 responses via Wdfy1. Full article

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13 pages, 3377 KiB

Open AccessArticle

Identifying Putative Causal Links between MicroRNAs and Severe COVID-19 Using Mendelian Randomization

by Chang Li, Aurora Wu, Kevin Song, Jeslyn Gao, Eric Huang, Yongsheng Bai and Xiaoming Liu

Cells 2021, 10(12), 3504; https://doi.org/10.3390/cells10123504 - 11 Dec 2021

Cited by 10 | Viewed by 4246

Abstract

The SARS-CoV-2 (COVID-19) pandemic has caused millions of deaths worldwide. Early risk assessment of COVID-19 cases can help direct early treatment measures that have been shown to improve the prognosis of severe cases. Currently, circulating miRNAs have not been evaluated as canonical COVID-19 [...] Read more.

The SARS-CoV-2 (COVID-19) pandemic has caused millions of deaths worldwide. Early risk assessment of COVID-19 cases can help direct early treatment measures that have been shown to improve the prognosis of severe cases. Currently, circulating miRNAs have not been evaluated as canonical COVID-19 biomarkers, and identifying biomarkers that have a causal relationship with COVID-19 is imperative. To bridge these gaps, we aim to examine the causal effects of miRNAs on COVID-19 severity in this study using two-sample Mendelian randomization approaches. Multiple studies with available GWAS summary statistics data were retrieved. Using circulating miRNA expression data as exposure, and severe COVID-19 cases as outcomes, we identified ten unique miRNAs that showed causality across three phenotype groups of COVID-19. Using expression data from an independent study, we validated and identified two high-confidence miRNAs, namely, hsa-miR-30a-3p and hsa-miR-139-5p, which have putative causal effects on developing cases of severe COVID-19. Using existing literature and publicly available databases, the potential causative roles of these miRNAs were investigated. This study provides a novel way of utilizing miRNA eQTL data to help us identify potential miRNA biomarkers to make better and early diagnoses and risk assessments of severe COVID-19 cases. Full article

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21 pages, 1367 KiB

Open AccessReview

MicroRNA Cues from Nature: A Roadmap to Decipher and Combat Challenges in Human Health and Disease?

by Gurjit Singh and Kenneth B. Storey

Cells 2021, 10(12), 3374; https://doi.org/10.3390/cells10123374 - 30 Nov 2021

Cited by 23 | Viewed by 4850

Abstract

MicroRNAs are small non-coding RNA (18–24 nt long) that fine-tune gene expression at the post-transcriptional level. With the advent of “multi-omics” analysis and sequencing approaches, they have now been implicated in every facet of basic molecular networks, including metabolism, homeostasis, and cell survival [...] Read more.

MicroRNAs are small non-coding RNA (18–24 nt long) that fine-tune gene expression at the post-transcriptional level. With the advent of “multi-omics” analysis and sequencing approaches, they have now been implicated in every facet of basic molecular networks, including metabolism, homeostasis, and cell survival to aid cellular machinery in adapting to changing environmental cues. Many animals must endure harsh environmental conditions in nature, including cold/freezing temperatures, oxygen limitation (anoxia/hypoxia), and food or water scarcity, often requiring them to revamp their metabolic organization, frequently on a seasonal or life stage basis. MicroRNAs are important regulatory molecules in such processes, just as they are now well-known to be involved in many human responses to stress or disease. The present review outlines the role of miRNAs in natural animal models of environmental stress and adaptation including torpor/hibernation, anoxia/hypoxia tolerance, and freeze tolerance. We also discuss putative medical applications of advances in miRNA biology including organ preservation for transplant, inflammation, ageing, metabolic disorders (e.g., obesity), mitochondrial dysfunction (mitoMirs) as well as specialized miRNA subgroups respective to low temperature (CryomiRs) and low oxygen (OxymiRs). The review also covers differential regulation of conserved and novel miRNAs involved at cell, tissue, and stress specific levels across multiple species and their roles in survival. Ultimately, the species-specific comparison and conserved miRNA responses seen in evolutionarily disparate animal species can help us to understand the complex miRNA network involved in regulating and reorganizing metabolism to achieve diverse outcomes, not just in nature, but in human health and disease. Full article

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28 pages, 1456 KiB

Open AccessReview

The Impact of MicroRNAs during Inflammatory Bowel Disease: Effects on the Mucus Layer and Intercellular Junctions for Gut Permeability

by Sarah Stiegeler, Kevin Mercurio, Miruna Alexandra Iancu and Sinéad C. Corr

Cells 2021, 10(12), 3358; https://doi.org/10.3390/cells10123358 - 30 Nov 2021

Cited by 18 | Viewed by 5147

Abstract

Research on inflammatory bowel disease (IBD) has produced mounting evidence for the modulation of microRNAs (miRNAs) during pathogenesis. MiRNAs are small, non-coding RNAs that interfere with the translation of mRNAs. Their high stability in free circulation at various regions of the body allows [...] Read more.

Research on inflammatory bowel disease (IBD) has produced mounting evidence for the modulation of microRNAs (miRNAs) during pathogenesis. MiRNAs are small, non-coding RNAs that interfere with the translation of mRNAs. Their high stability in free circulation at various regions of the body allows researchers to utilise miRNAs as biomarkers and as a focus for potential treatments of IBD. Yet, their distinct regulatory roles at the gut epithelial barrier remain elusive due to the fact that there are several external and cellular factors contributing to gut permeability. This review focuses on how miRNAs may compromise two components of the gut epithelium that together form the initial physical barrier: the mucus layer and the intercellular epithelial junctions. Here, we summarise the impact of miRNAs on goblet cell secretion and mucin structure, along with the proper function of various junctional proteins involved in paracellular transport, cell adhesion and communication. Knowledge of how this elaborate network of cells at the gut epithelial barrier becomes compromised as a result of dysregulated miRNA expression, thereby contributing to the development of IBD, will support the generation of miRNA-associated biomarker panels and therapeutic strategies that detect and ameliorate gut permeability. Full article

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15 pages, 838 KiB

Open AccessReview

Regulation of Hypoxic Signaling and Oxidative Stress via the MicroRNA–SIRT2 Axis and Its Relationship with Aging-Related Diseases

by Taku Kaitsuka, Masayuki Matsushita and Nobuko Matsushita

Cells 2021, 10(12), 3316; https://doi.org/10.3390/cells10123316 - 26 Nov 2021

Cited by 9 | Viewed by 3567

Abstract

The sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylase and ADP-ribosyl transferases plays key roles in aging, metabolism, stress response, and aging-related diseases. SIRT2 is a unique sirtuin that is expressed in the cytosol and is abundant in neuronal cells. Various microRNAs were recently [...] Read more.

The sirtuin family of nicotinamide adenine dinucleotide-dependent deacetylase and ADP-ribosyl transferases plays key roles in aging, metabolism, stress response, and aging-related diseases. SIRT2 is a unique sirtuin that is expressed in the cytosol and is abundant in neuronal cells. Various microRNAs were recently reported to regulate SIRT2 expression via its 3′-untranslated region (UTR), and single nucleotide polymorphisms in the miRNA-binding sites of SIRT2 3′-UTR were identified in patients with neurodegenerative diseases. The present review highlights recent studies into SIRT2-mediated regulation of the stress response, posttranscriptional regulation of SIRT2 by microRNAs, and the implications of the SIRT2–miRNA axis in aging-related diseases. Full article

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29 pages, 3234 KiB

Open AccessReview

MicroRNA-214 in Health and Disease

by Meer M. J. Amin, Christopher J. Trevelyan and Neil A. Turner

Cells 2021, 10(12), 3274; https://doi.org/10.3390/cells10123274 - 23 Nov 2021

Cited by 27 | Viewed by 4277

Abstract

MicroRNAs (miRNAs) are endogenously expressed, non-coding RNA molecules that mediate the post-transcriptional repression and degradation of mRNAs by targeting their 3′ untranslated region (3′-UTR). Thousands of miRNAs have been identified since their first discovery in 1993, and miR-214 was first reported to promote [...] Read more.

MicroRNAs (miRNAs) are endogenously expressed, non-coding RNA molecules that mediate the post-transcriptional repression and degradation of mRNAs by targeting their 3′ untranslated region (3′-UTR). Thousands of miRNAs have been identified since their first discovery in 1993, and miR-214 was first reported to promote apoptosis in HeLa cells. Presently, miR-214 is implicated in an extensive range of conditions such as cardiovascular diseases, cancers, bone formation and cell differentiation. MiR-214 has shown pleiotropic roles in contributing to the progression of diseases such as gastric and lung cancers but may also confer cardioprotection against excessive fibrosis and oxidative damage. These contrasting functions are achieved through the diverse cast of miR-214 targets. Through silencing or overexpressing miR-214, the detrimental effects can be attenuated, and the beneficial effects promoted in order to improve health outcomes. Therefore, discovering novel miR-214 targets and understanding how miR-214 is dysregulated in human diseases may eventually lead to miRNA-based therapies. MiR-214 has also shown promise as a diagnostic biomarker in identifying breast cancer and coronary artery disease. This review provides an up-to-date discussion of miR-214 literature by describing relevant roles in health and disease, areas of disagreement, and the future direction of the field. Full article

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19 pages, 7375 KiB

Open AccessArticle

microRNA-27a-3p but Not -5p Is a Crucial Mediator of Human Adipogenesis

by Hang Wu, Taner Pula, Daniel Tews, Ez-Zoubir Amri, Klaus-Michael Debatin, Martin Wabitsch, Pamela Fischer-Posovszky and Julian Roos

Cells 2021, 10(11), 3205; https://doi.org/10.3390/cells10113205 - 17 Nov 2021

Cited by 19 | Viewed by 3865

Abstract

MicroRNAs (miRNAs), a class of small, non-coding RNA molecules, play an important role in the posttranscriptional regulation of gene expression, thereby influencing important cellular functions. In adipocytes, miRNAs show import regulatory features and are described to influence differentiation as well as metabolic, endocrine, [...] Read more.

MicroRNAs (miRNAs), a class of small, non-coding RNA molecules, play an important role in the posttranscriptional regulation of gene expression, thereby influencing important cellular functions. In adipocytes, miRNAs show import regulatory features and are described to influence differentiation as well as metabolic, endocrine, and inflammatory functions. We previously identified miR-27a being upregulated under inflammatory conditions in human adipocytes and aimed to elucidate its function in adipocyte biology. Both strands of miR-27a, miR-27a-3p and -5p, were downregulated during the adipogenic differentiation of Simpson–Golabi–Behmel syndrome (SGBS) cells, human multipotent adipose-derived stem cells (hMADS), and human primary adipose-derived stromal cells (hASCs). Using miRNA-mimic transfection, we observed that miR-27a-3p is a crucial regulator of adipogenesis, while miR-27a-5p did not alter the differentiation capacity in SGBS cells. In silico screening predicted lipoprotein lipase (LPL) and peroxisome proliferator activated receptor γ (PPARγ) as potential targets of miR-27a-3p. The downregulation of both genes was verified in vitro, and the interaction of miR-27-3p with target sites in the 3′ UTRs of both genes was confirmed via a miRNA-reporter-gene assay. Here, the knockdown of LPL did not interfere with adipogenic differentiation, while PPARγ knockdown decreased adipogenesis significantly, suggesting that miR-27-3p exerts its inhibitory effect on adipogenesis by repressing PPARγ. Taken together, we identified and validated a crucial role for miR-27a-3p in human adipogenesis played by targeting the essential adipogenic transcription factor PPARγ. Though we confirmed LPL as an additional target of miR-27a-3p, it does not appear to be involved in regulating human adipogenesis. Thereby, our findings call the conclusions drawn from previous studies, which identified LPL as a crucial regulator for murine and human adipogenesis, into question. Full article

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12 pages, 403 KiB

Open AccessReview

A Review on the Evolving Roles of MiRNA-Based Technologies in Diagnosing and Treating Heart Failure

by Peter J. Kennel and P. Christian Schulze

Cells 2021, 10(11), 3191; https://doi.org/10.3390/cells10113191 - 16 Nov 2021

Cited by 14 | Viewed by 3425

Abstract

MiRNA-regulated processes are pivotal in cardiovascular homeostasis and disease. These short non-coding RNAs have ideal properties that could be utilized as potential biomarkers; moreover, their functions as post-transcriptional regulators of mRNA make them interesting therapeutic targets. In this review, we summarize the current [...] Read more.

MiRNA-regulated processes are pivotal in cardiovascular homeostasis and disease. These short non-coding RNAs have ideal properties that could be utilized as potential biomarkers; moreover, their functions as post-transcriptional regulators of mRNA make them interesting therapeutic targets. In this review, we summarize the current state of miRNA-based biomarkers in a variety of diseases leading to heart failure, as well as provide an outlook on developing miRNA-based therapies in the heart failure field. Full article

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21 pages, 1467 KiB

Open AccessFeature PaperReview

The Challenges and Opportunities in the Development of MicroRNA Therapeutics: A Multidisciplinary Viewpoint

by Mohammad Yahya Momin, Ravinder Reddy Gaddam, Madeline Kravitz, Anisha Gupta and Ajit Vikram

Cells 2021, 10(11), 3097; https://doi.org/10.3390/cells10113097 - 9 Nov 2021

Cited by 40 | Viewed by 4605

Abstract

microRNAs (miRs) are emerging as attractive therapeutic targets because of their small size, specific targetability, and critical role in disease pathogenesis. However, <20 miR targeting molecules have entered clinical trials, and none progressed to phase III. The difficulties in miR target identification, the [...] Read more.

microRNAs (miRs) are emerging as attractive therapeutic targets because of their small size, specific targetability, and critical role in disease pathogenesis. However, <20 miR targeting molecules have entered clinical trials, and none progressed to phase III. The difficulties in miR target identification, the moderate efficacy of miR inhibitors, cell type-specific delivery, and adverse outcomes have impeded the development of miR therapeutics. These hurdles are rooted in the functional complexity of miR’s role in disease and sequence complementarity-dependent/-independent effects in nontarget tissues. The advances in understanding miR’s role in disease, the development of efficient miR inhibitors, and innovative delivery approaches have helped resolve some of these hurdles. In this review, we provide a multidisciplinary viewpoint on the challenges and opportunities in the development of miR therapeutics. Full article

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36 pages, 22844 KiB

Open AccessReview

Perspectives on miRNAs Targeting DKK1 for Developing Hair Regeneration Therapy

by Dimitri Papukashvili, Nino Rcheulishvili, Cong Liu, Fengfei Xie, Deependra Tyagi, Yunjiao He and Peng George Wang

Cells 2021, 10(11), 2957; https://doi.org/10.3390/cells10112957 - 30 Oct 2021

Cited by 21 | Viewed by 9079

Abstract

Androgenetic alopecia (AGA) remains an unsolved problem for the well-being of humankind, although multiple important involvements in hair growth have been discovered. Up until now, there is no ideal therapy in clinical practice in terms of efficacy and safety. Ultimately, there is a [...] Read more.

Androgenetic alopecia (AGA) remains an unsolved problem for the well-being of humankind, although multiple important involvements in hair growth have been discovered. Up until now, there is no ideal therapy in clinical practice in terms of efficacy and safety. Ultimately, there is a strong need for developing a feasible remedy for preventing and treating AGA. The Wnt/β-catenin signaling pathway is critical in hair restoration. Thus, AGA treatment via modulating this pathway is rational, although challenging. Dickkopf-related protein 1 (DKK1) is distinctly identified as an inhibitor of canonical Wnt/β-catenin signaling. Thus, in order to stimulate the Wnt/β-catenin signaling pathway, inhibition of DKK1 is greatly demanding. Studying DKK1-targeting microRNAs (miRNAs) involved in the Wnt/β-catenin signaling pathway may lay the groundwork for the promotion of hair growth. Bearing in mind that DKK1 inhibition in the balding scalp of AGA certainly makes sense, this review sheds light on the perspectives of miRNA-mediated hair growth for treating AGA via regulating DKK1 and, eventually, modulating Wnt/β-catenin signaling. Consequently, certain miRNAs regulating the Wnt/β-catenin signaling pathway via DKK1 inhibition might represent attractive candidates for further studies focusing on promoting hair growth and AGA therapy. Full article

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20 pages, 2041 KiB

Open AccessReview

Deciphering the Long Non-Coding RNAs and MicroRNAs Coregulation Networks in Ovarian Cancer Development: An Overview

by César López-Camarillo, Erika Ruíz-García, Yarely M. Salinas-Vera, Macrina B. Silva-Cázares, Olga N. Hernández-de la Cruz, Laurence A. Marchat and Dolores Gallardo-Rincón

Cells 2021, 10(6), 1407; https://doi.org/10.3390/cells10061407 - 6 Jun 2021

Cited by 4 | Viewed by 4041

Abstract

Non-coding RNAs are emergent elements from the genome, which do not encode for proteins but have relevant cellular functions impacting almost all the physiological processes occurring in eukaryotic cells. In particular, microRNAs and long non-coding RNAs (lncRNAs) are a new class of small [...] Read more.

Non-coding RNAs are emergent elements from the genome, which do not encode for proteins but have relevant cellular functions impacting almost all the physiological processes occurring in eukaryotic cells. In particular, microRNAs and long non-coding RNAs (lncRNAs) are a new class of small RNAs transcribed from the genome, which modulate the expression of specific genes at transcriptional and posttranscriptional levels, thus adding a new regulatory layer in the flux of genetic information. In cancer cells, the miRNAs and lncRNAs interactions with its target genes and functional pathways are deregulated as a consequence of epigenetic and genetic alterations occurring during tumorigenesis. In this review, we summarize the actual knowledge on the interplay of lncRNAs with its cognate miRNAs and mRNAs pairs, which interact in coregulatory networks with a particular emphasis on the mechanisms underlying its oncogenic behavior in ovarian cancer. Specifically, we reviewed here the evidences unraveling the relevant roles of lncRNAs/miRNAs pairs in altered regulation of cell migration, angiogenesis, therapy resistance, and Warburg effect. Finally, we also discussed its potential clinical implications in ovarian cancer and related endocrine disease therapies. Full article

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20 pages, 2483 KiB

Open AccessArticle

Integrated microRNA and mRNA Expression Profiling Identifies Novel Targets and Networks Associated with Ebstein’s Anomaly

by Masood Abu-Halima, Viktoria Wagner, Lea Simone Becker, Basim M. Ayesh, Mohammed Abd El-Rahman, Ulrike Fischer, Eckart Meese and Hashim Abdul-Khaliq

Cells 2021, 10(5), 1066; https://doi.org/10.3390/cells10051066 - 30 Apr 2021

Cited by 5 | Viewed by 3297

Abstract

Little is known about abundance level changes of circulating microRNAs (miRNAs) and messenger RNAs (mRNA) in patients with Ebstein’s anomaly (EA). Here, we performed an integrated analysis to identify the differentially abundant miRNAs and mRNA targets and to identify the potential therapeutic targets [...] Read more.

Little is known about abundance level changes of circulating microRNAs (miRNAs) and messenger RNAs (mRNA) in patients with Ebstein’s anomaly (EA). Here, we performed an integrated analysis to identify the differentially abundant miRNAs and mRNA targets and to identify the potential therapeutic targets that might be involved in the mechanisms underlying EA. A large panel of human miRNA and mRNA microarrays were conducted to determine the genome-wide expression profiles in the blood of 16 EA patients and 16 age and gender-matched healthy control volunteers (HVs). Differential abundance level of single miRNA and mRNA was validated by Real-Time quantitative PCR (RT-qPCR). Enrichment analyses of altered miRNA and mRNA abundance levels were identified using bioinformatics tools. Altered miRNA and mRNA abundance levels were observed between EA patients and HVs. Among the deregulated miRNAs and mRNAs, 76 miRNAs (49 lower abundance and 27 higher abundance, fold-change of ≥2) and 29 mRNAs (25 higher abundance and 4 lower abundance, fold-change of ≥1.5) were identified in EA patients compared to HVs. Bioinformatics analysis identified 37 pairs of putative miRNA-mRNA interactions. The majority of the correlations were detected between the lower abundance level of miRNA and higher abundance level of mRNA, except for let-7b-5p, which showed a higher abundance level and their target gene, SCRN3, showed a lower abundance level. Pathway enrichment analysis of the deregulated mRNAs identified 35 significant pathways that are mostly involved in signal transduction and cellular interaction pathways. Our findings provide new insights into a potential molecular biomarker(s) for the EA that may guide the development of novel targeting therapies. Full article

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14 pages, 3339 KiB

Open AccessArticle

Nanoparticle Delivered Anti-miR-141-3p for Stroke Therapy

by Karishma Dhuri, Rutesh N. Vyas, Leslie Blumenfeld, Rajkumar Verma and Raman Bahal

Cells 2021, 10(5), 1011; https://doi.org/10.3390/cells10051011 - 25 Apr 2021

Cited by 29 | Viewed by 4889

Abstract

Ischemic stroke and factors modifying ischemic stroke responses, such as social isolation, contribute to long-term disability worldwide. Several studies demonstrated that the aberrant levels of microRNAs contribute to ischemic stroke injury. In prior studies, we established that miR-141-3p increases after ischemic stroke and [...] Read more.

Ischemic stroke and factors modifying ischemic stroke responses, such as social isolation, contribute to long-term disability worldwide. Several studies demonstrated that the aberrant levels of microRNAs contribute to ischemic stroke injury. In prior studies, we established that miR-141-3p increases after ischemic stroke and post-stroke isolation. Herein, we explored two different anti-miR oligonucleotides; peptide nucleic acid (PNAs) and phosphorothioates (PS) for ischemic stroke therapy. We used US FDA approved biocompatible poly (lactic-co-glycolic acid) (PLGA)-based nanoparticle formulations for delivery. The PNA and PS anti-miRs were encapsulated in PLGA nanoparticles by double emulsion solvent evaporation technique. All the formulated nanoparticles showed uniform morphology, size, distribution, and surface charge density. Nanoparticles also exhibited a controlled nucleic acid release profile for 48 h. Further, we performed in vivo studies in the mouse model of ischemic stroke. Ischemic stroke was induced by transient (60 min) occlusion of middle cerebral artery occlusion followed by a reperfusion for 48 or 72 h. We assessed the blood-brain barrier permeability of PLGA NPs containing fluorophore (TAMRA) anti-miR probe after systemic delivery. Confocal imaging shows uptake of fluorophore tagged anti-miR in the brain parenchyma. Next, we evaluated the therapeutic efficacy after systemic delivery of nanoparticles containing PNA and PS anti-miR-141-3p in mice after stroke. Post-treatment differentially reduced both miR-141-3p levels in brain tissue and infarct injury. We noted PNA-based anti-miR showed superior efficacy compared to PS-based anti-miR. Herein, we successfully established that nanoparticles encapsulating PNA or PS-based anti-miRs-141-3p probes could be used as a potential treatment for ischemic stroke. Full article

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10 pages, 1621 KiB

Open AccessArticle

Analysis of Circulating microRNA Signatures and Preeclampsia Development

by Margarita L. Martinez-Fierro and Idalia Garza-Veloz

Cells 2021, 10(5), 1003; https://doi.org/10.3390/cells10051003 - 24 Apr 2021

Cited by 18 | Viewed by 2964

Abstract

microRNAs are important regulators of cell processes and have been proposed as potential preeclampsia biomarkers. We evaluated serum microRNA expression profiling to identify microRNAs involved in preeclampsia development. Serum microRNA expression profiling was evaluated at 12, 16, and 20 weeks of gestation (WG), [...] Read more.

microRNAs are important regulators of cell processes and have been proposed as potential preeclampsia biomarkers. We evaluated serum microRNA expression profiling to identify microRNAs involved in preeclampsia development. Serum microRNA expression profiling was evaluated at 12, 16, and 20 weeks of gestation (WG), and at the time of preeclampsia diagnosis. Two groups were evaluated using TaqMan low-density array plates: a control group with 18 normotensive pregnant women and a case group with 16 patients who developed preeclampsia during the follow-up period. Fifty-three circulating microRNAs were differentially expressed between groups (p < 0.05). Compared with controls, hsa-miR-628-3p showed the highest relative quantity values (at 12 WG = 7.7 and at 20 WG = 3.45) and the hsa-miRs -151a-3p and -573 remained differentially expressed from 16 to 20 WG (p < 0.05). Signaling pathways including cancer-related, axon guidance, Neurotrophin, GnRH, VEGF, and B/T cell receptor, were most commonly altered. Further target gene prediction revealed that nuclear factor of activated T-cells 5 gene was included among the transcriptional targets of preeclampsia-modulated microRNAs. Specific microRNAs including hsa-miRs -628-3p, -151a-3p, and -573 were differentially expressed in serum of pregnant women before they developed preeclampsia compared with controls and their participation in the preeclampsia development should be considered. Full article

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