key: cord-0964984-bcrmgqwi
authors: Zheng, Zhi-Xue
title: Stem cell therapy: A promising treatment for COVID-19
date: 2021-12-26
journal: World J Clin Cases
DOI: 10.12998/wjcc.v9.i36.11148
sha: bd2056f214bd4bf69be65718e199c4ec2a929136
doc_id: 964984
cord_uid: bcrmgqwi

Novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic. SARS-CoV-2 is an RNA virus and has a glycosylated spike (S) protein used for genome encoding. COVID-19 can lead to a cytokine storm and patients usually have early respiratory signs and further secondary infections, which can be fatal. COVID-19 has entered an emergency phase, but there are still no specific effective drugs for this disease. Mesenchymal stem cells (MSCs) are multipotent stromal cells, which cause antiapoptosis and can repair damaged epithelial cells. Many clinical trials have proved that MSC therapy could be a potential feasible therapy for COVID-19 patients, especially those with acute respiratory distress syndrome, without serious adverse events or toxicities. However, more studies are needed in the future, in order to confirm the effect of this therapy.

Novel coronavirus disease 2019 (COVID-19) is a severe respiratory disease that was first identified in December 2019 in Wuhan, China. COVID-19 is caused by severe acute respiratory syndrome coronavirus (SARS-CoV)-2 and has become a global pandemic. To date, > 100 million SARS-CoV-2 infections and > 2 million deaths have been reported by the World Health Organization (WHO) [1, 2] . It has been established that SARS-CoV-2 has sequence homology with SARS-CoV-1, one of the coronaviruses found in bats [3] [4] [5] [6] [7] .

SARS-CoV-2 is one of the Coronaviridae family of viruses, which includes four types, α, β, γ and δ. SARS-CoV-2, SARS-CoV-1 and Middle East respiratory syndrome coronavirus (MERS-CoV),belong to the β group [4, 8] . SARS-CoV-2 is an RNA virus and has a glycosylated spike (S) protein used for genome encoding. The angiotensinconverting enzyme (ACE)2, a membrane receptor, binds the S protein. ACE2 is highly expressed on lung alveolar type II cells, and is commonly found in heart, liver, kidney and digestive system cells, but not in bone marrow, spleen, lymph nodes and macrophages [9, 10] . The transmembrane protease, serine 2 is also commonly expressed on type II lung cells, which can initiate S protein and help the virus to invade host cells [6,10].

Furthermore, this viral infection leads to cytokine release syndrome, also called cytokine storm, and increases the level of inflammatory cytokines [interleukin (IL)-2, IL-6, IL-8, IL-17, tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (CSF), granulocyte-macrophage CSF], and chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein 1α, interferon-induced protein 10)[11-13]. As a result, patients show early signs of fever, cough, headache, followed by high fever, pulmonary edema, difficult breathing, acute respiratory distress syndrome (ARDS) and further secondary infections, which can result in potentially fatal consequences[14-17]. COVID-19 usually affects the upper and lower respiratory tract with an incubation period of 2 wk. The diagnosis of SARS-CoV-2 infection is based on an RT-PCR test and specific IgM and IgG in patients [18] [19] [20] . However, there are still no specific drugs for treating this infection at present.

Mesenchymal stem cells (MSCs) are multipotent stromal cells that can differentiate into many different types of cells including chondrocytes, osteoblasts and adipocytes, which has been confirmed in a variety of cells. MSCs are usually found in bone marrow, umbilical cord, placenta, adipose fat pads and dental pulp [21, 22] . MSCs, which secrete numerous cytokines and chemokines, cause antiapoptosis, and can repair damaged epithelial cells [23, 24] . MSCs secrete cytokines and modulate the immune response by regulating cell function and downregulating inflammatory cytokines in graft versus host disease and systemic lupus erythematous [25, 26] . Therefore, MSCs may be a potential treatment for COVID-19, as they could move towards injured lung cells and repair them.

MSCs have proved effective in both experimental research and clinical studies, including many immune-mediated inflammatory diseases, with good safety and low risk [23, 24] . Previous studies have shown that MSCs could reduce H5N1 influenza virus in older patients with acute lung injury, and improve the survival rate of H7N9infected patients with ARDS without serious complications [27, 28] . MSCs can also intervene in the activation of inflammatory cytokine secretion in dendritic cells (DCs) [29, 30] . Ling et al [31] found that stage-specific embryonic antigen-1, stem cell antigen-1, cytokeratin-7 and ACE2 were expressed in lung epithelial cells and ACE2 was expressed in lung stem cells. Furthermore, SARS-CoV-infected lung cells that lacked differentiated stem cells failed to repair. For this reason, MSC transplantation may be a feasible therapy for COVID-19.

The COVID-19 pandemic has entered an emergency phase, but there are still no specific effective drugs for this infection [32] . Due to the lack of effective therapy for COVID-19, current treatment is based on individual symptoms and supportive treatment. Most patients receive oxygen therapy and extracorporeal membrane oxygenation is recommended for refractory hypoxemia[33]. December 26, 2021

Volume 9 Issue 36

At present, drugs for COVID-19 include antiviral drugs, antimalarial drugs, antihuman immunodeficiency virus drugs, anti-inflammatory drugs, and monoclonal antibodies, such as remdesivir, chloroquine, lopinavir/ritonavir, nitazoxanide, and traditional Chinese medicine, which have been used in China and western countries [34] [35] [36] [37] [38] [39] [40] [41] . Many studies on IL-1, IL-2, IL-6 and TNF-α drugs have demonstrated that they can suppress the inflammatory response in COVID-19 patients, and have provided some clues on anti-inflammatory therapy to treat SARS-CoV-2 infection with better outcomes [42] . Etoposide-based therapy has been proposed as a new treatment for COVID-19, which requires further clinical trials [43] . There are currently several ongoing clinical trials of drugs and vaccines for the treatment of COVID-19.

Zheng et al [44] showed that MSC therapy for ARDS resulted in no infusion toxicity or serious adverse events. Another study involving patients with ARDS who were treated with an infusion of allogenic bone-marrow-derived human MSCs demonstrated good safety and no treatment-related adverse events. Furthermore, this treatment reduced lung injury in a sheep model [23, 45] . Therefore, MSC-based therapy demonstrated promising results for ARDS without any prespecified adverse events, and was both tolerable and safe. However, there are no long-term data on MSCtherapy-associated adverse events [46, 47] .

CD147 is a marker of undifferentiated embryonic stem cells, and is the second entry receptor for SARS-CoV-2. Its protein is expressed in tissue-specific stem cells of human bone marrow origin. Inhibition of CD147 can prevent inflammatory processes in diabetic complications [48, 49] . SARS-CoV-2 infection can trigger pulmonary fibrosis in normal tissue, and probably originates from resident stem cells, which are also called MSC-like cells. In the early stage of COVID-19 pneumonia, type II pneumocytes are involved in the initial step of pulmonary fibrosis. Anti-CD147 antibodies that can suppress the normal lung cell differentiation of fibroblasts in vitro have been investigated, and MSC transplantation may lead to immunosuppression and tissue regeneration [50, 51] .

In the first study of MSCs, Leng et al [14] treated seven patients with COVID-19 pneumonia with an injection of MSCs, and showed a significant reduction in clinical symptoms and a decrease in serum proinflammatory cytokines without adverse effects. Most of the patients were negative on the SARS-CoV-2 nucleic acid test within 2 wk after MSCs transplantation. Chen et al [52] observed that all patients showed clinical improvement, including 64% of patients with chest CT improvement, but little improvement in immunomodulation and cardiotoxicity during MSC therapy.

Human umbilical cord-derived MSC (UC-MSC) transplantation has been carried out in COVID-19 patients. A female patient with severe COVID-19 was treated with an human UC-MSC injection, which resulted in good efficacy without side effects [53] . Twelve patients with severe COVID-19 treated with UC-MSC transplantation reported improvements in clinical outcome, reduced C-reactive protein and IL-6 levels, and no mortality [54, 55] . A Phase I clinical trial of UC-MSCs for COVID-19 found no serious adverse events, and lung lesions in four moderate-severe patients completely disappeared within 2 wk after injection [56] . Adipose-tissue-derived MSCs were used to treat 13 severe COVID-19 pneumonia patients, and 70% of patients had clinical improvement and reduced levels of inflammatory factors [57] . Tang et al [58] used menstrual-blood-derived MSCs to treat severe COVID-19 patients, and found that bilateral pulmonary exudation had been absorbed and SaO 2 and PO 2 were also improved. Similar to MSCs, immunity-and matrix-regulatory cells (IMRCs) also have self-renewal and mesenchymal differentiation ability. Following injection of IMRCs, COVID-19 patients recovered and tested negative for the virus, while many inflammatory cytokines such as IFN-α2, IL-3, M-CSF and TNF-α were suppressed [59] . Previous studies have shown that MSC therapy may activate the immune system, stem cells can repair tissues, and then prevent the cytokine storm and release anti-inflammatory mediators. Consequently, this may prevent pulmonary fibrosis caused by SARS-CoV-2 infection. The MSCs were resistant to viral infection due to expression of interferon-stimulated genes [60-62]. The characteristics of included studies are shown in Table 1 .

Recent studies have indicated that MSCs are able to secrete immunomodulatory factors that could suppress the cytokine storm, promote tissue regeneration and inhibit tissue fibrosis. Given the previous preclinical and clinical studies, MSC therapy has shown good safety and efficacy in the treatment of respiratory failure or ARDS [63, 64] . Therefore, MSC injection showed promising results for therapy of COVID-19 patients [65] . In addition, many clinical trials on MSCs for COVID-19 (NCT04315987, NCT04313322 and NCT04333368) are ongoing worldwide. More clinical data will support this effective therapy. However, the number of patients in these studies is small, and the long-term safety and efficacy of this treatment require further invest- 

Monocyte CD147 is induced by advanced glycation end products and high glucose concentration: possible role in diabetic complications

The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation

CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement

Mesenchymal stem cell therapy in severe COVID-19: A retrospective study of short-term treatment efficacy and side effects

Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: A case report

Stem Cell-Based Therapy for Coronavirus Disease

Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells

Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial

Adipose-derived mesenchymal stromal cells for the treatment of patients with severe SARS-CoV-2 pneumonia requiring mechanical ventilation. A proof of concept study

Clinical study using mesenchymal stem cells for the treatment of patients with severe COVID-19

Stem cell therapy for COVID-19, ARDS and pulmonary fibrosis

Mesenchymal stem cells: Emerging mechanisms of immunomodulation and therapy

Mesenchymal Stem Cell Microvesicles Restore Protein Permeability Across Primary Cultures of Injured Human Lung Microvascular Endothelial Cells

Intrinsic Immunity Shapes Viral Resistance of Stem Cells

Mesenchymal stem cell therapies for COVID-19: Current status and mechanism of action

Mesenchymal Stem Cell-Based Therapy for COVID-19: Possibility and Potential

Role of ACE2 receptor and the landscape of treatment options from convalescent plasma therapy to the drug repurposing in COVID-19