The therapeutic potential of mesenchymal stem cells in COVID-19: Present and future Текст научной статьи по специальности «Клиническая медицина»

# Research Results in Pharmacology

Research Results in Pharmacology 9(2): 75-84 UDC: 615.038 DOI 10.18413/rrpharmacology.9.10031

3 Review Article

The therapeutic potential of mesenchymal stem cells in COVID-19: Present and future

Mutiara Indah Sari1, Imam Budi Putra1, Dadik Wahyu Wijaya1

1 Universitas Sumatera Utara, Jl. Dr. Mcmsyur No. 5 Medcm, North Sumatra. Indonesia 20155 Corresponding author: Mutiara Indah Sari (mutiaraMusu.ac.id)

Academic editor: Tatyana Pokrovskaia ♦ Received 12 February 2023 ♦ Accepted 21 May 2023 ♦ Published 19 June 2023

Citation: Sari MI, Putra IB, Wijaya DW (2023) The therapeutic potential of mesenchymal stem cells in COVID-19: Present and future. Research Results in Pharmacology 9(2): 75-84. https://doi.Org/10.18413/rrphannacology.9.10031

Abstract

Introduction: Coronavirus disease 2019 (COVID-19) was first reported in 2019 and has since become a health concern due to its rapid spread and high mortality rate. With the discovery of vaccines, there has been a reduction in disease occurrence, transmission, mortality, and morbidity in a population. However, with the emergence of new variants, the available vaccines show varying efficiencies depending on the population and variants, while the present drugs may lose their effectiveness, hence the urgent need to explore effective therapies. Mesenchymal stem cells (MSCs) have been widely studied for their anti-inflammatory and immunomodulatory effects as COVID-19 treatment and shown their potential to improve the condition of COVID-19 patients. This systematic review aims to assess the therapeutic potential of MSCs as antiinflammatory and immunomodulatory agent in COVID-19.

Materials and Methods: A literature search is performed on PubMed, ScienceDirect, ProQuest, and Google Scholar and potentially relevant studies to review, based on the inclusion and exclusion criteria we have determined. We identified 14,090 publications from our search and excluded duplicates as well as irrelevant studies from title, abstract, and full-text screening. Data extraction and analysis were then performed in the 20 eligible studies.

Results and Discussion: Results show that MSCs improve immune system dysregulation through immunomodulatory and anti-inflammatory effects, through reducing blood C-reactive protein (CRP) and IL-6 levels.

Conclusion: We conclude that MSC is one of the promising treatments in COVID-19 regardless of variants.

Copyright Sari MI et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Graphical abstract:

Rapid transmission and high mortality rate Treatment is still symptomatic and supportive

Mesenchymal Stem Cells (MSCs)

^ Studies showed the potential of MSCs in improving ^^^J the condition of COVID-19 patients

1

Most focus on the association between MSC therapy with inflammatory markers and the immune system Some focus on the association between MSC therapy with respiratory function, lung imaging, and mortality MSCs have immunomodulatory and antiinflammatory effects that can suppress cytokine storm, the main cause of mortality in COVID-19

Based on the inclusion and exclusion criteria, 20 articles a included and analyzed

Keywords

anti-inflammatory, cell therapy, immunomodulatory, inflammation, virus

Introduction

The respiratory disease caused by novel coronavirus (SARS-CoV-2, previously known as 2019-nCoV) coronavirus disease 2019 (COVID-19) was first reported in China (Guo et al. 2020). Although the details of the virus emergence, such as its origins and transmission potential on humans, are unknown, the increasingly dire cases are thought to come from human-to-human transmission (Munster et al. 2020). COVID-19 could lead to various symptoms, ranging from asymptomatic infection to severe pneumonia as well as multisystem failure that can lead to death (Garcia 2020). COVID-19 has a mortality rate of 30-40% and often causes intensive care unit (ICU) admission. The main cause of death is the immune system dysregulation that will evolve into acute respiratory distress syndrome (ARDS). Up to 90% of ICU patients with ARDS require mechanical ventilation (COVID-ICU Group 2020).

COVID-19 patients are reported to increase in number, with more than 61.8 million cumulative cases and 1.4 million deaths globally (Dilogo et al. 2021). Per January 24, 2020, at least 830 cases had been diagnosed in nine countries in Asia and America. There were 26 deaths, mainly in patients with severe underlying diseases (Guo et al. 2020).

The first COVID-19 case in Indonesia was reported on March 2, 2020. The two patients, aged 31 and 64, were the country's first two cases. It was proposed that COVID-19 had entered Indonesia in the third week of January 2020. On May 21, 2020, 973 new cases of COVID-19 were reported in Indonesia. Indonesia has reported 1,278 cases of COVID-19 death, 6.3% of the country's COVID-19 cases, mainly in four provinces, namely East Java, Jakarta, West Java, and North Sumatra (Sari et al. 2021).

With the discovery of vaccines, there has been a

reduction in disease occurrence, transmission, morbidity, and mortality in a population (Alencar et al. 2021). A study by Liang et al. (2021) on a longitudinal data set of 90 countries over 25 weeks showed that an increase in vaccine coverage was associated with a reduction in case fatality ratio (CFR). A systematic review on seven studies involving a total of 1,366,700 participants by Huang and Kuan (2022) also shows that all types of COVID-19 vaccines could effectively prevent the occurrence of severe diseases.

However, with the emergence of new variants, the available vaccines show varying efficiencies (Rabaan et al. 2022). These variants contain mutations in the spike proteins, which many COVID-19 vaccines were based on (Rubin 2021). For example, the Omicron variant has at least 30 amino acid substitutions, with 15 of them located in the receptor-binding portion (Liu et al. 2022). An experiment of incubating the virus from the convalescent sera of patients infected with prior subtypes by Zhang et al. (2021) showed that the sera has relatively low neutralization ability against the Omicron variant. Moreover, the rapid mutation of the virus may cause the present drugs to lose their effectiveness against SARS-CoV-2 spread, hence the urgent need to explore effective clinical therapies (Yin et al. 2022). Currently, there are hundreds of on-going clinical trials of potential COVID-19 drugs. The therapeutic effects of these drugs range from preventing the virus from entering cells, inhibiting viral RNA-dependent RNA polymerase or proteases activities, to maintaining the equilibrium of the immune system of the host and reducing inflammation (Beeraka et al. 2020; Zhou et al. 2021; Yin et al. 2022).

Mesenchymal stem cells (MSCs) from the umbilical cord tissue, placental cells, bone marrow, adipose tissue, and dental pulp have been extensively studied for their anti-inflammatory effects (Galipeau and Sensébé 2018). Mesenchymal stem cells with conditioned media are

called secretomes which function as an effective alternative therapy, mediating their therapeutic effects by retaining trophic molecules in the form of a number of factors (Gwam et al. 2021). Biological factors secreted from cells into the extracellular space can be in the form of dissolved proteins, free nucleic acids, lipids, extracellular vesicles (EV), apoptotic bodies, microparticles, and exosomes (Daneshmandi et al. 2020). MSCs is known to modulate the immune response by cell-to-cell contact and soluble secretory factors. Currently, the immunomodulatory effects of MSCs are mostly attributed to the paracrine activity of MSCs (Weiss et al. 2020).

Since the COVID-19 pandemic, clinical trials using stem cell therapy have been carried out. These studies have reported that MSCs reduce inflammatory cell infiltration and improve lung damage and recovery time as well as the survival of patients in the early phase (Tang et al. 2020). MSCs also show immunomodulatory potential, but the safety and long-term effectiveness of using MSC therapy for severe COVID-19 remains unknown (Tang et al. 2020; Shi et al. 2022).

In this systematic review, we assess the therapeutic potential of MSCs in COVID-19 by reviewing previous studies on MSC therapy in COVID-19.

Materials and Methods

A literature search was conducted in PubMed, Science Direct, ProQuest, and Google Scholar from April 15, 2022 to May 3, 2022. The search was conducted using keywords based on MesH to find research subjects for studies published in the last 3 years (2019-2022) in English language.

Case control, cohort, clinical trials, randomized controlled trials, cross-sectional, retrospective, prospective, pilot, meta-analyses, and observational studies are included. Review articles, comments, abstracts, book excerpts, case reports, bulletin reviews, dissertations and master theses as well as studies in animals and pediatric populations are excluded. The relevance of the study was determined using the inclusion criteria formulated using PICO (Population, Intervention, Comparison and Outcomes), as presented in Table 1.

Table 1. List of questions used for inclusion and exclusion of studies during screening stage

Screening Stage

Questions

Results

Title and

abstract

screening

Is this study focused on COVID-19? Does the study population consist of adult humans?

Is the population of this study

treated with MSCs?

Has this study been published

within the last 3 years?

Is this study in English?

Is the study design a case control,

cohort, clinical trial, randomized

controlled trial, cross-sectional,

retrospective, prospective, pilot,

meta-analysis, or observational

study?

Literature included if all questions are answered with 'yes'

Full text • Is there full access to this study? screening • Does this study have a control group as a comparison?

Literature included if all questions are answered with 'yes'

Results

We identified 14,090 publications related to mesenchymal stem cells and COVID-19 in the PubMed, ScienceDirect, ProQuest, and Google Scholar databases. 10,872 duplicates were identified and excluded. Titles and abstracts were then screened. We found 3,182 irrelevant studies and performed full text screening on studies that were not excluded. Data extraction and analysis were performed on 22 eligible studies. These data are illustrated in Figure 1.

Figure 1. Study selection flowchart

The study design, number of cases, and outcome of the selected articles are summarized in Table 2. Most studies focus on the association between MSC therapy with inflammatory markers and the immune system, though there are several studies that focus on the association between MSC therapy with respiratory function, lung imaging, and mortality.

Discussion

From various sources of MSCs, umbilical cord MSCs can be obtained and cultured easily. These MSCs have demonstrated immunomodulating and tissue repairing effects with low immunogenicity, making them ideal candidates for allogeneic adoptive transfer therapy (Liang et al. 2020). Processing and collection of MSCs from the umbilical cord are simple as well. Cord blood collection can be performed before or after delivery of the placenta and is painless for both the mother and the child. In addition, the number of cells per unit volume in umbilical cord blood is higher than that in bone marrow (Alatyyat et al. 2020). Many studies in this systematic review used the umbilical cord as a source of MSCs for the therapy (Feng et al. 2020; Meng et al. 2020; Shu et al. 2020;

Table 1. Summary of the included studies

Reference Study Design Patients MSC Source Outcome

Adas et al. (2021) Prospective Study 30 patients with moderate and critical COVID-19 clinical manifestations; First group (n=10), moderate COVID-19 with conventional treatment. Second group (n = 10), critical COVID-19 with conventional treatment. Third group (n=10), critical COVID-19, with conventional treatment plus MSCs transplantation therapy Wharton's Jelly • Statistically lower mortality rate in Group 3 (p<0.001) than in Group 2 • Duration of stay in hospital and ICU of Group 2 and Group 3 were not statistically different (p>0.05) • Duration of stay in the ICU were significantly lower in Group 3 compared to Group 2 (p<0.05) • Lower serum ferritin, fibrinogen, and CRP levels in Group 3 than Group 2 (p<0.05)

Dilogo et al. (2021) Randomized Controlled Trial 40 COVID-19 patients; 20 UC-MSC group, 20 control group Umbilical Cord • Higher survival rate in the UC-MSC group than in the control group (p=0.047) • No significant difference in duration of ICU and ventilator usage • Lower IL-6 in the UC-MSC group (p=0.023)

Fathi-Kazeeroni et al. (2022) Randomized Controlled Trial 30 COVID-19 patients; 15 given MSC-Secretome, 15 control Menstrual Blood • Significantly higher survival rate in the intervention group (p<0.001) • Significant improvement in the percentage of pulmonary involvement of the intervention group (p<0.0001)

Feng et al. (2020) Pilot Study 16 COVID-19 patients; 8 severe type patients and 7 critically severe type patients Umbilical Cord • Overall death rate was 6.25%, whereas the historical mortality rate was 45.4% • Improved oxygenation index after UC-MSCs transplantation • No statistical significance between the D28 mortality rate of severe type and critically severe type (p=1.0000)

Feng et al. (2022) Cohort Study 28 COVID-19 patients; 8 patients in hUC-MSC group, 20 patients included in control group Umbilical Cord • Higher mean FEV1 in hUC-MSC group compared to control group (p<0.01) • Significantly higher FEV1/FVC ratio of the hUC-MSC group than the control group (p<0.05) • Significantly lower rate of wheezing in the hUC-MSC group than the control group (p<0.05) • No significant differences in CT scores between the two groups (p=0.917)

Häberle et al. (2021) Case Control Study 23 patients with severe COVID-19 ARDS; 5 treated with MSC, 18 control Unspecified • No statistically significant difference in ICU stay length in both groups (p=0.07) • Lower mortality rate in MSC group (p=0.32) • No significant difference in CRP and IL-6 between the groups • MSC group had lower number of leukocytes and neutrophils than controls at discharge • Significant increase in ferritin levels in the MSC group

Karyana et al. (2022) Randomized Controlled Trial 9 COVID-19 patients; 3 given high dose DW-MSC, 3 given low dose DW-MSC, 3 given placebo Unspecified • No statistically significant differences among the three groups based on the WHO ordinal scale, PaO2/ FiO2 ratio, NEWS2, or chest X-ray data

Lanzoni et al. (2020) Randomized Controlled Trial 24 COVID-19 patients; 12 patients in UC-MSC group, 12 patients in control group Umbilical Cord • Significantly improved survival rate in the treatment group than the control group (p=0.015) • Significantly improved SAE-free survival rate in the treatment group than the control group (p=0.0081) • Significantly shorter time to recovery in the treatment group than the control group (p=0.0307) • Lower median values and significant differences in the concentration (p<0.05) of various cytokines in the treatment group • Statistically significant decrease in inflammatory cytokine concentrations from day 0 to day 6 in the treatment group • Insignificant differences in viral load between groups at day 0 (p=0.196) or day 6 (p=0.136)

Meng et al. (2020) Clinical Trial 18 COVID-19 patients; 9 patients in UC-MSC treatment group, 9 patients in control group Umbilical Cord • No significant difference in the duration from admission to discharge in both groups (p=0.306) • Numerical, but not statistical decrease in median IgG (p=0.174) and IgM (p=0.114) antibodies titer in UC-MSC treatment group compared to control group

Monsel et al. (2022) Randomized Controlled Trial 47 COVID-19 patients; 22 assigned to receive UC-MSCs, 25 assigned to receive the placebo Umbilical Cord • Insignificant difference in PaO2/FiO2-ratio change between day 0 and day 7 between treatment and control group • Significantly lower inflammatory markers in the treatment group • No significant difference in SOFA scores, PaO2/FiO2 ratios, compliance, driving pressure change between day 0 and day 7 and day 14, organ-failure-free days, ventilation-free days, duration of ventilation, time to weaning, time to ICU discharge, time to reach PaO2/FiO2 > 200 or > 300, and mortality to D28 between two groups

Montanuc ci et al. (2021) In Vitro Study 18 COVID-19 patients and 14 healthy subjects as control; blood samples collected from the patients Wharton's Jelly • In COVID-19 patients, co-culture with free, but mostly microencapsulated hUCMS, was associated with an higher percentage of live cells and lymphocytes • Percentage of the apoptotic peripheral blood mononuclear cell (PBMC) cells significantly raised upon co-culture with both, microencapsulated and hUCMS free cells, as compared to controls

Rebelatto et al. (2022) Randomized Controlled Trial 17 COVID-19 patients; 11 UC-MSC group, 6 placebo group Umbilical Cord • No significant difference in the reduction of viral load over time in both groups • Significantly lower D-dimer value in treatment group than controls (p=0.01) • Lower number of neutrophils in the treatment group than the controls in the

second month (p=0.03) and fourth month (p=0.01)

• Different IL-6 level in treatment group between baseline and the fourteenth day (p=0.02), second month (p=0.01) and fourth month (p=0.01)

• Higher IL-6 values in the treatment group than controls at baseline (p=0.01), day 2 (p=0.01) and day 4 (p=0.04)

• Significantly lower IL-6 in the treatment group and higher IL-6 level in the controls at the fourth month (p=0.01)

• Higher IL-8 values until the fourteenth day in the treatment group than the controls, a large reduction in values in both groups at the second and fourth months (treatment group, baseline vs 2 months, p=0.01; baseline vs 4 months, p=0.01; control group, baseline vs 2 months, p=0.01, baseline vs 4 months, p=0.01)

• No significant difference in chest CT abnormalities between groups

Table 1. Summary of the included studies (continue)

Study Design

MSC Source

Outcome

Saleh et al. (2021)

Pilot Study

5 severe COVID-19 patients treated with WJ- MSC

Wharton's • Increased percentage of lymphocytes, absolute lymphocyte count,

Jelly and CD4 and CD8 T cell ratio after cell therapy

• Increased SDF-1 and IL-10 levels after cell therapy

• Decreased VEGF, TGF-ß, IFN-y, IL-6, and TNFa levels after cell therapy

Sengupta Clinical Patients who met acceptance criteria were

et al. Trial enrolled into the following three study

(2020) cohorts: Cohort A, 1 COVID-19

outpatient with fever and dyspnea with objective vitals of respiratory rate (RR) >20 and/or SpO2 <94% on room air (RA); Cohort B, 20 in-patients with hypoxemia

as defined by SpO2 <90% on RA or patients who require supplemental oxygen

to maintain SpO2 >94%, who require noninvasive oxygen support; Cohort C, 3

intubated COVID-19 patients with hypoxic respiratory failure on mechanical ventilation

Bone • The survival rate in the study was 83%.

Marrow • Average PaO2/FiO2 ratio increase was 191% (p<0.001)

• Mean reductions of CRP, ferritin, and D-dimer were 77%, 43%, and 42% (><0.001; p<0.001; p<0.05), respectively

• Mean reduction of ANC was 32% (p < 0.001)

• Total lymphocyte count increased by 36% (p<0.05) with CD3+, CD4+, and CD8+ T lymphocytes increased by 46% (p<0.05), 45% (p<0.05), and 46% (p<0.001), respectively

Shi et al. (2021) Randomized Controlled Trial 100 severe COVID-19 patients; 65 UC-MSC group, 35 placebo group Umbilical Cord • Numerical improvement in whole lung lesion volume from baseline to the twenty-eighth day in the treatment group compared with the controls (p=0.080) • Significant reduction in the proportions of solid component lesion volume in the treatment group compared to the control group (p=0.043)

Shi et al. (2021) Cohort Study 100 severe COVID-19 patients; 65 UC-MSC group, 35 placebo group Umbilical Cord • Improvement in whole lung lesion volume in treatment group compared to control group (p=0.030) • Reduction in the proportions of solid component lesion volume compared to the controls (p=0.013)

Shu et al. (2020) Randomized Controlled Trial 41 COVID-19 patients; 12 patients in the hUC-MSC treatment group and 29 patients assigned to placebo group Umbilical Cord • Shorter median time to clinical improvement in the treatment group (9.0 days) vs. the control group (14.0 days), p=0.006 • Lower day 28 death rate in the treatment group (p=0.543) • Shorter hospital stay in the treatment group (p=0.054) • Significant decrease in CRP and IL-6 levels after the third day in treatment group compared to control group • Significantly better CT scores in treatment group compared to control group

Xu et al. (2021) Clinical Trial 44 COVID-19 patients; 26 included for experimental group, 18 included for control group Menstrual Blood • Lower death rate in experimental group (p=0.048) • Significant improvement in dyspnea while undergoing MSC infusion on the first (p=0.016), third (p=0.040), and fifth (p=0.031) day • No significant improvement in dyspnea while undergoing MSC infusion on the seventh (p=0.631), fourteenth (p=0.635), and thirtieth (p=1.000) day • No significant differences in CRP (p=0.486), IL-6 (p=0.375), FiO2 (p=0.174), and SaO2 (p=0.068) before and after MSC infusion • Significantly improved SpO2 (p<0.001) and PaO2 (p=0.015) after MSC infusion

Zhu et al. (2021) Randomized Controlled Trial 58 COVID-19 patients; 29 MSC group, 29 placebo group Umbilical Cord • Shorter hospital stay in MSC-treatment group (p=0.0198) • Less time required for symptoms remission (p=0.0194) • Significant decrease in CRP levels in MSC group on the third (p=0.044) and fifth (p=0.0035) day • Substantially lower levels of plasma pro-inflammatory cytokines at the twenty-eighth day in MSC group than in placebo group (p<0.05)

Zhu et al. (2022) Pilot Study 7 severe COVID-19 patients receive aerosol inhalation of haMSC-Exos Adipose Tissue • An increase in lymphocyte counts in all patients • A decrease in CRP (6 out of 7), IL-6 (5 out of 7), LDH (6 out of 7)

Different degrees of resolution of pulmonary lesions in all patients

Dilogo et al. 2021; Lanzoni et al. 2021; Shi et al. 2021; Zhu et al. 2021; Monsel et al. 2022; Rebelatto et al. 2022; Shi et al. 2022).

Three studies used Wharton's jelly as a source of MSCs (Montanucci et al. 2020; Adas et al. 2021; Saleh et al. 2022). Wharton's jelly is a gelatinous tissue in the umbilical cord that surrounds two arteries and veins and contains myofibroblast-like stromal cells (Kim et al. 2013; Alatyyat et al. 2020). Neonatal tissues, including the placenta, umbilical cord, amnion, and umbilical cord blood, are readily available, therefore, avoiding invasive procedures and ethical issues (Kim et al. 2013).

Studies by Fathi-Kazerooni et al. (2022) and Xu et al. (2021) used menstrual blood as a source of MSCs. Menstrual blood MSCs show pluripotency and easily accessible and developed (Meng et al. 2007). These cells are a good alternative to MSCs from other sources such as bone marrow, adipose, and postpartum tissue because

they have high proliferation rate and can be easily obtained, without the need for surgical procedures or hospitalization. These cells are also free from ethical dilemmas and exhibit novel properties when compared to stem cells derived from adult tissues (Khoury et al. 2014).

Research by Sengupta et al. (2020) used bone marrow as a source of MSCs. MSCs from bone marrow take a long time to collect and process, and are more expensive. Anesthesia and hospitalization are also required for the post-collection pain (Alatyyat et al. 2020). However, MSCs from bone marrow have better osteogenic and chondrogenic differentiation capacities compared to MSCs from adipose tissue, so it is necessary to consider the selection of MSC sources for specific clinical applications (Li et al. 2015).

One study used MSC secretome (Fathi-Kazerooni et al. 2022). MSCs maintain and repair damaged tissue, and secrete factors for tissue regeneration. These are

known as the secretome. Secretome exhibits immunomodulating, anti-inflammatory, pro-angiogenic, and anti-protease properties (de Witte et al. 2018). Compared to MSCs, secretome has advantages in terms of production, storage, management, shelf-life, and potential as a ready-to-use biological product (Vizoso et al. 2017).

A number of studies found that mortality was lower in patients treated with MSCs (Feng et al. 2020; Shu et al.2020; Adas et al. 2021; Hâberle et al. 2021; Xu et al.

2021). COVID-19 patients with ARDS and multi-organ dysfunction experience a higher risk of death (Que et al.

2022). Several studies show that this is associated with cytokine release syndrome (CRS), which is sometimes called the cytokine storm. A prior study reported that excessive amounts of pro-inflammatory cytokines were found in the deceased COVID-19 patients (Huang et al. 2019). Another previous study reported that IL-10, IFN-y. IL-10, and Monocyte Chemoattractant Protein (MCP)-1 levels were elevated in patients with COVID-19 when compared to healthy controls, while IP-10, MCP-1, MIP1a, and TNF-a levels were elevated in ICU patients compared to non-ICU patients, indicating that disproportionate cytokine production may be associated with severe COVID-19 (Bassetti et al. 2020). However, a systematic review and meta-analysis by Halim et al. (2022) reported that no definitive results could be drawn regarding the association of TNF-a with the severity and mortality of COVID-19.

CRS is one of the main contributing factors in COVID-19 mortality. Pro-inflammatory cytokines produced by immune cells in a positive feedback process cause CRS. Cytokine storms potentially cause organ damage, acute respiratory distress failure, acute heart injury, and secondary infection, which potentially lead to mortality. Therefore, avoiding cytokine storms and neutralizing the key inflammatory factors in CRS may play an important role in reducing mortality in severe cases (Atluri et al. 2020; Zhang et al. 2020).

MSC therapy has often been associated with inflammatory markers and immune function in COVID-19. Several studies have found that MSC therapy lowers IL-6 levels (Shu et al. 2020; Dilogo et al. 2021; Lanzoni et al. 2021; Saleh et al.2021; Rebelatto et al. 2022; Zhu et al. 2022). Cytokine storm plays a contributing role in severe COVID-19 cases. SARS-CoV-2 binds and enters alveolar epithelial cells. The innate and adaptive immune systems are activated by the virus and released numerous cytokines, including IL-6. IL-6 is one of the main mediators in acute inflammatory response and is considered to be the main marker of severe systemic inflammation in patients with SARS-CoV 2 (Zhang et al.2020; Bacca et al. 2021). A systematic review and meta-analysis by Halim et al. (2022) analyzed IL-6 as an independent prognostic factor in COVID-19 severity and mortality.

Systemic inflammation and hypoxic respiratory failure in COVID-19 are associated with an increase in pro-inflammatorymolecules including C-reactive protein (CRP), D-dimer, ferritin, and cytokines (Bacca et al. 2021). Some studies in this systematic review found that MSC therapy caused a decrease in blood CRP levels (Adas et al. 2021; Hâberle et al. 2021; Sengupta et al. 2020; Shu et al. 2020; Zhu et al. 2021; Zhu et al. 2022). Elevated serum CRP, a protein whose production is affected by IL-6, had been found to lead

to severe clinical manifestations in COVID-19 (Melo et al. 2021).

In the current pandemic, the inflammation due to COVID-19 infection may be the main mechanism for increased CRP, which activates the macrophage complement system and induces an unrestrained inflammatory response. CRP has been studied and found to play a role in acute and chronic inflammation, dysfunction of endothelial cell, formation of thrombus, and activation of coagulation cascade, and will eventually lead to organ failure (Noris et al. 2020; Luan et al.2021). The cytokine storm in severe COVID-19 is highly correlated with elevated CRP (Luan et al. 2021; Stringer et al. 2021).

Studies by Sengupta et al. (2020) and Rebelatto et al. (2022) found that MSC therapy led to a decrease in blood D-dimer levels. Elevated levels of D-dimer may play a role in COVID-19 deaths, but the mechanism is unknown (Li et al. 2021). Various studies have differing opinions, such as an increase in D-dimer levels is due to the development of COVID-19. One study proposed that SARS-CoV-2 infection is often accompanied by a hyperinflammation, which led to endothelial cell dysfunction and damage, which in turn caused increased D-dimer and excessive thrombin production (Levi and van der Poll 2017).

Xu et al. (2021) found a reduction in mortality after MSC therapy, but without a significant change in inflammatory factor levels. However, it is hard to draw a strong conclusion due to the limited size of the study. There may also be a difference in the consistency of service standards at the two different hospitals where this experiment was conducted.

Several studies have found an increase in lymphocytes in patients treated with MSC (Sengupta et al. 2020; Montanucci et al. 2021; Saleh et al. 2021; Zhu et al. 2022). Lymphopenia is found to lead to poorer prognosis in COVID-19 and younger patients (Huang and Pranata, 2020). COVID-19 patients generally exhibit lymphopenia, which is often associated with severe COVID-1 9 and had a poor outcome, and the deceased patients were reported to have significantly lower lymphocyte counts (Huang et al. 2020; Ruan et al. 2020; Yang et al. 2020). According to streaming mass cytometry results, viral infection causes total lymphocyte dysfunction, even the entire immune system. MSCs are involved in the repair of the lymphocyte population generally through dendritic cells (Leng et al. 2020).

MSCs exhibit good immunomodulatory abilities and are involved in both innate and adaptive immune system (Kavianpour et al. 2020). The interaction mechanism is associated with cell-to-cell contact and induces MSC-regulated immunomodulation (Kean et al. 2013). Immunosuppressive ligands such as Fas ligand (Fas-L) and programmed death-ligand 1 (PD- L1) bind to receptors on immune cells, leading to the loss of immune cell function (Strasser et al.2009; Ostrand-Rosenberg et al. 2014). At the molecular level, both MSC phenotypes can switch between pro- and anti-inflammatory regulation (Becerra and Duran 2021).

Indoleamine 2,3-dioxygenase (IDO) is a rate-limiting enzyme, which degrades tryptophan (Trp) to N-formylkynurenine (Nasef et al. 2007). Human MSCs, stimulated by IFNy, TNFa or IL-1, express IDO. This leads to immunosuppressive effect. IFNy triggers MSCs to express IDO in a Signal Transducer and Activator of

Transcription 1 (STATl)-dependent manner. T-cell suppression in vitro is known to be caused by STAT-1 overexpression, mediated by an increase in MSC (Mounayar et al. 2015). Silencing IDO in human MSCs will lead to immunostimulation, and increase PBMC proliferation at low and high cell density (Li et al. 2012).

In several studies, MSC therapy has been associated with improvements in lung imaging outcome (Fathi-Kazerooni et al.2022; Shi et al. 2021; Shi et al. 2022; Zhu et al. 2022). Studies have also shown improvement in lung function after MSC therapy (Feng et al. 2020; Feng et al. 2021; Monsel et al. 2022). In addition to having immunomodulatory properties to suppress injury due to immune reactions, MSCs can also suppress ARDS exacerbations, repair damaged tissue, and inhibit pulmonary fibrosis (Irmak and Karaoz 2021). MSCs enter the body through the intravenous route and are concentrated in the lungs. This leads to better lung microenvironment, alveolar cell protection, lung function and alsoprevent lung fibrosis (Sinclair et al. 2013).

Various anti-inflammatory mediators are released into the pulmonary microenvironment through various activating receptors. Toll-like receptors (TLRs) are receptors found in many immune cells which could bind to unmethylated CpF-DNA and viral RNA (TLR 9 and TLR3, respectively), leading to downwards cellular signaling pathways. Growth factors such as angiopoietin-1 (Ang-1) and keratinocyte growth factor (KGF) help repair the impaired alveolar-capillary barrier caused by the pathogenesis of ARDS (Levi and van der Poll 2020; Rajarshi et al. 2020; Chouw et al. 2022).

TSG-6, an amino acid glycoprotein 277 produced in response to pro-inflammatory factors by various cells, gives MSCs a notable anti-inflammatory property for repairing acute lung injury (Danchuk et al. 2011). Deposition of metabolites such as lactic acid due to relative hypoxic conditions and metabolism of immune cells at inflammatory locations forms anacidic environment, drawing TSG-6 to the injured site (Han et al. 2022).

However, several studies found that MSC therapy did not lead to significant improvements in pulmonary imaging outcomes (Feng et al. 2021; Karyana et al. 2022; Rebelatto et al. 2022). Administration of MSCs is done intravenously in general. MSCs will end up in the pulmonary microvasculature and many will disappear

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within 24 hours (Eggenhofer et al. 2011). A study in mice demonstrated that monocytes and neutrophils contribute to MSC clearance from the lung through phagocytosis. Then, these cells will migrate through the bloodstream to the other parts of the body, especially the liver. MSCs may lack the time to secrete adequate levels of immunomodulatory factors before they are lost, but the disintegration of MSCs may lead to the release of intracellular cytokines and growth factors (de Witte et al. 2018).

MSCs are resistant to viral infection. This is because viruses are unable to enter MSCs due to the presence of IFN-stimulated genes (ISG) that can prevent viruses from entering cells. MSCs also secrete IDO, which has antiviral properties (Rocha et al. 2021). However, studies by Lanzoni et al. (2021) and Rebelatto et al. (2022) found no significant difference in viral load between MSC-treated patients and controls.

The rationale of using MSCs to treat COVID-19 is their immunomodulatory effects, which are achieved through autocrine, paracrine, and endocrine pathways (Xu et al. 2022). As the viral variants evade the immune system through the mutations in the spike proteins, with MSCs targeting the regulatory dynamics in the hosts, this approach can be versatile in treating the manifestations caused by the new probable variants (Rubin 2021; Karaka§ et al. 2022).

Conclusion

MSCs possess immunomodulatory and anti-inflammatory effects that can suppress cytokine storm, the main cause of mortality in COVID-19, making it a promising treatment for COVID-19. Along with the regenerative properties, MSCs are also capable of improving the lung functions and imaging outcome in the patients. While further studies are needed, we believe MSCs therapy may serve in future clinical applications in treating COVID-19 regardless of variants.

Conflicts of Interests

The authors have no conflict of interests.

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Author Contributions

■ Mutiara Indah Sari, MD, Department of Biochemistry, Faculty of Medicine, Universitas Sumatera Utara; e-mail: mutiara@usu.ac.id; ORCID ID https://orcid.org/0000-0001-6510-2196. The author created the concept and the methodology of the study and participated in drafting the manuscript.

■ Imam Budi Putra, MD, PhD, Department of Dermatology & Venereology, Faculty of Medicine, Universitas Sumatera Utara; e-mail: imam_65@yahoo.com. The author drafted, revised, edited, and finalized the manuscript.

■ Dadik Wahyu Wijaya, MD, PhD, Department of Anesthesiology and Intensive Care, Faculty of Medicine, Universitas Sumatera Utara; e-mail: dadikwahyuwijaya@yahoo.com. The author analyzed the data, participated in revising the manuscript, and provided the final conclusions.