Mesenchymal stem cells therapy and COVID19: a narrative review

Mohsen Ebrahimi, Ali Ahmadi, Fatemeh Mohseni, and Mohammad Taha Saadati Rad

Abstract—At the end of 2019, a new type of coronavirus pneumonia broke out in China and swept the world, and the World Health Organization named it COVID-19. Mesenchymal stem cells (MSCs) are cells with high differentiation potential and their ability to regenerate. The therapeutic effects of mesenchymal stem cells are mediated by the secretion of various agents, including conventional secretory proteins such as cytokines and growth factors, as well as exosomes. MSC injection in patients with COVID-19 was found to have potent anti-inflammatory activity of mesenchymal stem cells. Such processes were evident from numerous beneficial outcomes, including an increase in peripheral lymphocyte counts, a decrease in C-reactive protein, and a decrease in active cytokine-secreting immune cells in the circulating blood for 3 to 6 days. It is suggested that due to the favorable results of studies in this field, more studies be done on this treatment method.

Key words—COVID19, Mesenchymal stem cells (MSCs), Pneumonia

INTRODUCTION

Coronavirus (CoV) is a virus that infects the digestive and respiratory systems of humans and other organisms. Coronaviruses include subfamilies of alpha coronavirus, beta coronavirus, gamma coronavirus, and delta corona virus [1]. Among them, several human coronaviruses are responsible for mild respiratory illness. However, the most important coronaviruses that are highly harmful to humans are Acute Respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV), which can cause severe respiratory diseases [2]. SARS in 2002 and MERS in 2012 are both other coronaviruses that can be transmitted from animals to humans [2, 3]. In the last days leading up to the end of 2019, the Chinese government officially announced the outbreak of a new type of coronavirus, later called COVID-19 [4]. Less than three months after the outbreak began, more than 100,000 cases and about 4,000 deaths from the disease were reported worldwide [5]. At a time when dozens of countries are witnessing a growing number of new cases, the pattern of disease spread in China is declining. At the beginning of the global spread of the disease, some countries, such as Iran and Italy, became significantly more affected by the disease [6].

SYMPTOMS

Early signs and symptoms of SARS patients included cough, fever, myalgia, shortness of breath, and diarrhea [7], and the prognosis of patients was associated with host characteristics [8]. During hospitalization, respiratory distress occurred in 90.8% of COVID-19 patients [7]. During the disease, leukopenia, lymphopenia, and thrombocytopenia in some patients are overregulated by aspartate transaminase, alanine aminotransferase, lactic dehydrogenase, and C-reactive protein [9]. The term from the onset of symptoms to death, adjusted from 6 to 41 days with the middle of 14 days [10]. It also depends on the age and condition of the immune system. The overall survival of people over 70 years old is shorter than that of people under 70 years old [11]. Most of the symptoms of this disease can be referred to as fever, cough, fatigue, headache, hemoptysis, diarrhea, shortness of breath, and lymphopenia [12]. Clinical and therapeutic signs and symptoms with chest CT scans are known as pneumonia, but abnormal features such as RNA anemia, acute respiratory distress syndrome, and acute heart damage leading to death. [13]. There are also similarities and features between the symptoms of COVID-19 and coronary beta virus such as fever, dry cough, shortness of breath, and so on. [14]. Despite being a type of pneumonia, COVID-19 has some unique clinical and therapeutic features, which are characterized by signs and symptoms of the upper respiratory tract such as rhinorrhea, sneezing, and sore throat [15]. Symptoms of SARS-CoV-2 pathogenesis have been identified with cytokine storms in the lung. Dissemination and acute transmission of cytokine GSCF, IP10, MCP1, MIP1A, IL-2, IL-6, IL-7, and TNF cause pulmonary infection, air exchange disorders, acute respiratory distress syndrome (ARDS), and acute heart damage [16]. In most patients, SARS-CoV-2 infections range from asymptomatic to seasonal symptoms such as the flu [17]. Due to lung and multiple organ failure associated with virus-induced cytokine storms with a distinct pattern and tissue damage, severe cases require ICU care [18]. Depending on the patient’s sex/age, comorbidities, and available ICU capacity, mortality in the critically ill patient population with respiratory failure with septic shock has been reported to be the leading cause of death [19].

MESENCHYMAL STEM CELLS

MSCs are cells with high differentiation potential and self-renewal abilities [20]. The therapeutic effects of mesenchymal stem cells are mediated by the secretion of various agents, including conventional and related secretory proteins such as cytokines and growth and maintenance agents, as well as exosomes [21]. Exosomes are a type of extracellular vesicles originating from endosomes with a diameter of 40-200 nm. Mesenchymal stem cell-derived exosomes have the same immune regulatory functions as their maternal cells, such as carrying immunosuppressive factors, affecting the polarization of macrophages to M2 type, regulating T cell differentiation and antigen presentation. MSCs utilizing their immunomodulatory properties and their ability to differentiate and isolate can prevent the death of lung tissue in the face of cytokine storms and the repair of unhealthy tissues. There are also reports that the use of MSCs in the clinical treatment of H5N1 virus infection has similar effects on the lungs [22]. H5N1 influenza virus is a highly pathogenic subtype of influenza A virus. The common initial symptoms are high fever and cough, followed by symptoms and signs involving the lower respiratory tract, including difficulty breathing or shortness of breath. Studies have shown that due to the effect of proinflammatory cytokines, especially the combined induction of IFNγ and TNFα, MSCs will have an immunosuppressive effect. The anti-inflammatory function of MSCs is based on the secretion of effector molecules, such as TSG-6 and IGF-2 [17]. The utilization of MSC therapy with an effective approach in maintaining or repairing damaged vital organs, widely utilized in the treatment of type 2 diabetes, autoimmune disease, Graft versus host disease (GVHD), and various other diseases especially with high immunity rates have been utilized [23].

MESENCHYMAL STEM CELLS

MSCs are cells with high differentiation potential and self-renewal abilities [20]. The therapeutic effects of mesenchymal stem cells are mediated by the secretion of various agents, including conventional and related secretory proteins such as cytokines and growth and maintenance agents, as well as exosomes [21]. Exosomes are a type of extracellular vesicles originating from endosomes with a diameter of 40-200 nm. Mesenchymal stem cell-derived exosomes have the same immune regulatory functions as their maternal cells, such as carrying immunosuppressive factors, affecting the polarization of macrophages to M2 type, regulating T cell differentiation and antigen presentation. MSCs utilizing their immunomodulatory properties and their ability to differentiate and isolate can prevent the death of lung tissue in the face of cytokine storms and the repair of unhealthy tissues. There are also reports that the use of MSCs in the clinical treatment of H5N1 virus infection has similar effects on the lungs [22]. H5N1 influenza virus is a highly pathogenic subtype of influenza A virus. The common initial symptoms are high fever and cough, followed by symptoms and signs involving the lower respiratory tract, including difficulty breathing or shortness of breath. Studies have shown that due to the effect of proinflammatory cytokines, especially the combined induction of IFNγ and TNFα, MSCs will have an immunosuppressive effect. The anti-inflammatory function of MSCs is based on the secretion of effector molecules, such as TSG-6 and IGF-2 [17]. The utilization of MSC therapy with an effective approach in maintaining or repairing damaged vital organs, widely utilized in the treatment of type 2 diabetes, autoimmune disease, Graft versus host disease (GVHD), and various other diseases especially with high immunity rates have been utilized [23].

MSCS & CYTOKINE STORM ON COVID-19 CONDITION

Mesenchymal stem cells (MSCs), which originate in bone marrow, fat, umbilical cord, placenta, and other tissues, have mechanisms and processes that provide the potential for differentiation, strong immune regulation, and endogenous repair and regeneration [24, 25] They have anti-inflammatory and immune system regulation effects. After intravenous injection, there are several uses for MSC to treat bronchial asthma, shortness of breath, chronic lung disease, and interstitial lung. [26, 27] The safety and function of mesenchymal stem cells in human functions and applications have been confirmed through clinical trials. Extracellular vehicles (EVS) have also performed an extraordinary mass spectrometric analysis of more than 850 products and more than 150 miRNA genes. This enrichment in miRNAs or the immune system regulators of mesenchymal stem cells can alter the behavior of adaptive and innate immune cells. They can release keratinocyte growth factor, prostaglandin E2, granulocyte-macrophage colony-stimulating factor, and IL-6 and IL-13 to facilitate phagocytosis and activate alveolar macrophage replacement, cytokine secretion. [28, 29] In COVID-19, there is no significant effect of MSC gene expression profiles on ACE2 and TMPRSS2, they can be used to treat damaged tissues. In addition, mesenchymal stem cells reduced the cytokine-induced by proinflammatory cytokines and restricted the entry of mononuclear cells into alveolar cells. In addition, MSCs can secrete factors that improve the lung microenvironment, promote tissue repair, and improve pulmonary compliance [30] Therapeutic researchers in this field have observed that pre-ventilated stem cells (hypoxia, ischemic environment) can improve the function and survival rate of stem cells during transplantation in the injured area. Experimental methods, such as the culture of MSC in spheroids (approximately 500 μM) for a short time (3 days) can improve the adhesion and attachment of stem cells to the environment by increasing CXCR4 expression. Treating MSCs with medications and supplements such as vitamin E can counteract the damage, and MSCs can help you understand the dosage of medications and supplements. It can also help MSC function and protect as a productive agent [27, 31].

THERAPEUTIC EFFECTS OF MSCS ON COVID-19

It has been pointed out in multiple reports that MSCs are very optimistic about the treatment results of acute respiratory distress syndrome (ARDS). Because MSCs show effective results in improving pulmonary fibrosis while reducing inflammation and edema [32, 33] Immunomodulatory properties and mesenchymal stem cell regeneration are potential therapeutic cells for lung injury in patients with COVID-19 and require evaluation in a randomized controlled trial. A COVID-19 patient is still progressing after receiving intensive treatment and laboratory tests. The specific manifestation of this patient who used a ventilator during treatment showed liver damage. The patient was treated with an allogeneic human umbilical cord MSC using 3 intravenous ampoules 3 days apart. Within four days of the second cell injection, he was able to walk and remove the patient from the ventilator.The number of circulating T cells, which may have decreased due to deposition in the lungs and inflamed tissues, has returned to normal and no obvious side effects have been observed. [32, 34]. COVID-19 causes an exaggerated immune response in the body by producing various inflammatory factors, including several cytokines, chemokines, and immune-reacting cells. MSC treatment may prevent cytokine storm stimulation by the active immune system, and the compensatory properties of stem cells can be endogenous repair [35, 36] Based on experiments from various studies, a phase 2 test was performed to evaluate the efficacy and safety of human umbilical cord mesenchymal stem cells (UC-MSCs) for the treatment of severe COVID-19 patients with lung injury. In this clinical trial, 101 severe COVID-19 patients with placebo, double-blind, and placebo-controlled lung injury were selected. They were randomly assigned a 2: 1 ratio to receive UC-MSCs or placebo on days 0, 3, and 6. In total, 100 COVID-19 patients (n = 65) received UC-MSC or placebo (n = 35). The UC-MSC administration performed a numerical improvement in lung lesion volume from baseline to day 28 compared to placebo (mean difference: 13.31, 95% CI -29.14, 2.13,P= 0.080). UC-MSC significantly reduces the lesion volume ratio except for solid except compared to placebo (mean difference: 15.45, 95% CI -30.82, 0.39,P= 0.034). 6-MWT showed a greater distance in patients treated with UC-MSC (mean difference: 27.00, 95% CI 0.00, 57.00;P= 0.057). The incidence of side effects was similar in the UC-MSC group and the placebo group. These results indicate that UC-MSC injection therapy is a safe, effective and reliable method for treating patients with COVID-19 lung injury.

Table 1 Ongoing clinical studies exploring the contribution of MSCs

Another study in China reported on the treatment process and laboratory test results of a 65-year-old female patient with acute COVID-19 syndrome. The results of CT examination 21 days after umbilical cord mesenchymal stem cell treatment provide evidence that the treatment is effective [37, 38]. The patient had an 87% increase in neutrophils and a 9.8% decrease in lymphocytes and was treated with antiviral drugs such as lopinavir, IFN-α, and oseltamivir. The patient has also undergone non-invasive mechanical ventilation to facilitate breathing and relieve muscle fatigue due to a lack of oxygen. As vital signs worsened, the patient was treated three times with umbilical cord mesenchymal stem cells and α1 thymosin cells. The results of this study showed that after the second injection, serum albumin, CRP and ALT/AST, and other vital signs improved. The number of CD3+T cells, CD4+T cells, and CD8+T cells increased significantly. The results of CT images after the second and third injections of umbilical cord stem cells showed that the pneumonia was very relieved and improved, 2 days after the third injection the patient was discharged from the ICU and many vital signs and clinical laboratory parameters were normal. The results showed that umbilical cord mesenchymal stem cells alone or in combination with other immune modulators could be an ideal treatment option for acute COVID-19 patients [35]. In another study, 7 patients with COVID 19 pneumonia underwent MSCs transplantation and clinical manifestations of altered immune function. The results of this study showed that the clinical signs and symptoms of all patients improved 2 days after stem cell transplantation. The results showed that increasing the level of peripheral lymphocytes destroys the immune cells that secrete cytokines. MSC gene expression profiles have shown that these cells are ACE2 and TMPRSS2-, indicating that mesenchymal stem cells do not have COVID19 infection [39] Use and transplantation of mesenchymal stem cells in patients with COVID-19 pneumonia can lower C-plasma levels. Reactive protein indicates inflammatory status [40] Mesenchymal stem cells can induce mature dendritic cells into dentate gyrus-dependent regulatory dendritic cells [41]. In a study by Zhao et al., Seven patients with COVID-19 pneumonia were selected who improved clinically after the intravenous introduction of human mesenchymal stem cells. Chest CT imaging results showed that the penetration of thoracic pneumonia was significantly reduced and most patients showed negative results for the SARS-CoV-2 nucleic acid test after MSC injection. In this case report, elderly critically ill patients with COVID-19 showed significant improvement due to the use of mesenchymal stem cells. This treatment suggests that mesenchymal stem cells have strong anti-inflammatory activity. In addition, there have been many beneficial results during the treatment, including increased lymphocyte counts, decreased C-reactive protein concentration, and decreased cytokine-secreting immune cells in the peripheral blood for 3-6 days. It is suggested that due to the favorable results of studies in this field, more studies be done on this treatment method [20].

CONCLUSION

At present, many studies have shown that mesenchymal stem cells have a certain effect in the treatment of COVID-19. COVID-19 triggers an immune response in the body by producing various inflammatory factors, including several cytokines, chemokines, and immune-reacting cells. MSCs treatment may inhibit the stimulation of the cytokine storm by the active immune system, and the compensatory and replacement properties of stem cells can improve endogenous repair. In view of the current mutations and constant outbreaks of the new crown, MSCs therapy as an effective therapy should be actively promoted.

ACKNOWLEDGMENT

The authors did not receive any funding for this study.

Competing interests:The authors declare that they have no conflict of interest.

Citation:Mohsen E, Ali A, Fatemeh M, Mohammad Taha SR. Mesenchymal stem cells therapy and COVID19: a narrative review. Precision Medicine Research. 2021;3(3):15. doi: 10.53388/PMR2021070201.

Executive editor:Jin-Feng Liu.

Submitted:02 July 2021,Accepted:05 August 2021,Online:06 September 2021

© 2021 By Authors. Published by TMR Publishing Group Limited. This is an open access article under the CC-BY license (http://creativecommons.org/licenses/BY/4.0/)