RESUMO
We propose that the teratoma, a recognized standard for validating pluripotency in stem cells, could be a promising platform for studying human developmental processes. Performing single-cell RNA sequencing (RNA-seq) of 179,632 cells across 23 teratomas from 4 cell lines, we found that teratomas reproducibly contain approximately 20 cell types across all 3 germ layers, that inter-teratoma cell type heterogeneity is comparable with organoid systems, and teratoma gut and brain cell types correspond well to similar fetal cell types. Furthermore, cellular barcoding confirmed that injected stem cells robustly engraft and contribute to all lineages. Using pooled CRISPR-Cas9 knockout screens, we showed that teratomas can enable simultaneous assaying of the effects of genetic perturbations across all germ layers. Additionally, we demonstrated that teratomas can be sculpted molecularly via microRNA (miRNA)-regulated suicide gene expression to enrich for specific tissues. Taken together, teratomas are a promising platform for modeling multi-lineage development, pan-tissue functional genetic screening, and tissue engineering.
Assuntos
Linhagem da Célula , Modelos Biológicos , Teratoma/patologia , Animais , Células HEK293 , Humanos , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , MicroRNAs/genética , MicroRNAs/metabolismo , Reprodutibilidade dos Testes , Teratoma/genéticaRESUMO
Small RNAs base pair with and regulate mRNA translation and stability. For both bacterial small regulatory RNAs and eukaryotic microRNAs, association with partner proteins is critical for the stability and function of the regulatory RNAs. We review the mechanisms for degradation of these RNAs: displacement of the regulatory RNA from its protein partner (in bacteria) or destruction of the protein and its associated microRNAs (in eukaryotes). These mechanisms can allow specific destruction of a regulatory RNA via pairing with a decay trigger RNA or function as global off switches by disrupting the stability or function of the protein partner.
Assuntos
MicroRNAs , Estabilidade de RNA , MicroRNAs/metabolismo , MicroRNAs/genética , Estabilidade de RNA/genética , Animais , Humanos , RNA Bacteriano/metabolismo , RNA Bacteriano/genética , Regulação da Expressão GênicaRESUMO
Microprocessor (MP), DROSHA-DGCR8, processes primary miRNA transcripts (pri-miRNAs) to initiate miRNA biogenesis. The canonical cleavage mechanism of MP has been extensively investigated and comprehensively validated for two decades. However, this canonical mechanism cannot account for the processing of certain pri-miRNAs in animals. In this study, by conducting high-throughput pri-miRNA cleavage assays for approximately 260,000 pri-miRNA sequences, we discovered and comprehensively characterized a noncanonical cleavage mechanism of MP. This noncanonical mechanism does not need several RNA and protein elements essential for the canonical mechanism; instead, it utilizes previously unrecognized DROSHA dsRNA recognition sites (DRESs). Interestingly, the noncanonical mechanism is conserved across animals and plays a particularly significant role in C. elegans. Our established noncanonical mechanism elucidates MP cleavage in numerous RNA substrates unaccounted for by the canonical mechanism in animals. This study suggests a broader substrate repertoire of animal MPs and an expanded regulatory landscape for miRNA biogenesis.
Assuntos
MicroRNAs , Animais , MicroRNAs/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Ligação a RNA/metabolismo , Ribonuclease III/metabolismo , RNA de Cadeia Dupla , Processamento Pós-Transcricional do RNARESUMO
MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression that play critical roles in development and disease. Target-directed miRNA degradation (TDMD), a pathway in which miRNAs that bind to specialized targets with extensive complementarity are rapidly decayed, has emerged as a potent mechanism of controlling miRNA levels. Nevertheless, the biological role and scope of miRNA regulation by TDMD in mammals remains poorly understood. To address these questions, we generated mice with constitutive or conditional deletion of Zswim8, which encodes an essential TDMD factor. Loss of Zswim8 resulted in developmental defects in the heart and lungs, growth restriction, and perinatal lethality. Small RNA sequencing of embryonic tissues revealed widespread miRNA regulation by TDMD and greatly expanded the known catalog of miRNAs regulated by this pathway. These experiments also uncovered novel features of TDMD-regulated miRNAs, including their enrichment in cotranscribed clusters and examples in which TDMD underlies "arm switching," a phenomenon wherein the dominant strand of a miRNA precursor changes in different tissues or conditions. Importantly, deletion of two miRNAs, miR-322 and miR-503, rescued growth of Zswim8-null embryos, directly implicating the TDMD pathway as a regulator of mammalian body size. These data illuminate the broad landscape and developmental role of TDMD in mammals.
Assuntos
MicroRNAs , Camundongos , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Mamíferos/genética , Sequência de BasesRESUMO
The distribution, dynamics, and function of RNA structures in human development are under-explored. Here, we systematically assayed RNA structural dynamics and their relationship with gene expression, translation, and decay during human neurogenesis. We observed that the human ESC transcriptome is globally more structurally accessible than differentiated cells and undergoes extensive RNA structure changes, particularly in the 3' UTR. Additionally, RNA structure changes during differentiation are associated with translation and decay. We observed that RBP and miRNA binding is associated with RNA structural changes during early neuronal differentiation, and splicing is associated during later neuronal differentiation. Furthermore, our analysis suggests that RBPs are major factors in structure remodeling and co-regulate additional RBPs and miRNAs through structure. We demonstrated an example of this by showing that PUM2-induced structure changes on LIN28A enable miR-30 binding. This study deepens our understanding of the widespread and complex role of RNA-based gene regulation during human development.
Assuntos
Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Neurogênese , Neurônios/metabolismo , Transcrição Gênica , Regiões 3' não Traduzidas , Diferenciação Celular , Análise por Conglomerados , Técnicas Genéticas , Células HEK293 , Humanos , MicroRNAs/metabolismo , Modelos Estatísticos , Neurônios/fisiologia , Conformação de Ácido Nucleico , RNA/análise , Splicing de RNA , Proteínas de Ligação a RNA/metabolismo , Especificidade por Substrato , Biologia de Sistemas , TranscriptomaRESUMO
Exosomes are small extracellular vesicles that carry lipids, proteins, and microRNAs (miRNAs). They are released by all cell types and can be found not only in circulation but in many biological fluids. Exosomes are essential for interorgan communication because they can transfer their contents from donor to recipient cells, modulating cellular functions. The miRNA content of exosomes is responsible for most of their biological effects, and changes in exosomal miRNA levels can contribute to the progression or regression of metabolic diseases. As exosomal miRNAs are selectively sorted and packaged into exosomes, they can be useful as biomarkers for diagnosing diseases. The field of exosomes and metabolism is expanding rapidly, and researchers are consistently making new discoveries in this area. As a result, exosomes have great potential for a next-generation drug delivery platform for metabolic diseases.
Assuntos
Exossomos , Doenças Metabólicas , MicroRNAs , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Biomarcadores/metabolismo , Doenças Metabólicas/metabolismoRESUMO
Identifying miRNA target genes is difficult, and delineating which targets are the most biologically important is even more difficult. We devised a novel strategy to test the phenotypic impact of individual microRNA-target interactions by disrupting each predicted miRNA-binding site by CRISPR-Cas9 genome editing in C. elegans We developed a multiplexed negative selection screening approach in which edited loci are deep sequenced, and candidate sites are prioritized based on apparent selection pressure against mutations that disrupt miRNA binding. Importantly, our screen was conducted in vivo on mutant animals, allowing us to interrogate organism-level phenotypes. We used this approach to screen for phenotypic targets of the essential mir-35-42 family. By generating 1130 novel 3'UTR alleles across all predicted targets, we identified egl-1 as a phenotypic target whose derepression partially phenocopies the mir-35-42 mutant phenotype by inducing embryonic lethality and low fecundity. These phenotypes can be rescued by compensatory CRISPR mutations that retarget mir-35 to the mutant egl-1 3'UTR. This study demonstrates that the application of in vivo whole organismal CRISPR screening has great potential to accelerate the discovery of phenotypic negative regulatory elements in the noncoding genome.
Assuntos
Caenorhabditis elegans/genética , MicroRNAs/metabolismo , Regiões 3' não Traduzidas/genética , Alelos , Animais , Sítios de Ligação/genética , Sistemas CRISPR-Cas , Edição de Genes , Testes Genéticos , MicroRNAs/genética , Mutação , FenótipoRESUMO
The tightly regulated feedback loops linking small RNAs (sRNAs) and transposable elements (TEs) offer the opportunity for an adaptive response to changing environments at the molecular level. Environmentally induced changes in TE and sRNA profiles may affect expression of coding genes and trigger an organismic and transgenerational response. Understanding this link may provide a mechanistic explanation for how species can adapt to changing climates and may offer novel molecular targets for biomedical and agricultural applications.
Assuntos
Elementos de DNA Transponíveis , RNA Interferente Pequeno/genética , Elementos de DNA Transponíveis/genéticaRESUMO
Transforming growth factor beta (TGF-ß) signaling is essential for a balanced immune response by mediating the development and function of regulatory T cells (Tregs) and suppressing autoreactive T cells. Disruption of this balance can result in autoimmune diseases, including multiple sclerosis (MS). MicroRNAs (miRNAs) targeting TGF-ß signaling have been shown to be upregulated in naïve CD4 T cells in MS patients, resulting in a limited in vitro generation of human Tregs. Utilizing the murine model experimental autoimmune encephalomyelitis, we show that perinatal administration of miRNAs, which target the TGF-ß signaling pathway, enhanced susceptibility to central nervous system (CNS) autoimmunity. Neonatal mice administered with these miRNAs further exhibited reduced Treg frequencies with a loss in T cell receptor repertoire diversity following the induction of experimental autoimmune encephalomyelitis in adulthood. Exacerbated CNS autoimmunity as a result of miRNA overexpression in CD4 T cells was accompanied by enhanced Th1 and Th17 cell frequencies. These findings demonstrate that increased levels of TGF-ß-associated miRNAs impede the development of a diverse Treg population, leading to enhanced effector cell activity, and contributing to an increased susceptibility to CNS autoimmunity. Thus, TGF-ß-targeting miRNAs could be a risk factor for MS, and recovering optimal TGF-ß signaling may restore immune homeostasis in MS patients.
Assuntos
Autoimunidade , Sistema Nervoso Central , Encefalomielite Autoimune Experimental , MicroRNAs , Esclerose Múltipla , Transdução de Sinais , Linfócitos T Reguladores , Células Th17 , Fator de Crescimento Transformador beta , MicroRNAs/genética , MicroRNAs/imunologia , Animais , Linfócitos T Reguladores/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/genética , Fator de Crescimento Transformador beta/metabolismo , Camundongos , Transdução de Sinais/imunologia , Autoimunidade/imunologia , Esclerose Múltipla/imunologia , Esclerose Múltipla/genética , Humanos , Sistema Nervoso Central/imunologia , Células Th17/imunologia , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Diferenciação Celular/imunologia , FemininoRESUMO
BACKGROUND: Diabetes is a spectrum of metabolic diseases affecting millions of people worldwide. The loss of pancreatic ß-cell mass by either autoimmune destruction or apoptosis, in type 1-diabetes (T1D) and type 2-diabetes (T2D), respectively, represents a pathophysiological process leading to insulin deficiency. Therefore, therapeutic strategies focusing on restoring ß-cell mass and ß-cell insulin secretory capacity may impact disease management. This study took advantage of powerful integrative bioinformatic tools to scrutinize publicly available diabetes-associated gene expression data to unveil novel potential molecular targets associated with ß-cell dysfunction. METHODS: A comprehensive literature search for human studies on gene expression alterations in the pancreas associated with T1D and T2D was performed. A total of 6 studies were selected for data extraction and for bioinformatic analysis. Pathway enrichment analyses of differentially expressed genes (DEGs) were conducted, together with protein-protein interaction networks and the identification of potential transcription factors (TFs). For noncoding differentially expressed RNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which exert regulatory activities associated with diabetes, identifying target genes and pathways regulated by these RNAs is fundamental for establishing a robust regulatory network. RESULTS: Comparisons of DEGs among the 6 studies showed 59 genes in common among 4 or more studies. Besides alterations in mRNA, it was possible to identify differentially expressed miRNA and lncRNA. Among the top transcription factors (TFs), HIPK2, KLF5, STAT1 and STAT3 emerged as potential regulators of the altered gene expression. Integrated analysis of protein-coding genes, miRNAs, and lncRNAs pointed out several pathways involved in metabolism, cell signaling, the immune system, cell adhesion, and interactions. Interestingly, the GABAergic synapse pathway emerged as the only common pathway to all datasets. CONCLUSIONS: This study demonstrated the power of bioinformatics tools in scrutinizing publicly available gene expression data, thereby revealing potential therapeutic targets like the GABAergic synapse pathway, which holds promise in modulating α-cells transdifferentiation into ß-cells.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Insulinas , MicroRNAs , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Redes Reguladoras de Genes/genética , Perfilação da Expressão Gênica , MicroRNAs/genética , Diabetes Mellitus Tipo 2/genética , Fatores de Transcrição/genética , Insulinas/genética , Biologia Computacional , Proteínas de Transporte/genética , Proteínas Serina-Treonina Quinases/genéticaRESUMO
Extracellular matrix (ECM) stiffness regulates development and homeostasis in vivo and affects both physiological and pathological processes. A variety of studies have demonstrated that mRNAs, such as Piezo1, integrin ß1, and Yes-associated protein (YAP)/tafazzin (TAZ), can sense the mechanical signals induced by ECM stiffness and transmit them from the extracellular space into the cytoplasm. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), have been reported to play important roles in various cellular processes. Therefore, the interactions between ncRNAs and ECM stiffness, as well as the underlying molecular mechanisms, have become intriguing. In this review, we summarize recent findings on miRNAs and lncRNAs that interact with ECM stiffness. Several miRNAs and lncRNAs are involved in the progression of liver cancer, breast cancer, osteosarcoma, and cardiovascular diseases under the regulation of ECM stiffness. Through these ncRNAs, cellular behaviors including cell differentiation, proliferation, adhesion, migration, invasion, and epithelial-mesenchymal transition (EMT) are affected by ECM stiffness. We also integrate the ncRNA signaling pathways associated with ECM stiffness, in which typical signaling pathways like integrin ß1/TGFß1, phosphatidylinositol-3 kinase (PI3K)/AKT, and EMT are involved. Although our understanding of the relationships between ncRNAs and ECM stiffness is still limited, further investigations may provide new insights for disease treatment. ECM-associated ncRNAs may serve as disease biomarkers or be targeted by drugs.
Assuntos
MicroRNAs , RNA Longo não Codificante , MicroRNAs/genética , RNA Longo não Codificante/genética , Integrina beta1/metabolismo , Matriz Extracelular/metabolismo , Diferenciação CelularRESUMO
Intramuscular fat (IMF) content significantly impacts meat quality. influenced by complex interactions between skeletal muscle cells and adipocytes. Adipogenesis plays a pivotal role in IMF formation. Exosomes, extracellular membranous nanovesicles, facilitate intercellular communication by transporting proteins, nucleic acids (DNA and RNA), and other biomolecules into target cells, thereby modulating cellular behaviors. Recent studies have linked exosome-derived microRNAs (miRNAs) and other cargo to adipogenic processes. Various cell types, including skeletal muscle cells, interact with adipocytes via exosome secretion and uptake. Exosomes entering adipocytes regulate adipogenesis by modulating key signaling pathways, thereby influencing the extent and distribution of IMF deposition. This review comprehensively explores the origin, formation, and mechanisms of exosome action, along with current research and their applications in adipogenesis. Emphasis is placed on exosome-mediated regulation of miRNAs, non-coding RNAs (ncRNAs), proteins, lipids, and other biomolecules during adipogenesis. Leveraging exosomal contents for genetic breeding and treating obesity-related disorders is discussed. Insights gathered contribute to advancing understanding and potential therapeutic applications of exosome-regulated adipogenesis mechanisms.
Assuntos
Adipogenia , Exossomos , MicroRNAs , Adipogenia/genética , Exossomos/metabolismo , Exossomos/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Animais , Adipócitos/metabolismoRESUMO
Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) patients receiving targeted therapy. However, the mechanism that causes cetuximab resistance, especially microRNA (miRNA) regulation, remains unclear. Growing evidence suggests that miRNAs may act as "nuclear activating miRNAs" for targeting promoter regions or enhancers related to target genes. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, quantitative real-time polymerase chain reaction (qRTâPCR) and fluorescence in situ hybridization (FISH) results provided compelling evidence of miR-451a nuclear enrichment in response to cetuximab treatment. Chromatin isolation via RNA purification, microarray analysis, and bioinformatic analysis revealed that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It has also been demonstrated that the activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Logistic regression analyses of 87 HNSCC samples indicated the significance of miR-451a and KDM7A in the development of cetuximab resistance. These discoveries support the potential of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear-activating miRNAs.
Assuntos
Cetuximab , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço , MicroRNAs , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Cetuximab/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Histona Desmetilases com o Domínio Jumonji/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Animais , Camundongos , Núcleo Celular/metabolismo , Núcleo Celular/genética , Feminino , Camundongos NusRESUMO
SignificanceHatching from the zona pellucida is a prerequisite for embryo implantation and is less likely to occur in vitro for reasons unknown. Extracellular vesicles (EVs) are secreted by the embryo into the culture medium. Yet the role that embryonic EVs and their cargo microRNAs (miRNAs) play in blastocyst hatching has not been elucidated, partially due to the difficulties of isolating them from low amounts of culture medium. Here, we optimized EV-miRNA isolation from medium conditioned by individually cultured bovine embryos and subsequently showed that miR-378a-3p, which was up-regulated in EVs secreted by blastocysts, plays a crucial role in promoting blastocyst hatching. This demonstrates the regulatory effect of miR-378-3p on hatching, which is an established embryo quality parameter linked with implantation.
Assuntos
Vesículas Extracelulares , MicroRNAs , Animais , Blastocisto , Bovinos , Meios de Cultura , Técnicas de Cultura Embrionária , Embrião de Mamíferos , Vesículas Extracelulares/genética , MicroRNAs/genéticaRESUMO
Cancer 'stemness' is fundamental to cancer existence. It defines the ability of cancer cells to indefinitely perpetuate as well as differentiate. Cancer stem cell populations within a growing tumor also help evade the inhibitory effects of chemo- as well as radiation-therapies, in addition to playing an important role in cancer metastases. NF-κB and STAT-3 are representative transcription factors (TFs) that have long been associated with cancer stemness, thus presenting as attractive targets for cancer therapy. The growing interest in non-coding RNAs (ncRNAs) in the recent years has provided further insight into the mechanisms by which TFs influence cancer stem cell characteristics. There is evidence for a direct regulation of TFs by ncRNAs, such as, microRNAs (miRNAs), long non-coding RNAs (lncRNAs) as well as circular RNAs (circRNAs), and vice versa. Additionally, the TF-ncRNAs regulations are often indirect, involving ncRNA-target genes or the sponging of other ncRNA species by individual ncRNAs. The information is rapidly evolving and this review provides a comprehensive review of TF-ncRNAs interactions with implications on cancer stemness and in response to therapies. Such knowledge will help uncover the many levels of tight regulations that control cancer stemness, providing novel opportunities and targets for therapy in the process.
Assuntos
MicroRNAs , Neoplasias , Humanos , Fatores de Transcrição/genética , RNA não Traduzido/genética , MicroRNAs/genética , Neoplasias/genética , Epigênese GenéticaRESUMO
In the brain, microRNAs (miRNAs) are believed to play a role in orchestrating synaptic plasticity at a higher level by acting as an additional mechanism of translational regulation, alongside the mRNA/polysome system. Despite extensive research, our understanding of the specific contribution of individual miRNA to the function of dopaminergic neurons (DAn) remains limited. By performing a dopaminergic-specific miRNA screening, we have identified miR-218 as a critical regulator of DAn activity in male and female mice. We have found that miR-218 is specifically expressed in mesencephalic DAn and is able to promote dopaminergic differentiation of embryonic stem cells and functional maturation of transdifferentiated induced DA neurons. Midbrain-specific deletion of both genes encoding for miR-218 (referred to as miR-218-1 and mir218-2) affects the expression of a cluster of synaptic-related mRNAs and alters the intrinsic excitability of DAn, as it increases instantaneous frequencies of evoked action potentials, reduces rheobase current, affects the ionic current underlying the action potential after hyperpolarization phase, and reduces dopamine efflux in response to a single electrical stimulus. Our findings provide a comprehensive understanding of the involvement of miR-218 in the dopaminergic system and highlight its role as a modulator of dopaminergic transmission.SIGNIFICANCE STATEMENT In the past decade, several miRNAs have emerged as potential regulators of synapse activity through the modulation of specific gene expression. Among these, we have identified a dopaminergic-specific miRNA, miR-218, which is able to promote dopaminergic differentiation and regulates the translation of an entire cluster of synapse related mRNAs. Deletion of miR-218 has notable effects on dopamine release and alters the intrinsic excitability of dopaminergic neurons, indicating a direct control of dopaminergic activity by miR-218.
Assuntos
Dopamina , MicroRNAs , Camundongos , Masculino , Feminino , Animais , Dopamina/metabolismo , Diferenciação Celular , Neurônios Dopaminérgicos/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Neurotransmissores/metabolismoRESUMO
We have demonstrated that directly reprogramming cardiac fibroblasts into new cardiomyocytes via miR combo improves cardiac function in the infarcted heart. However, major challenges exist with delivery and efficacy. During a screening based approach to improve delivery, we discovered that C166-derived EVs were effective delivery agents for miR combo both in vitro and in vivo. In the latter, EV mediated delivery of miR combo induced significant conversion of cardiac fibroblasts into cardiomyocytes (â¼20%), reduced fibrosis and improved cardiac function in a myocardial infarction injury model. When compared to lipid-based transfection, C166 EV mediated delivery of miR combo enhanced reprogramming efficacy. Improved reprogramming efficacy was found to result from a miRNA within the exosome: miR-148a-3p. The target of miR-148a-3p was identified as Mdfic. Over-expression and targeted knockdown studies demonstrated that Mdfic was a repressor of cardiomyocyte specific gene expression. In conclusion, we have demonstrated that C166-derived EVs are an effective method for delivering reprogramming factors to cardiac fibroblasts and we have identified a novel miRNA contained within C166-derived EVs which enhances reprogramming efficacy.
Assuntos
Reprogramação Celular , Fibroblastos , MicroRNAs , Miócitos Cardíacos , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Reprogramação Celular/genética , Miócitos Cardíacos/metabolismo , Fibroblastos/metabolismo , Camundongos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/terapia , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/genética , Exossomos/metabolismo , Regulação da Expressão Gênica , HumanosRESUMO
Infections caused by viruses as the smallest infectious agents, pose a major threat to global public health. Viral infections utilize different host mechanisms to facilitate their own propagation and pathogenesis. MicroRNAs (miRNAs), as small noncoding RNA molecules, play important regulatory roles in different diseases, including viral infections. They can promote or inhibit viral infection and have a pro-viral or antiviral role. Also, viral infections can modulate the expression of host miRNAs. Furthermore, viruses from different families evade the host immune response by producing their own miRNAs called viral miRNAs (v-miRNAs). Understanding the replication cycle of viruses and their relation with host miRNAs and v-miRNAs can help to find new treatments against viral infections. In this review, we aim to outline the structure, genome, and replication cycle of various viruses including hepatitis B, hepatitis C, influenza A virus, coronavirus, human immunodeficiency virus, human papillomavirus, herpes simplex virus, Epstein-Barr virus, Dengue virus, Zika virus, and Ebola virus. We also discuss the role of different host miRNAs and v-miRNAs and their role in the pathogenesis of these viral infections.
RESUMO
Macrophages are immune cells that play different roles under different physiological conditions. They are present in all tissues where they primarily protect from bacteria and pathogens in addition to assisting in tissue repair. During tumor progression, macrophages can exert contrasting effects based on the M1 vs. M2 polarization. The M2 macrophages support tumor growth through mechanisms that help suppress immune responses and/or circumvent immune-surveillance. A number of such mechanisms such as production of IL-10 and arginase, and expression of PD-L1, V-domain Ig suppressor of T cell activation and B7 family molecule B7-H4 are now believed central to the immunosuppressive effects of tumor-associated macrophages (TAMs). Emerging data has identified epigenetic regulation of these immunosuppressive mechanisms by small non-coding RNAs, the microRNAs (miRNAs). This review discusses the available literature on the subject, including the exosomes mediated transfer of miRNAs between cancer cells and the macrophages within the tumor microenvironment. A number of miRNAs are now believed to be involved in TAMs' production of IL-10 and expression of PD-L1 while the information on such regulation of other immunosuppressive mechanisms is slowly emerging. A better understanding of epigenetic regulation of macrophages-mediated immunosuppressive effect can help identify novel targets for therapy and aid the design of future studies aimed at sensitizing tumors to immune responses.
Assuntos
MicroRNAs , Neoplasias , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Epigênese Genética/genética , Humanos , Interleucina-10/metabolismo , MicroRNAs/genética , Neoplasias/patologia , Microambiente Tumoral/genética , Macrófagos Associados a TumorRESUMO
The immune system is a well-known vital regulator of tumor growth, and one of the main hallmarks of cancer is evading the immune system. Immune system deregulation can lead to immune surveillance evasion, sustained cancer growth, proliferation, and metastasis. Tumor-mediated disruption of the immune system is accomplished by different mechanisms that involve extensive crosstalk with the immediate microenvironment, which includes endothelial cells, immune cells, and stromal cells, to create a favorable tumor niche that facilitates the development of cancer. The essential role of non-coding RNAs such as microRNAs (miRNAs) in the mechanism of cancer cell immune evasion has been highlighted in recent studies. miRNAs are small non-coding RNAs that regulate a wide range of post-transcriptional gene expression in a cell. Recent studies have focused on the function that miRNAs play in controlling the expression of target proteins linked to immune modulation. Studies show that miRNAs modulate the immune response in cancers by regulating the expression of different immune-modulatory molecules associated with immune effector cells, such as macrophages, dendritic cells, B-cells, and natural killer cells, as well as those present in tumor cells and the tumor microenvironment. This review explores the relationship between miRNAs, their altered patterns of expression in tumors, immune modulation, and the functional control of a wide range of immune cells, thereby offering detailed insights on the crosstalk of tumor-immune cells and their use as prognostic markers or therapeutic agents.