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      Recent Progress in Stem Cell Modification for Cardiac Regeneration

      review-article
      1 , 2 , , 1 , 2 , 1 , 2 , 1 , 2 ,
      Stem Cells International
      Hindawi

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          Abstract

          During the past decades, stem cell-based therapy has acquired a promising role in regenerative medicine. The application of novel cell therapeutics for the treatment of cardiovascular diseases could potentially achieve the ambitious aim of effective cardiac regeneration. Despite the highly positive results from preclinical studies, data from phase I/II clinical trials are inconsistent and the improvement of cardiac remodeling and heart performance was found to be quite limited. The major issues which cardiac stem cell therapy is facing include inefficient cell delivery to the site of injury, accompanied by low cell retention and weak effectiveness of remaining stem cells in tissue regeneration. According to preclinical and clinical studies, various stem cells (adult stem cells, embryonic stem cells, and induced pluripotent stem cells) represent the most promising cell types so far. Beside the selection of the appropriate cell type, researchers have developed several strategies to produce “second-generation” stem cell products with improved regenerative capacity. Genetic and nongenetic modifications, chemical and physical preconditioning, and the application of biomaterials were found to significantly enhance the regenerative capacity of transplanted stem cells. In this review, we will give an overview of the recent developments in stem cell engineering with the goal to facilitate stem cell delivery and to promote their cardiac regenerative activity.

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          Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans.

          During C. elegans development, the temporal pattern of many cell lineages is specified by graded activity of the heterochronic gene Lin-14. Here we demonstrate that a temporal gradient in Lin-14 protein is generated posttranscriptionally by multiple elements in the lin-14 3'UTR that are regulated by the heterochronic gene Lin-4. The lin-14 3'UTR is both necessary and sufficient to confer lin-4-mediated posttranscriptional temporal regulation. The function of the lin-14 3'UTR is conserved between C. elegans and C. briggsae. Among the conserved sequences are seven elements that are each complementary to the lin-4 RNAs. A reporter gene bearing three of these elements shows partial temporal gradient activity. These data suggest a molecular mechanism for Lin-14p temporal gradient formation: the lin-4 RNAs base pair to sites in the lin-14 3'UTR to form multiple RNA duplexes that down-regulate lin-14 translation.
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            Isolation and expansion of adult cardiac stem cells from human and murine heart.

            Cardiac myocytes have been traditionally regarded as terminally differentiated cells that adapt to increased work and compensate for disease exclusively through hypertrophy. However, in the past few years, compelling evidence has accumulated suggesting that the heart has regenerative potential. Recent studies have even surmised the existence of resident cardiac stem cells, endothelial cells generating cardiomyocytes by cell contact or extracardiac progenitors for cardiomyocytes, but these findings are still controversial. We describe the isolation of undifferentiated cells that grow as self-adherent clusters (that we have termed "cardiospheres") from subcultures of postnatal atrial or ventricular human biopsy specimens and from murine hearts. These cells are clonogenic, express stem and endothelial progenitor cell antigens/markers, and appear to have the properties of adult cardiac stem cells. They are capable of long-term self-renewal and can differentiate in vitro and after ectopic (dorsal subcutaneous connective tissue) or orthotopic (myocardial infarction) transplantation in SCID beige mouse to yield the major specialized cell types of the heart: myocytes (ie, cells demonstrating contractile activity and/or showing cardiomyocyte markers) and vascular cells (ie, cells with endothelial or smooth muscle markers).
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              Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles and Their Potential as Novel Immunomodulatory Therapeutic Agents

              Extracellular vesicles (EVs), such as exosomes and microvesicles, have been identified as mediators of a newly-discovered intercellular communication system. They are essential signaling mediators in various physiological and pathophysiological processes. Depending on their origin, they fulfill different functions. EVs of mesenchymal stem/stromal cells (MSCs) have been found to promote comparable therapeutic activities as MSCs themselves. In a variety of in vivo models, it has been observed that they suppress pro-inflammatory processes and reduce oxidative stress and fibrosis. By switching pro-inflammatory into tolerogenic immune responses, MSC-EVs very likely promote tissue regeneration by creating a pro-regenerative environment allowing endogenous stem and progenitor cells to successfully repair affected tissues. Accordingly, MSC-EVs provide a novel, very promising therapeutic agent, which has already been successfully applied to humans. However, the MSC-EV production process has not been standardized, yet. Indeed, a collection of different protocols has been used for the MSC-EV production, characterization and application. By focusing on kidney, heart, liver and brain injuries, we have reviewed the major outcomes of published MSC-EV in vivo studies.
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                Author and article information

                Contributors
                Journal
                Stem Cells Int
                Stem Cells Int
                SCI
                Stem Cells International
                Hindawi
                1687-966X
                1687-9678
                2018
                16 January 2018
                : 2018
                : 1909346
                Affiliations
                1Department of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), University of Rostock, Schillingallee 69, 18057 Rostock, Germany
                2Department Life, Light and Matter of the Interdisciplinary Faculty, University of Rostock, Albert-Einstein Straße 25, 18059 Rostock, Germany
                Author notes

                Academic Editor: Jia-Qiang He

                Author information
                http://orcid.org/0000-0003-2821-2323
                http://orcid.org/0000-0002-8273-3616
                Article
                10.1155/2018/1909346
                5822776
                29535769
                55912535-988a-4028-9c82-3668017ddbc1
                Copyright © 2018 Heiko Lemcke et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 August 2017
                : 12 November 2017
                Funding
                Funded by: Bundesministerium für Bildung und Forschung
                Award ID: FKZ 0312138A
                Award ID: FKZ 316159
                Funded by: European Social Fund
                Award ID: ESF/IVWM-B34-0030/10
                Award ID: ESF/IVBM-B35-0010/12
                Funded by: Deutsche Forschungsgemeinschaft
                Award ID: DA1296-1
                Funded by: Rostock University Medical Centre
                Award ID: 889001
                Award ID: 889006
                Funded by: DAMP Foundation
                Funded by: Bundesministerium für Bildung und Forschung
                Award ID: VIP+ 00240
                Funded by: Käthe und Josef Klinz Foundation
                Award ID: T319/29737/2017
                Categories
                Review Article

                Molecular medicine
                Molecular medicine

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