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      Transforming growth factor (TGF)-β1-induced miR-133a inhibits myofibroblast differentiation and pulmonary fibrosis

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          Abstract

          Transforming growth factor (TGF)-β1, a main profibrogenic cytokine in the progression of idiopathic pulmonary fibrosis (IPF), induces differentiation of pulmonary fibroblasts to myofibroblasts that produce high levels of collagen, leading to concomitantly loss of lung elasticity and function. Recent studies implicate the importance of microRNAs (miRNAs) in IPF but their regulation and individual pathological roles remain largely unknown. We used both RNA sequencing and quantitative RT-PCR strategies to systematically study TGF-β1-induced alternations of miRNAs in human lung fibroblasts (HFL). Our data show that miR-133a was significantly upregulated by TGF-β1 in a time- and concentration-dependent manner. Surprisingly, miR-133a inhibits TGF-β1-induced myofibroblast differentiation whereas miR-133a inhibitor enhances TGF-β1-induced myofibroblast differentiation. Interestingly, quantitative proteomics analysis indicates that miR-133a attenuates myofibroblast differentiation via targeting multiple components of TGF-β1 profibrogenic pathways. Western blot analysis confirmed that miR-133a down-regulates TGF-β1-induced expression of classic myofibroblast differentiation markers such as ɑ-smooth muscle actin (ɑ-SMA), connective tissue growth factor (CTGF) and collagens. miRNA Target Searcher analysis and luciferase reporter assays indicate that TGF-β receptor 1, CTGF and collagen type 1-alpha1 (Col1a1) are direct targets of miR-133a. More importantly, miR-133a gene transferred into lung tissues ameliorated bleomycin-induced pulmonary fibrosis in mice. Together, our study identified TGF-β1-induced miR-133a as an anti-fibrotic factor. It functions as a feed-back negative regulator of TGF-β1 profibrogenic pathways. Thus, manipulations of miR-133a expression may provide a new therapeutic strategy to halt and perhaps even partially reverse the progression of IPF.

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          Most cited references 33

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          Control of translation and mRNA degradation by miRNAs and siRNAs.

          The control of translation and mRNA degradation is an important part of the regulation of gene expression. It is now clear that small RNA molecules are common and effective modulators of gene expression in many eukaryotic cells. These small RNAs that control gene expression can be either endogenous or exogenous micro RNAs (miRNAs) and short interfering RNAs (siRNAs) and can affect mRNA degradation and translation, as well as chromatin structure, thereby having impacts on transcription rates. In this review, we discuss possible mechanisms by which miRNAs control translation and mRNA degradation. An emerging theme is that miRNAs, and siRNAs to some extent, target mRNAs to the general eukaryotic machinery for mRNA degradation and translation control.
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            Transforming growth factor beta in tissue fibrosis.

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              Simple method of estimating severity of pulmonary fibrosis on a numerical scale.

              A continuous numerical scale for determining the degree of fibrosis in lung specimens was devised for correlation with other pulmonary variables such as lung function tests or mineral burden. Grading was scored on a scale from 0 to 8, using the average of microscope field scores. The system allows fibrosis to be measured in small samples of tissue (1 cm) which can provide a detailed description of the changes in a lung, currently not possible with most existing methods.
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                Author and article information

                Contributors
                +86-10-6488-8566 , weitt@moon.ibp.ac.cn
                +402.280.2173 , Yat60399@creighton.edu
                Journal
                Cell Death Dis
                Cell Death Dis
                Cell Death & Disease
                Nature Publishing Group UK (London )
                2041-4889
                11 September 2019
                11 September 2019
                September 2019
                : 10
                : 9
                Affiliations
                [1 ]ISNI 0000 0004 1792 5640, GRID grid.418856.6, National Laboratory of Biomacromolecules, , Institute of Biophysics, Chinese Academy of Sciences, ; Beijing, 100101 China
                [2 ]ISNI 0000 0004 1936 8876, GRID grid.254748.8, Department of Pharmacology and Neuroscience, , Creighton University School of Medicine, ; Omaha, NE 68178 USA
                [3 ]ISNI 0000 0004 1797 8419, GRID grid.410726.6, University of Chinese Academy of Sciences, ; Beijing, 100049 China
                [4 ]ISNI 0000 0004 0644 6935, GRID grid.464209.d, Key Laboratory of Genomics and Precision Medicine, , Beijing Institute of Genomics, Chinese Academy of Sciences, ; Beijing, 100101 China
                [5 ]ISNI 0000 0004 0369 153X, GRID grid.24696.3f, Department of Anesthesiology, , Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, ; Beijing, 101149 China
                [6 ]Kansas City University of Medicine and Biosciences-Joplin, Joplin, MO 64804 USA
                Article
                1873
                10.1038/s41419-019-1873-x
                6739313
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/100010537, Nebraska Department of Health and Human Services (Nebraska DHHS);
                Award ID: LB595
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000009, Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.);
                Award ID: R01HL116849
                Award Recipient :
                Funded by: The National Laboratory of Biomacromolecules and the Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences (CAS)
                Funded by: The National Natural Science Foundation of China 31671175 The CAS/SAFEA International Partnership Program for Creative Research Teams;
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                © The Author(s) 2019

                Cell biology

                cell signalling, respiratory tract diseases

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