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      Therapeutic Potential of Mesenchymal Stem Cells and Their Secretome in the Treatment of SARS-CoV-2-Induced Acute Respiratory Distress Syndrome

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          Abstract

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent responsible for the development of a new coronavirus disease (COVID-19), is a highly transmittable virus which, in just ten months, infected more than 40 million people in 214 countries worldwide. After inhalation, aerosols containing SARS-CoV-2 penetrate to the depths of the lungs and cause severe pneumonia, alveolar injury, and life-threatening acute respiratory distress syndrome (ARDS). Since there are no specific drugs or vaccines available to cure or prevent COVID-19 infection and COVID-19-related ARDS, a new therapeutic agent which will support oxygen supply and, at the same time, efficiently alleviate SARS-CoV-2-induced lung inflammation is urgently needed. Due to their potent immuno- and angiomodulatory characteristics, mesenchymal stem cells (MSCs) may increase oxygen supply in the lungs and may efficiently alleviate ongoing lung inflammation, including SARS-CoV-2-induced ARDS. In this review article, we described molecular mechanisms that are responsible for MSC-based modulation of immune cells which play a pathogenic role in the development of SARS-CoV-2-induced ARDS and we provided a brief outline of already conducted and ongoing clinical studies that increase our understanding about the therapeutic potential of MSCs and their secretome in the therapy of COVID-19-related ARDS.

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          Most cited references38

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          The Cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

          Highlights • COVID-19 pandemic is raging worldwide and is putting health-care systems under severe strain. • The “cytokine storm” and the subsequent Acute Respiratory Distress Syndrome results from the effects of a combination of several immune-active molecules. • the “cytokine storm” appears as one of the most dangerous and potentially life-threatening event related to COVID-19 sustaining its major clinical consequences. • The chemokine system appears to be deeply involved in the pathogenesis of severe clinical sequelae of COVID-19, similarly to what was observed in SARS and MERS epidemics.
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            Transplantation of ACE2 - Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia

            A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.
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              The Clinical and Chest CT Features Associated With Severe and Critical COVID-19 Pneumonia

              Objective The aim of this study was to investigate the clinical and computed tomography (CT) features associated with severe and critical coronavirus disease 2019 (COVID-19) pneumonia. Materials and Methods Eighty-three patients with COVID-19 pneumonia including 25 severe/critical cases and 58 ordinary cases were enrolled. The chest CT images and clinical data of them were reviewed and compared. The risk factors associated with disease severity were analyzed. Results Compared with the ordinary patients, the severe/critical patients had older ages, higher incidence of comorbidities, cough, expectoration, chest pain, and dyspnea. The incidences of consolidation, linear opacities, crazy-paving pattern, and bronchial wall thickening in severe/critical patients were significantly higher than those of the ordinary patients. Besides, severe/critical patients showed higher incidences of lymph node enlargement, pericardial effusion, and pleural effusion than the ordinary patients. The CT scores of severe/critical patients were significantly higher than those of the ordinary patients (P < 0.001). Receiver operating characteristic curve showed that the sensitivity and specificity of CT score were 80.0% and 82.8%, respectively, for the discrimination of the 2 types. The clinical factors of age older than 50 years, comorbidities, dyspnea, chest pain, cough, expectoration, decreased lymphocytes, and increased inflammation indicators were risk factors for severe/critical COVID-19 pneumonia. Computed tomography findings of consolidation, linear opacities, crazy-paving pattern, bronchial wall thickening, high CT scores, and extrapulmonary lesions were features of severe/critical COVID-19 pneumonia. Conclusions There are significant differences in clinical symptoms, laboratory examinations, and CT manifestations between the ordinary patients and the severe/critical patients. Many factors are related to the severity of the disease, which can help clinicians to judge the severity of the patient and evaluate the prognosis.
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                Author and article information

                Contributors
                Journal
                Anal Cell Pathol (Amst)
                Anal Cell Pathol (Amst)
                ACP
                Analytical Cellular Pathology (Amsterdam)
                Hindawi
                2210-7177
                2210-7185
                2020
                20 November 2020
                : 2020
                : 1939768
                Affiliations
                1Regenerative Processing Plant, LLC, 34176 US Highway 19 N Palm Harbor, Palm Harbor, Florida, USA
                2Department of Infectious Diseases, Faculty of Medical Sciences, University of Kragujevac, Svetozara Markovica 69, 34000 Kragujevac, Serbia
                3Institute of Anatomy, University of Bern, 2 Baltzerstrasse, 3012 Bern, Switzerland
                4Department for Microbiology and Immunology, Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozar Markovic Street, Kragujevac, Serbia
                Author notes

                Academic Editor: Consuelo Amantini

                Author information
                https://orcid.org/0000-0002-5906-9198
                https://orcid.org/0000-0001-9280-2251
                https://orcid.org/0000-0002-5062-1169
                https://orcid.org/0000-0001-5948-9902
                Article
                10.1155/2020/1939768
                7678745
                33274176
                eafbbec5-bca3-469d-bb5a-e5f5abb60e61
                Copyright © 2020 Carl Randall Harrell 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
                : 10 June 2020
                : 6 November 2020
                Funding
                Funded by: Faculty of Medical Sciences University of Kragujevac
                Award ID: MP01/18
                Funded by: Serbian Ministry of Science
                Award ID: ON175103
                Award ID: ON175069
                Funded by: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
                Award ID: IZSEZ0 185546
                Funded by: University of Catania
                Funded by: ECLAT
                Funded by: European Crohn's and Colitis Organization
                Categories
                Research Article

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