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      Mesenchymal stem cells as a potential treatment for critically ill patients with coronavirus disease 2019

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          Abstract

          To the Editor, We read with interest the article by Abraham and Krasnodembskaya regarding mesenchymal stem cells (MSCs)‐derived extracellular vesicles for the treatment of acute respiratory distress syndrome (ARDS). 1 Since December 2019, the outbreak of coronavirus disease 2019 (COVID‐19) in Wuhan, China, has drawn worldwide attention. As of February 26, 2020, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) had infected more than 82 000 people and had led to 2800 deaths from acute lung injury (ALI) and ARDS worldwide. Unfortunately, the numbers of both infected patients and fatalities are still growing and no effective drugs are clinically approved. Similar to two other lethal coronaviruses, SARS‐CoV and MERS‐CoV, SARS‐CoV‐2 induces excessive and aberrant host immune responses that are always accompanied by cytokine storms (CS) and subsequent ALI or even ARDS, resulting in multiple organ failure and death. 2 Even in patients who were treated in intensive care units for CS, persistent inflammation led to serious sequelae of lung fibrosis, causing lung dysfunction and reduced quality of life. 3 Although corticosteroid given to reverse catabolism in critical illness decreased the mortality after SARS and MERS infection, the clinical application of corticosteroid has been restricted in COVID‐19, considering its delay in virus clearance and complications in survivors. There is an urgent need for advancing therapeutic interventions with both functions for CS suppression and lung reparation in critical patients. MSCs have been found to be capable of modulating immune responses, thereby reducing inflammation as well as immunopathology and protecting alveolar epithelial cells during ALI and ARDS.4, 5, 6, 7 More importantly, MSCs were efficacious in reducing the nonproductive inflammation and in promoting lung generation in a phase 2 clinical trial (NCT03608592), as well as in patients with ALI and ARDS in clinical practice.8, 9, 10 As a result, MSCs may alleviate the SARS‐CoV‐2‐derived CS and ARDS, and have a potential effect on the treatment of subsequent chronic respiratory dysfunction and lung fibrosis. To alleviate acute respiratory disease and reverse pulmonary fibrosis in intensive‐care SARS‐CoV‐2‐infected patients, three curative properties of MSCs have emerged (Figure 1): (a) directly inducing the apoptosis of activated T cells to relieve the aberrant and excessive immune responses, (b) homing toward specific injuries of lung to maintain homeostasis as well as promote regeneration, and (c) releasing cytokines to diminish inflammation and extracellular vesicles (EVs) to stimulate tissue reparation. 1 Notably, it has been proved that MSC‐released cytokines can potently inhibit neutrophil intravasation and enhance the differentiation of macrophages.5, 6 Moreover, these MSC‐released EVs can deliver microRNA, mRNA, DNA, proteins, and metabolites into host cells in specific injuries of the lung to promote lung repair as well as regeneration and restore lung function. 1 FIGURE 1 Potential mechanism of MSCs in the treatment of severe COVID‐19 As the continuing epidemic threat of SARS‐CoV‐2 to global health and the fast‐growing number of fatalities, advancing new therapeutic development becomes central or primary to minimize the death and sequelae from SARS‐CoV‐2 infection. Thus, MSCs should be considered as a potential treatment for these critical patients. A recent clinical trial (NCT04252118) is expected to verify its efficacy and safety. CONFLICT OF INTEREST The authors declared no potential conflicts of interest.

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          Most cited references 10

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer.

            Acute respiratory distress syndrome (ARDS) remains a major cause of respiratory failure in critically ill patients. Mesenchymal stromal cells (MSCs) are a promising candidate for a cell-based therapy. However, the mechanisms of MSCs' effects in ARDS are not well understood. In this study, we focused on the paracrine effect of MSCs on macrophage polarization and the role of extracellular vesicle (EV)-mediated mitochondrial transfer.
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              Mesenchymal stem cells: a new strategy for immunosuppression?

              In vitro-generated mesenchymal stem cells (MSCs) initially attracted interest for their ability to undergo differentiation toward cells of different lineages. More recently, a major breakthrough was the discovery that MSCs exert a profound inhibitory effect on T cell proliferation in vitro and in vivo. Subsequently, MSCs were shown also to exert similar effects on B cells, dendritic cells and natural killer cells. These results suggested that MSCs could be used to dampen immune-mediated diseases and transplant rejection. It is possible that some of the beneficial effects of MSCs might reflect, in part, the trophic and protective activities they exert on injured cells and tissues, rather than resulting from a true transdifferentiation. In immune-mediated diseases, the protective effects might function in concert with the immunosuppressive and anti-inflammatory activities.
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                Author and article information

                Contributors
                yanjin@fmmu.edu.cn
                wenjialiu23@163.com
                Journal
                Stem Cells Transl Med
                Stem Cells Transl Med
                10.1002/(ISSN)2157-6580
                SCT3
                Stem Cells Translational Medicine
                John Wiley & Sons, Inc. (Hoboken, USA )
                2157-6564
                2157-6580
                22 April 2020
                Affiliations
                [ 1 ] Department of Infectious Diseases the Second Affiliated Hospital of Xi'an Jiaotong University Xi'an People's Republic of China
                [ 2 ] State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology Fourth Military Medical University Xi'an People's Republic of China
                [ 3 ] National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, the Second Affiliated Hospital Xi'an Jiaotong University Xi'an People's Republic of China
                [ 4 ] Key Laboratory of Environment and Genes Related to Diseases Xi'an Jiaotong University, Ministry of Education of China Xi'an People's Republic of China
                Article
                SCT312697
                10.1002/sctm.20-0083
                7264790
                32320535
                © 2020 The Authors. stem cells translational medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                Page count
                Figures: 1, Tables: 0, Pages: 2, Words: 1063
                Product
                Funding
                Funded by: Fundamental Research Funds for the Central Universities for COVID‐19
                Award ID: xzy032020040
                Categories
                Letter to the Editor
                Letters to the Editor
                Custom metadata
                2.0
                corrected-proof
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.3 mode:remove_FC converted:02.06.2020

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