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      Exosomes as Critical Agents of Cardiac Regeneration Triggered by Cell Therapy

      research-article
      Author(s): 1 , 1 , 1 , ∗
      Publication date (Electronic):
      Journal: Stem Cell Reports
      Publisher: Elsevier

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          Summary

          The CADUCEUS trial of cardiosphere-derived cells (CDCs) has shown that it may be possible to regenerate injured heart muscle previously thought to be permanently scarred. The mechanisms of benefit are known to be indirect, but the mediators have yet to be identified. Here we pinpoint exosomes secreted by human CDCs as critical agents of regeneration and cardioprotection. CDC exosomes inhibit apoptosis and promote proliferation of cardiomyocytes, while enhancing angiogenesis. Injection of exosomes into injured mouse hearts recapitulates the regenerative and functional effects produced by CDC transplantation, whereas inhibition of exosome production by CDCs blocks those benefits. CDC exosomes contain a distinctive complement of microRNAs, with particular enrichment of miR-146a. Selective administration of a miR-146a mimic reproduces some (but not all) of the benefits of CDC exosomes. The findings identify exosomes as key mediators of CDC-induced regeneration, while highlighting the potential utility of exosomes as cell-free therapeutic candidates.

          Highlights

          • •

            Cardiosphere-derived cells (CDCs) regenerate the heart by unclear indirect mechanisms

          • •

            Exosomes from CDCs promote angiogenesis, cardiomyocyte survival and proliferation

          • •

            CDC exosomes are necessary and sufficient to explain the therapeutic effects of CDCs

          • •

            MicroRNAs transferred by CDC exosomes at least partially mediate the benefits of CDCs

          Abstract

          Marbán and colleagues pinpoint exosomes as critical mediators of myocardial regeneration triggered by cardiosphere-derived cells (CDCs). CDC exosomes inhibit apoptosis, promote proliferation of cardiomyocytes, and enhance angiogenesis. Injection of exosomes into injured mouse hearts recapitulates the CDC effect. CDC exosomes contain a distinctive complement of microRNAs, including miR-146a, that reproduces some of the benefits of CDC exosomes. Our findings highlight the utility of exosomes as therapeutic candidates.

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          Most cited references38

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          Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes

          K. Teng, M Adam Mahmood, C Wu … (1985)
          Using ferritin-labeled protein A and colloidal gold-labeled anti-rabbit IgG, the fate of the sheep transferrin receptor has been followed microscopically during reticulocyte maturation in vitro. After a few minutes of incubation at 37 degrees C, the receptor is found on the cell surface or in simple vesicles of 100-200 nm, in which the receptor appears to line the limiting membrane of the vesicles. With time (60 min or longer), large multivesicular elements (MVEs) appear whose diameter may reach 1-1.5 micron. Inside these large MVEs are round bodies of approximately 50-nm diam that bear the receptor at their external surfaces. The limiting membrane of the large MVEs is relatively free from receptor. When the large MVEs fuse with the plasma membrane, their contents, the 50-nm bodies, are released into the medium. The 50-nm bodies appear to arise by budding from the limiting membrane of the intracellular vesicles. Removal of surface receptor with pronase does not prevent exocytosis of internalized receptor. It is proposed that the exocytosis of the approximately 50-nm bodies represents the mechanism by which the transferrin receptor is shed during reticulocyte maturation.
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            Open mass spectrometry search algorithm.

            Lewis Geer, Sanford Markey, Jeffrey Kowalak … (2004)
            Large numbers of MS/MS peptide spectra generated in proteomics experiments require efficient, sensitive and specific algorithms for peptide identification. In the Open Mass Spectrometry Search Algorithm (OMSSA), specificity is calculated by a classic probability score using an explicit model for matching experimental spectra to sequences. At default thresholds, OMSSA matches more spectra from a standard protein cocktail than a comparable algorithm. OMSSA is designed to be faster than published algorithms in searching large MS/MS datasets.
            Article 0 comments Cited 309 times – based on 0 reviews     Review now
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              Exosome: from internal vesicle of the multivesicular body to intercellular signaling device.

              K Denzer, M Kleijmeer, H Heijnen … (2000)
              Exosomes are small membrane vesicles that are secreted by a multitude of cell types as a consequence of fusion of multivesicular late endosomes/lysosomes with the plasma membrane. Depending on their origin, exosomes can play roles in different physiological processes. Maturing reticulocytes externalize obsolete membrane proteins such as the transferrin receptor by means of exosomes, whereas activated platelets release exosomes whose function is not yet known. Exosomes are also secreted by cytotoxic T cells, and these might ensure specific and efficient targeting of cytolytic substances to target cells. Antigen presenting cells, such as B lymphocytes and dendritic cells, secrete MHC class-I- and class-II-carrying exosomes that stimulate T cell proliferation in vitro. In addition, dendritic-cell-derived exosomes, when used as a cell-free vaccine, can eradicate established murine tumors. Although the precise physiological target(s) and functions of exosomes remain largely to be resolved, follicular dendritic cells (accessory cells in the germinal centers of secondary lymphoid organs) have recently been shown to bind B-lymphocyte-derived exosomes at their cell surface, which supports the notion that exosomes play an immunoregulatory role. Finally, since exosomes are derived from multivesicular bodies, their molecular composition might provide clues to the mechanism of protein and lipid sorting in endosomes.
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                Author and article information

                Contributors
                Eduardo Marbán
                Journal
                Journal ID (nlm-ta): Stem Cell Reports
                Journal ID (iso-abbrev): Stem Cell Reports
                Title: Stem Cell Reports
                Publisher: Elsevier
                ISSN (Electronic): 2213-6711
                Publication date PMC-release: 8 May 2014
                Publication date (Electronic): 8 May 2014
                Publication date Collection: 06 May 2014
                Volume: 2
                Issue: 5
                Pages: 606-619
                Affiliations
                [1 ]Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA
                Author notes
                [∗ ]Corresponding author eduardo.marban@ 123456cshs.org
                Article
                Publisher ID: S2213-6711(14)00113-1
                DOI: 10.1016/j.stemcr.2014.04.006
                PMC ID: 4050492
                SO-VID: 1e777f6a-6dd8-41f7-826c-a1db1b82e944
                Copyright © © 2014 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                Date received : 2 January 2014
                Date revision received : 8 April 2014
                Date accepted : 9 April 2014
                Categories
                Subject: Article

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