4
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Circulating myocardial microRNAs from infarcted hearts are carried in exosomes and mobilise bone marrow progenitor cells

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Myocardial microRNAs (myo-miRs) are released into the circulation after acute myocardial infarction (AMI). How they impact remote organs is however largely unknown. Here we show that circulating myo-miRs are carried in exosomes and mediate functional crosstalk between the ischemic heart and the bone marrow (BM). In mice, we find that AMI is accompanied by an increase in circulating levels of myo-miRs, with miR-1, 208, and 499 predominantly in circulating exosomes and miR-133 in the non-exosomal component. Myo-miRs are imported selectively to peripheral organs and preferentially to the BM. Exosomes mediate the transfer of myo-miRs to BM mononuclear cells (MNCs), where myo-miRs downregulate CXCR4 expression. Injection of exosomes isolated from AMI mice into wild-type mice downregulates CXCR4 expression in BM-MNCs and increases the number of circulating progenitor cells. Thus, we propose that myo-miRs carried in circulating exosomes allow a systemic response to cardiac injury that may be leveraged for cardiac repair.

          Abstract

          During myocardial infarction, microRNAs (myo-miRs) are released into the circulation. Here Cheng et al. show that myo-miRs carried in exosomes are transferred to the bone marrow (BM), downregulate expression of CXCR4 in mononuclear cells, and increase the number of circulating BM progenitor cells, thus orchestrating a systemic response to myocardial injury.

          Related collections

          Most cited references20

          • Record: found
          • Abstract: found
          • Article: not found
          Is Open Access

          Endogenous RNAs modulate microRNA sorting to exosomes and transfer to acceptor cells.

          MicroRNA (miRNA) transfer via exosomes may mediate cell-to-cell communication. Interestingly, specific miRNAs are enriched in exosomes in a cell-type-dependent fashion. However, the mechanisms whereby miRNAs are sorted to exosomes and the significance of miRNA transfer to acceptor cells are unclear. We used macrophages and endothelial cells (ECs) as a model of heterotypic cell communication in order to investigate both processes. RNA profiling of macrophages and their exosomes shows that miRNA sorting to exosomes is modulated by cell-activation-dependent changes of miRNA target levels in the producer cells. Genetically perturbing the expression of individual miRNAs or their targeted transcripts promotes bidirectional miRNA relocation from the cell cytoplasm/P bodies (sites of miRNA activity) to multivesicular bodies (sites of exosome biogenesis) and controls miRNA sorting to exosomes. Furthermore, the use of Dicer-deficient cells and reporter lentiviral vectors (LVs) for miRNA activity shows that exosomal miRNAs are transferred from macrophages to ECs to detectably repress targeted sequences. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found
            Is Open Access

            Nontemplated nucleotide additions distinguish the small RNA composition in cells from exosomes.

            Functional biomolecules, including small noncoding RNAs (ncRNAs), are released and transmitted between mammalian cells via extracellular vesicles (EVs), including endosome-derived exosomes. The small RNA composition in cells differs from exosomes, but underlying mechanisms have not been established. We generated small RNA profiles by RNA sequencing (RNA-seq) from a panel of human B cells and their secreted exosomes. A comprehensive bioinformatics and statistical analysis revealed nonrandomly distributed subsets of microRNA (miRNA) species between B cells and exosomes. Unexpectedly, 3' end adenylated miRNAs are relatively enriched in cells, whereas 3' end uridylated isoforms appear overrepresented in exosomes, as validated in naturally occurring EVs isolated from human urine samples. Collectively, our findings suggest that posttranscriptional modifications, notably 3' end adenylation and uridylation, exert opposing effects that may contribute, at least in part, to direct ncRNA sorting into EVs.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              MicroRNA-mediated in vitro and in vivo direct reprogramming of cardiac fibroblasts to cardiomyocytes.

              Repopulation of the injured heart with new, functional cardiomyocytes remains a daunting challenge for cardiac regenerative medicine. An ideal therapeutic approach would involve an effective method at achieving direct conversion of injured areas to functional tissue in situ. The aim of this study was to develop a strategy that identified and evaluated the potential of specific micro (mi)RNAs capable of inducing reprogramming of cardiac fibroblasts directly to cardiomyocytes in vitro and in vivo. Using a combinatorial strategy, we identified a combination of miRNAs 1, 133, 208, and 499 capable of inducing direct cellular reprogramming of fibroblasts to cardiomyocyte-like cells in vitro. Detailed studies of the reprogrammed cells demonstrated that a single transient transfection of the miRNAs can direct a switch in cell fate as documented by expression of mature cardiomyocyte markers, sarcomeric organization, and exhibition of spontaneous calcium flux characteristic of a cardiomyocyte-like phenotype. Interestingly, we also found that miRNA-mediated reprogramming was enhanced 10-fold on JAK inhibitor I treatment. Importantly, administration of miRNAs into ischemic mouse myocardium resulted in evidence of direct conversion of cardiac fibroblasts to cardiomyocytes in situ. Genetic tracing analysis using Fsp1Cre-traced fibroblasts from both cardiac and noncardiac cell sources strongly suggests that induced cells are most likely of fibroblastic origin. The findings from this study provide proof-of-concept that miRNAs have the capability of directly converting fibroblasts to a cardiomyocyte-like phenotype in vitro. Also of significance is that this is the first report of direct cardiac reprogramming in vivo. Our approach may have broad and important implications for therapeutic tissue regeneration in general.
                Bookmark

                Author and article information

                Contributors
                min_cheng@hust.edu.cn
                gqin@uab.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                27 February 2019
                27 February 2019
                2019
                : 10
                : 959
                Affiliations
                [1 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Cardiology, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan, 430022 China
                [2 ]ISNI 0000000106344187, GRID grid.265892.2, Department of Biomedical Engineering, , University of Alabama at Birmingham, School of Medicine and School of Engineering, ; 35294 Birmingham, AL USA
                [3 ]ISNI 0000 0001 0125 2443, GRID grid.8547.e, Department of Cardiology, Huashan Hospital, , Fudan University, ; Shanghai, 200040 China
                [4 ]ISNI 0000 0004 0368 7223, GRID grid.33199.31, Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, , Huazhong University of Science and Technology, ; Wuhan, 430022 China
                [5 ]ISNI 0000000106344187, GRID grid.265892.2, Division of Cardiovascular Disease, Department of Medicine, , University of Alabama at Birmingham, School of Medicine, ; Birmingham, 35294 AL USA
                [6 ]ISNI 0000000106344187, GRID grid.265892.2, Department of Neurology and Epidemiology, , University of Alabama at Birmingham, School of Medicine, ; Birmingham, 35294 AL USA
                Author information
                http://orcid.org/0000-0002-3955-6554
                http://orcid.org/0000-0002-3135-7307
                Article
                8895
                10.1038/s41467-019-08895-7
                6393447
                30814518
                03d2523e-41b8-4956-8a8f-9a9befcb328f
                © 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/.

                History
                : 19 April 2018
                : 1 February 2019
                Categories
                Article
                Custom metadata
                © The Author(s) 2019

                Uncategorized
                Uncategorized

                Comments

                Comment on this article

                scite_

                Similar content285

                Cited by85

                Most referenced authors661