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REVIEW
Mesenchymal Stem Cell-Derived Extracellular Vesicles: Promising Treatment for COVID-19 Pandemic

The pandemic of severe acute respiratory syndrome coronavirus-2 infection has prompted the urgent need for novel therapeutic approaches, especially for patients in critically severe conditions. To date, the pathogenesis of COVID-19 is not completely understood, and finding an effective new drug is still inconclusive. Mesenchymal stromal cell-derived extracellular vesicles contain large amounts of proteins, messenger RNA, and microRNAs that act as vehicles that transfer the cargo between cells. These nanotherapeutic materials exert anti-inflammatory effects on the immune system, which are necessary for subsidence of acute inflammation and promotion of tissue repair and regeneration. Therefore, the consideration of mesenchymal stromal cell-derived extracellular vesicles as a new, safe, and effective therapeutic approach in the treatment of COVID-19 pneumonia is suggested.


Key words : Mesenchymal stromal cell-derived extracellular vesicles, Respiratory viruses, Severe acute respiratory syndrome coronavirus 2

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly across the world, with a broad spectrum of clinical manifestations from mild clinical symptoms to multiple organ failure. This novel coronavirus can enter the host cell by binding of the viral S protein to the human angiotensin converting enzyme 2 (ACE-2) receptor, which is widely expressed in different tissues, including the intestine, lung, heart, kidney, and liver.1 Different clinical manifestations of the virus include diarrhea, acute respiratory distress syndrome (ARDS), acute kidney injury to myocarditis, and multiple organ dysfunction syndrome.

Whereas ACE cleaves angiotensin I to generate angiotensin II, ACE-2 is a terminal carboxypeptidase that reduces angiotensin II levels. Therefore, it plays important roles in the negative regulation of the renin-angiotensin system.2 Experimental studies have shown that angiotensin receptor blockers and an ACE inhibitor can increase ACE-2 expression in the cardiovascular and renal systems.3,4 Researchers have reported that knockout of ACE-2 extensively decreases SARS-CoV infection in mice.5 Thus, it was proposed that binding of the SARS-CoV-S protein to ACE-2 is essential for this infection.6

The major mechanism of extensive lung damage by respiratory viruses such as influenza or COVID-19 is induction of unregulated inflammatory responses with a subsequent cytokine storm. Therefore, older individuals are more affected due to immunosenescence.7,8

Different treatment strategies, including antiviral drugs such as remdesivir or lopinavir-ritonavir and immune modulating drug like interferon beta-1 are currently under investigation. Hydroxychloroquine is another therapeutic option that was approved by the US Food and Drug Administration. Other medical choices that might be useful to modify the cytokine storm are anti-interleukin (IL) 6 (anti-IL-6) and anti-IL-1.9 However, no accepted standard pharmacological management or vaccine is currently available for patients with SARS-CoV-2.

Cell-based therapies have emerged as new therapeutic approaches to ARDS. Of the various clinically applicable cell sources, mesenchymal stem/stromal cells (MSCs) have the potential to reduce lung injury from infectious causes. Presently, MSCs are considered as “medicinal signaling cells” because of their secretion-based mechanism of action. These cells with immunomodulatory properties facilitate tissue repair.10,11

Mesenchymal Stromal Cells Alleviate Viral-Induced Lung Injury
In a study conducted by Zhu and associates,12 the intratracheal injection of umbilical cord-derived MSCs alleviated pulmonary inflammation in mice with acute lung injury. The therapeutic potential of these cells was mediated by the secretion of prostaglandin E2, granulocyte-macrophage colony-stimulating factor, IL-6, and IL-13. Prostaglandin E2 enhanced the propagation of M2 macrophages. The paracrine effects of granulocyte-macrophage colony-stimulating factor that were mediated by increases in number of alveolar macrophages improved the host defense. Interleukin 6 was considered as a key player during inflammatory responses, which can promote the survival of CD11b+ peripheral blood mononuclear cells and induce M2 macrophage polarization. The induction of M2-type macrophages was also mediated by IL-13, transforming growth factor beta (TGF-?), and indoleamine 2,3-dioxygenase, which are essential for amelioration of lung inflammation.13,14 Release of paracrine factors, including keratinocyte growth factor, angiopoietin 1, and tumor necrosis factor alpha-stimulated gene 6, attenuated epithelial and endothelial damage in lung injury.15

Activation of inflammatory pathways in acute lung injury after influenza A H5N1 infection is associated with downregulation of sodium and chloride transporters in the alveolar epithelium, which disturbs the normal fluid transport and subsequently increases protein permeability.16 Treatment with MSCs ameliorated the downregulation of these pumps and reduced alveolar cell damage. Mitochondrial transfer from MSCs to injured alveolar epithelium was another mechanism that reduced lung injury in mice. This effect was dependent on connexin 43 and enhanced intracellular ATP levels in damaged cells.17 Mitochondrial transfer from MSCs to macrophages also enhanced the phagocytosis potential of macrophages.18

Treatment of ARDS in clinical settings is supportive, and improved survival may be achieved with use of ventilators and correction of the underlying causes of ARDS. Presently, MSC therapy is believed to be a new horizon for the treatment of ARDS. The safety of cell-based therapies has been tested in phase 1 and 2 human clinical trials for ARDS with various causes.12,19

Cell-based therapeutic approaches can have a range of dosing and sources of MSCs. In this regard, the sources of bone marrow, adipose, umbilical cord, cord blood, and placenta have been investigated. McIntyre and colleagues20 reported that MSCs from bone marrow and umbilical cord were more effective than adipose tissue-derived MSCs in reducing mortality in preclinical ARDS animal models. Two recently published clinical reports used MSCs to treat patients with COVID-19 pneumonia. The results were shown to be promising, with significant reversal of symptoms.21,22 In a report that included 1 patient, the patient was treated with allogeneic human umbilical cord MSCs with 3 doses of intravenous infusion of 5 × 107 cells every 3 days.21 The patient’s condition improved, and he was removed from a ventilator with no clinically recorded side effects. All paraclinical parameters, including lymphopenia and T-cell counts, gradually returned to normal levels. The other study reported the results of 7 patients with clinical COVID-19 pneumonia who had clinical symptoms that ranged that ranged from critically severe to nonsevere conditions.22 Before cell transplant, patients had high-grade fever, shortness of breath, and low oxygen saturation. The patients were treated with a single intravenous dose of 1 × 106 cells/kg body weight. The results were promising, and all were discharged from the hospital in good condition. No acute transfusion complications, allergic reactions, or delayed hypersensitivities were recorded. The efficacy of transplanted cells was confirmed by clinical improvements, increased arterial oxygen saturation, decreased plasma C-reactive protein level, alleviation of lymphopenia, and return to baseline levels of aspartic aminotransferase and creatine kinase. After cell therapy, the numbers of regulatory CD4+ T cells and dendritic cells were increased, with concomitant decreases of tumor necrosis factor alpha, a proinflammatory cytokine, and increases of IL-10. Both anti-inflammatory and paracrine secretion of trophic factors, including hepatocyte growth factor, leukemia inhibitory factor, vascular endothelial growth factor, epidermal growth factor, brain-derived neurotrophic factor, nerve growth factor, and TGF, changed the microenvironment of the damaged alveolar epithelial and endothelial cells and promoted endogenous repair. After intravenous infusion of MSCs, approximately 70% of the cells accumulated in the lung. The presence of these cells, as well as their paracrine secretion, improved lung function. However, the major obstacle in this way was the ability of influenza virus to infect the MSCs, and this event may affect the proper antiviral and immunomodulatory function of MSCs in virus-induced acute lung injury and ARDS.22

Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles Alleviate Viral-Induced Lung Injury
The secretome of MSCs, composed of soluble extracellular vesicles (EVs), works as cargo that contains the paracrine growth factors, cytokines, and genetic materials that mediate the therapeutic potential of these cells on cell proliferation and differentiation, as well as inflammation and tissue repair.23-26

Several preclinical reports on mouse and pig models emphasized the protective effects of MSC-EVs in influenza virus (influenza strains H5N1 and H9N2)-induced ARDS. In an animal study that used a pig model of influenza virus conducted by Khatri and associates,27 MSC-EVs inhibited viral activity with suppression of influenza virus replication in lung epithelial cells. Afterward, the production of proinflammatory cytokines was suppressed. The investigators believed that the inhibition of EV-related viral replication was mediated by mRNA content because the pretreatment of EVs with RNAase enzyme ameliorated the antiviral effects.27 On the other hand, in a mouse study, Hao and associates28 found that MSC-EVs induced production of IL-10, with conco­mitant increase of cyclooxygenase 2 mRNA expression and subsequently the production of prostaglandin E2, which was essential in reprogramming the proin­flammatory macrophages (M1) to the anti-inflam­matory (M2) type. The interaction of MSC-EVs with inflammatory cells, surrounding the infected alveolar epithelial cells, led to production of TGF-? through the induction of regulatory T cells.29

Another therapeutic soluble factor, released by MSCs, is indoleamine 2,3-dioxygenase, which can inhibit influenza virus replication.28 Therefore, the immunomodulatory effects of MSC-EVs are mediated by modulation of both the adaptive and innate immune systems, the induction of tolerogenic dendritic cells, and the inhibition of B-cell proliferation and function.15

Conclusion

Major Advantage of Mesenchymal Stem/Stromal Cell-Derived Extracellular Vesicles in the Treatment of SARS-CoV-2 Although the safety of MSCs has been confirmed in both preclinical and clinical human studies,30,31 there are concerns about pulmonary embolization and the possibility of long-term tumor formation.32 It seems that the use of EVs may be safer than MSCs because EVs are stable in blood circulation and after injection. Moreover, due to their small size and lack of MHC molecules, they are well tolerated by recipients. The EVs are easily stored at -80 °C, and their biochemical properties are preserved after thawing.33,34 The unique immunomodulatory properties of MSC-EVs candidate them as a “magic” therapeutic material. However, their safety and effectiveness for treatment of patients with COVID-19 pneumonia must be confirmed in future clinical trials. Because of the susceptibility of MSCs to COVID-19 infection, the secretome of these cells may not be affected by the virus, and it is another promising point that candidate MSC-EVs as a therapeutic strategy. In this way, the production of large-scale EVs using good manufacturing practice preparation procedures is critical. In addition, the consideration of ethical guidelines approved by the World Health Organization during epidemics and other public health emergencies is mandatory.35


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DOI : 10.6002/ect.2020.0296


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From the 1Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; the 2Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran; the 3Department of Tissue Engineering and Cell Therapy, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran; and the 4Marquette University School of Dentistry, Milwaukee, Wisconsin, USA
Acknowledgements: The authors thank Dr. Nasrin Shokrpour at the Research Consultation Center (RCC) of Shiraz University of Medical Sciences for her invaluable assistance in editing this manuscript. The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Negar Azarpira, Transplant Research Center, Khalili street, Shiraz, Iran 7193711351 Phone: +98 7136281529
E-mail:negarazarpira@gmail.com