From Pluripotency to Islets. MiRNAs as Critical Regulators of Human Cellular Differentiation

Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, CA, USA.
Advances in genetics (Impact Factor: 6.76). 09/2012; 79:1-34. DOI: 10.1016/B978-0-12-394395-8.00001-3
Source: PubMed


MicroRNAs (miRNAs) actively regulate differentiation as pluripotent cells become cells of pancreatic endocrine lineage, including insulin-producing β cells. The process is dynamic; some miRNAs help maintain pluripotency, while others drive cell fate decisions. Here, we survey the current literature and describe the biological role of selected miRNAs in maintenance of both mouse and human embryonic stem cell (ESC) pluripotency. Subsequently, we review the increasing evidence that miRNAs act at selected points in differentiation to regulate decisions about early cell fate (definitive endoderm and mesoderm), formation of pancreatic precursor cells, endocrine cell function, as well as epithelial to mesenchymal transition.

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Available from: Andrew Hinton, Feb 19, 2014
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    • "During their biogenesis, the miRNA genes are transcribed into primary miRNAs (pri-miR), which are processed by Drosha and Dicer to generate miRNA duplexes consisting of a mature and a passenger miR strand [16]. Recent studies have shown that miRNAs play crucial roles in immune cell development and immune system function [17] [18] and regulate various aspect of cell physiology, including developmental timing, cell differentiation, apoptosis , and anti-viral defense [18] [19] [20]. Given the crucial role of miRNAs in human physiology, the abnormal expression of specific miRNAs may lead to the development of diverse diseases, such as cancer, cardiovascular disorders, mental disorders, musculoskeletal disorders, and lung diseases [21] [22] [23] [24] [25]. "
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    ABSTRACT: Background: Even though increasing evidences on miRNA involvement in human pathological responses, the distinct roles and related mechanisms of miRNAs in the pathology of osteoarthritis (OA) are not yet fully understood. Method: RNA levels or protein levels of Apoptotic genes, HDACs, MMP-13, and miRNAs in human chondrocytes isolated from normal biopsy sample and OA cartilages were analyzed by real-time PCR or western blotting. Exogenous modulation of miR-222 level was performed using delivery of its specific precursor or specific inhibitor and target validation assay was applied to identify its potent target. In vivo study using DMM mice model was performed and assessed the degree of cartilage degradation. Results: According to miRNA profiling, miR-222 was significantly down-regulated in OA chondrocytes. Over-expression of miR-222 significantly suppressed apoptotic death by down-regulating HDAC-4 and MMP-13 level. Moreover, 3'-UTR reporter assays showed that HDAC-4 is a direct target of miR-222. The treatment of chondrocytes with the HDAC inhibitor, trichostatin A (TSA), suppressed MMP-13 protein level and apoptosis, whereas the over-expression of HDAC-4 displayed opposite effects. The introduction of miR-222 into the cartilage of medial meniscus destabilized mice significantly reduced cartilage destruction and MMP-13 level. Conclusion: Taken together, our data suggest that miR-222 may be involved in cartilage destruction by targeting HDAC-4 and regulating MMP-13 level.
    Full-text · Article · Jun 2015 · Biochimica et Biophysica Acta - Clinical
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    • "miRNAs can function post-transcriptionally through imperfect base pairing with specific sequences in the 3 0 untranslated regions (UTRs) of target mRNAs, leading to transcript degradation or translational inhibition (Valencia-Sanchez et al, 2006; Ying et al, 2008). Increasing evidence has shown that miRNAs have critical roles in the control of various human biological processes, such as development, angiogenesis, apoptosis and differentiation (Amiel et al, 2012; Roy and Sen, 2012; Liwak et al, 2012; Hinton et al, 2012). Dysregulation of specific miRNAs contributes to a variety of diseases, most notably the development and progression of cancer, including lung cancer (Qi and Mu, 2012). "
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    ABSTRACT: Background: Increasing evidence has shown that microRNAs (miRNAs) can serve as oncogenes and tumour suppressors to participate in tumour development. However, the roles of miRNAs in chemoresistance of human lung adenocarcinoma (LA) remain largely undefined. Methods: On the basis of miRNA microarray data, miR-224 was identified as the most upregulated miRNA in cisplatin (DDP; cis-diamminedichloroplatinum II)-resistant A549 cells compared with parental A549 cells. The aim of our study was to investigate the roles of miR-224 in the formation of DDP-resistant phenotype of LA cells and its possible molecular mechanisms. Results: Here we showed that miR-224 could promote the in vitro and in vivo DDP resistance of LA cells via regulating G1/S cell cycle transition and apoptosis. p21WAF1/CIP1, a potent cyclin-dependent kinase inhibitor, was identified as the direct and functional target gene of miR-224. Overexpression of p21WAF1/CIP1 could phenocopy the effect of miR-224 downregulation and silencing of p21WAF1/CIP1 could partially reverse the effect of miR-224 downregulation on DDP resistance of DDP-resistant LA cells. In addition, miR-224 could affect the G1/S transition of cell cycle and apoptosis in LA cells through the p21WAF1/CIP1-pRb pathway and the intrinsic mitochondrial death pathway. Furthermore, miR-224 was found to be downregulated in DDP-responding LA tissues, and its expression was inversely correlated with p21WAF1/CIP1. Multivariate analyses indicated that the status of miR-224 might be an independent prognostic factor for predicting the survival of LA patients. Conclusions: Our findings shed novel light on the roles of miR-224/p21WAF1/CIP1 signalling in the DDP resistance of LA cells, and targeting it will be a potential strategic approach for reversing the DDP resistance in human LAs.
    Full-text · Article · Jun 2014 · British Journal of Cancer
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    • "Many of the subphenotypes involved in bleomycin-induced pulmonary fibrosis have been shown to be independently influenced by microRNAs, including inflammation [10], tissue repair [11,12], cell differentiation [13,14] and cell proliferation [15]. MicroRNAs are small non-coding RNA molecules of approximately 22 nucleotides that regulate gene expression through complimentary binding, usually to the 3′-untranslated region of target mRNAs. "
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    ABSTRACT: Idiopathic pulmonary fibrosis is a disease characterized by alveolar epithelial cell injury, inflammatory cell infiltration and deposition of extracellular matrix in lung tissue. As mouse models of bleomycin-induced pulmonary fibrosis display many of the same phenotypes observed in patients with idiopathic pulmonary fibrosis, they have been used to study various aspects of the disease, including altered expression of microRNAs. In this work, microRNA expression profiling of the lungs from treated C57BL/6J mice, relative to that of untreated controls, was undertaken to determine which alterations in microRNAs could in part regulate the fibrosis phenotype induced by bleomycin delivered through mini-osmotic pumps. We identified 11 microRNAs, including miR-21 and miR-34a, to be significantly differentially expressed (P < 0.01) in lungs of bleomycin treated mice and confirmed these data with real time PCR measurements. In situ hybridization of both miR-21 and miR-34a indicated that they were expressed in alveolar macrophages. Using a previously reported gene expression profile, we identified 195 genes to be both predicted targets of the 11 microRNAs and of altered expression in bleomycin-induced lung disease of C57BL/6J mice. Pathway analysis with these 195 genes indicated that altered microRNA expression may be associated with hepatocyte growth factor signaling, cholecystokinin/gastrin-mediated signaling, and insulin-like growth factor (IGF-1) signaling, among others, in fibrotic lung disease. The relevance of the IGF-1 pathway in this model was then demonstrated by showing lung tissue of bleomycin treated C57BL/6J mice had increased expression of Igf1 and that increased numbers of Igf-1 positive cells, predominantly in macrophages, were detected in the lungs. We conclude that altered microRNA expression in macrophages is a feature which putatively influences the insulin-like growth factor signaling component of bleomycin-induced pulmonary fibrosis.
    Full-text · Article · Aug 2013 · Fibrogenesis & Tissue Repair
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