Effectiveness of RCTs Pooling Evidence on Mesenchymal Stem Cell (MSC) Therapeutic Applications During COVID-19 Epidemic: A Systematic Review

Introduction

The treatment (TX) of severe Coronavirus disease 2019 (COVID-19) is extremely difficult.¹ COVID-19, induced by SARS-CoV-2 infection,² causes significant lung damage ranging from moderate respiratory symptoms to SARS and death.^3–5 COVID-19 caused widespread fear and apprehension since it is extremely communicable.^6–8 The World Health Organization (WHO) has termed COVID-19 pneumonia a global pandemic and a public health emergency.⁹ Because of a lack of clear awareness in the initial days of the epidemic, the number of infected individuals rapidly rose, quickly spreading to more and more continents.^10,11

Globally, the number of infected victims is growing constantly.¹² COVID-19 has an incubation period that can differ from 0 to 14 days but is commonly around 3 and 7 days.¹³ Fever, headache, dry cough, and breathlessness are the most frequent symptoms.^14–16 A sore throat, diarrhea, nasal congestion, and rhinorrhea are other significant complaints among patients.^17,18 Expiratory Hypertension (HTN) and dyspnea are common in severe individuals one week following the commencement of the illness. According to a biopsy and autopsy investigation, individuals in the most severe instances might have Acute Respiratory Distress Syndrome (ARDS), severe acute lung damage (LD), septic shock, metabolic acidosis, and coagulopathy.⁵

The leading causes of mortality include severe pneumonia, ARDS, pulmonary edema, or multiple organ failure.⁴ ARDS is a severe lung injury characterized by an uncontrolled inflammatory process that creates significant alveolar destruction and capillary basement membrane leaking, leading to progressive respiratory distress. There is currently no effective TX for ARDS; however, a variety of TXs, including cell-based therapies, have been proposed.^19,20 Successful repair and regeneration of endothelium and alveolar cells²¹ and regulation of excessive inflammatory immune responses may be critical aspects of ARDS recovery in afflicted individuals. COVID-19 has the potential to cause expiratory dyspnea and ARDS. 13.8% of COVID-19 patients had severe cases, 6.1% had critical cases, and roughly 2.3% had fatal outcomes.^22,23

There are different vaccinations which were approved by the Food and Drug Administration (FDA) for avoiding COVID-19 infections, and a breakthrough in the therapeutic strategy is crucial for the TX of COVID-19, particularly in severely or critically ill patients who may develop ARDS and/or expiratory dyspnea.^24,25 Currently, a few medicines such as remdesivir and dexamethasone have demonstrated intriguing early outcomes in randomized, controlled, open-label clinical studies.^26,27

In addition to this, some specific medicines have been proven to be successful in the TX of COVID-19. Furthermore, SARS-CoV-2-induced secondary infections have been attributed to multiple organ dysfunction syndrome (MODS) in extremely or critically sick patients and this remains a significant concern globally.¹² Immune dysregulation in both the innate and adaptive immune systems (AIS) has been implicated in disease intensity, lung injury, and long-term functional disability.^28–31

There are presently some preemptive vaccinations or effective antiviral medicines available to address COVID-19, and COVID-19 patients are managed primarily with symptomatic and supportive therapy.³² As a result, there is an immediate need for safe and viable TX approaches to reduce inflammatory organ damage. Currently, immunotherapeutic methods in clinical studies include convalescent plasma treatment (CPT), monoclonal antibodies against interleukin-6 (IL-6), including cell therapies.^26,33,34

The FDA has established forward regulatory procedures to enable the development of COVID-19 vaccines that fulfills the FDA’s stringent scientific specifications. The different kinds of vaccinations were as follows:

Pfizer-BioNTech COVID-19 Vaccines: On August 23, 2021, the FDA revealed the first clearance of a COVID-19 vaccine. The vaccine has been known as the Pfizer-BioNTech COVID-19 Vaccine, and the approved vaccine is sold as Comirnaty (monovalent COVID-19 vaccine), for the protection of COVID-19 among individuals who are 12 years of age and older.³⁵

Moderna COVID-19 Vaccines: The FDA declared the second clearance of a COVID-19 vaccine on January 31, 2022. The vaccine, previously known as the Moderna COVID-19 Vaccine, will now be sold as Spikevax (monovalent COVID-19 vaccine) for the protection of COVID-19 in people aged 18 and older.³⁶

Janssen COVID-19 Vaccine: The Janssen COVID-19 Vaccine is obtainable under the EUA to prevent COVID-19 in individuals 18 years of age and older for whom other FDA-authorized or accepted COVID-19 vaccines are not available or clinically appropriate, as well as individuals 18 years of age and older who select to receive the Janssen COVID-19 Vaccine because they would not otherwise acquire a COVID-19 vaccine.³⁷

Novavax COVID-19 Vaccine, Adjuvanted: Novavax COVID-19 Adjuvanted Vaccine is offered under emergency use authorization (EUA) to avoid COVID-19 in people aged 12 and older. The SARS-CoV-2 spike protein and Matrix-M adjuvant are both included in the Novavax COVID-19 Vaccine, Adjuvanted. Adjuvants are added to some vaccines to improve the immune reaction of the immunized person.³⁸

In addition to this, remdesivir has shown clinical advantages such as reduced hospitalisation time, lower progression to artificial breathing, and lower utilisation of other hospital facilities; it is uncertain whether it lowers mortality, but one randomised controlled study indicated potential longevity benefits. According to the accessible information, remdesivir has been approved (or authorised for early use) in 48 different countries.³⁹ Other medications are hydroxychloroquine/chloroquine and azithromycin, favipiravir, interleukin (IL)-6 pathway inhibitor, lopinavir/ritonavir, histamine 2 receptor antagonist (H2RA), interferon (IFN) beta, convalescent plasma (CP), plasma adsorption and exchange.⁴⁰

Stem Cells (SC)

Cellular TXs have considerable potential for the TX of COVID-19.⁴¹ SC TXs are emerging as viable therapeutic techniques that can reduce inflammation and repair LD caused by COVID-19, either alone or in conjunction with existent therapy regimens.^22,42 The SC secretome has been determined to exhibit strong antifibrotic, anti-inflammatory assets, immunomodulatory (IMD), and angiogenic biological functions.^43,44

The secretome, which can be studied in conditioned medium, consists of growth factors, cytokines, and extracellular vesicles such as microvesicles and exosomes.⁴⁵ These components have a multitude of biological functions which can be targeted by a variety of procedures. The secretome is emerging as a potential alternative treatment due to the absence of conventional therapeutics.

These are multi-potent cells that are being applied extensively in regenerative medicine. MSC TX has a large body of preclinical evidence and early, preliminary clinical data indicating its ability to repair and restore the function of injured tissues and organs.⁴⁶ MSCs are being studied for their potential application in the TX of ARDS induced by SARS-CoV-2 infection.⁴⁷ MSCs are a therapeutic agent that is generally accessible, safe for the patient, and exempt from ethics issues due to their successful acquisition from a wide range of human body tissues, notably bone marrow (BM), adipose cells (AC), synovial surfaces of joints (SSJ), umbilical cord (UC), and placenta.⁴⁸

Mesenchymal Stem Cells (MSCs)

MSCs show extraordinary IMD features, as well as minimal immunogenicity, paracrine characteristics, and the potential to develop into diverse cell lines. These abilities make them attractive therapeutic possibilities for the TX of neurological, cardiovascular, and pulmonary ailments, which may be occupational problems.⁴⁹ Preclinical research utilizing experimental animal designs has shown that MSCs have therapeutic implications in illnesses such as silicosis and pulmonary disease. Currently, MSC TXs have the potential to improve the management of the new illness COVID-19.⁴⁹ MSCs are non-hematopoietic cells (n-HPC) with a strong proliferative capacity and multi-lineage differentiation abilities.^50,51

MSCs have been employed for almost 3 decades and have demonstrated tremendous advances.⁵² MSCs may help with COVID-19 consequences such as cytokine storm (CS), ARDS, and acute lung injury (ALI).⁵³ MSCs were observed to generate exosomes that had strong IMD ability for tissue restoration.⁵⁴ Intravenous (IV) injection is a common way of administering SC therapy.^55,56 MSCs and their generated extracellular vesicles (ECVs) have the potential to treat COVID-19 because of their capacity to modify the immune response, enhance pathogen clearance, and reduce the degree of organ damage.⁵⁷

Many clinical investigations have found that MSCs and their exosomes (MSCs-Exo) effectively alleviated lung inflammation caused by various forms of LD. So far, they have been employed successfully in multiple trials to treat a variety of illnesses, including Systemic Lupus Erythematosus (SLE), Amyotrophic Lateral Sclerosis (ALS), Graft-Versus-Host Disease (GVHD), and ARDS. In this context, several studies on the usage of these cells for COVID-19 clients have been officially registered, but only a portion of them have been finalized and released their findings.⁵⁸

By the International Society for Cell & Gene Therapy (ISCGT) guidelines for 2019, mesenchymal stem cells should be renamed as mesenchymal stromal cells (MSCs).^59,60 Due to the cells’ self-renewing ability, multi-potent possibility, low immunogenicity, anti-inflammatory efficacy, and ability to adhere to injured tissue, MSC-based cellular TX has been the focus of an increasing number of studies.^61,62 More significantly, MSCs have distinct IMD capabilities that affect both innate and adaptive immune responses (AIRs), making them a highly appealing cell TX tool.^62,63

MSCs primarily control AIRs by targeting T- and B-lymphocytes, antigen-presenting cells (APCs), dendritic cells (DCs), natural killer (NK) cells, and regulatory T-cells (Tregs).⁶² MSCs also have a role in innate immune responses, primarily by targeting DCs, NK cells, innate TH17 cells, neutrophils, monocytes, macrophages, and mast cells.⁶³ Furthermore, MSC-based TXs have demonstrated promising effects in several clinical investigations across a wide range of diseases.^64,65

Researchers have observed that after injecting MSCs, the human body activates the host’s innate immune cascade mechanism, such as complement and blood coagulation, which is described as the immediate blood-mediated inflammatory response (IBMIR).⁶⁶ IBMIR is crucial given the extremely procoagulant state of many critically and severely ill patients requiring MSC treatment.⁶⁷

MSCs can be derived from a variety of sources, such as BM, AT, UC, placenta, menstrual blood (MB), muscles, the dental pulp (DP), Wharton’s jelly (WJ), fetal liver, amniotic membranes, amniotic fluid, urine, and others.^65,68,69 Additionally, MSC-based therapy has shown favorable outcomes in investigations on inflammatory lung illness, limiting alveolar collapse, cell death, and collagen aggregation in lung tissues.⁷⁰ The angiotensin-converting enzyme-2 (ACE-2) has been recognized as a receptor for SARS-CoV-2 passage into target cells.^71,72 Similarly, studies have shown that MSCs do not express ACE-2 and that MSCs are resilient to SARS-CoV-2 invasion as well as when confronted with SARS-CoV-2 infected cells.^73,74

Wilson et al⁷⁵ also reported no pre-specified adverse effects after infusion of allogeneic MSCs into 9 patients with ARDS, including cardiac arrhythmia (CA), hypoxemia, and ventricular tachycardia (VT). Moreover, the study team revealed that MSC transplantation dramatically reduces mortality in patients with pandemic Influenza A (H7N9) induced ARDS.⁷⁶ MSCs may be beneficial in treating COVID-19, particularly in severe and critical patients.¹²

MSCs are n-HPC that have immunological modulatory, regeneration, and differentiation capabilities.⁶⁵ In animal models and clinical studies, MSC therapy decreased lung pathology and inhibited the cell-mediated immune inflammatory response caused by the influenza virus.^76–78 MSC has also been studied for its safety and possible effectiveness in ARDS patients.^75,79–81 MSCs’ IMD and regenerative characteristics provide a possible cellular TX strategy for lung injury in COVID-19 patients, but they must be validated in RCTs. Since the emergence of the COVID-19 pandemic, several SC TX clinical studies have been conducted, and the findings have shown that MSCs not only reduce LD and recovery time but also enhance patient survival with good tolerance in the early phase.^1,82,83

The earlier double-blind, randomized, placebo-controlled trial noted the short-term safety and efficacy of UC-MCS TX, from base point to day 28 after TX, and noticed that UC-MCS management greatly decreased the proportions of solid constituent lesion volume in the lungs and quantitatively increased the 6-minute walk test (6-MWD), especially in comparison to the placebo control.¹ MSCs’ potential advantages make them suitable for potential new therapy in ARDS patients.⁵⁰

MSCs are safe, ACE-2 negative, and capable of effectively suppressing the overactive immune system in COVID-19 individuals. Furthermore, IV injections of MSCs can rapidly transport a large number of them to the lungs, which are the primary damaged organs in ARDS.⁵⁸ Existing clinical trials suggested the potential effectiveness of MSCs-Exo in the treatment of COVID-19.⁵⁷ MSCs might be used as an alternative or supplemental therapy. To present, therapeutic trials utilizing MSCs in COVID-19 patients have raised hopes for the safe and beneficial use of this SC type. MSCs might be a viable therapeutic or supplemental agent for COVID-19 therapy.⁴⁹

They are widely used because of factors such as their low immunogenicity. MSCs are not identified by the human Immune System (IS) due to poor expression of Major Histocompatibility Complex (MHC) particles and an undetectable level of MHC-II.⁸⁴ Clinical investigations on COVID-19 patients with MSCs indicated their utility in the acute period of the disease.⁸⁵

Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs)

UC-MSCs may have IMD capabilities.^86,87 Regarding the COVID-19 outbreak, MSCs from various sources, particularly UC-MSCs, have been employed in clinical trials.^74,88,89 These UC-MSC features, which may be due to their more primitive origin as compared to adult tissue-derived MSCs,⁹⁰ may explain why cord-derived MSCs were the most often employed in a recent evaluation of registered studies investigating MSCs in COVID-19 patients.⁹¹ Another justification for employing UC-MSCs in the setting of SARS-CoV-2-induced severe ARDS is that they do not exhibit the ACE-2 receptor.⁷⁴

Previous study findings indicated that IV of human UC-MSCs was safe and well tolerated in patients with mild to severe COVID-19 in a phase-1 trial.⁸⁸ Another study published the findings of a randomized, double-blind, placebo-controlled trial conducted at 2 medical institutions in Wuhan, China, to assess the safety and effectiveness of IV therapy with UC-MSCs in severe COVID-19 patients with LD.¹ A study of 11 patients with COVID-19-associated ARDS found that IV (60x10⁷ cells) of human UC-MSCs or placental MSCs (PLMSCs) immediately reduced respiratory distress (RD) while also lowering the excessive inflammatory response.⁹²

Several randomized, double-blind, placebo-controlled studies found that UC-MSC (a total of 10–12 × 10⁷ cells) enhanced lung lesion repair in COVID-19 patients without posing any safety risks.^86,93 Anecdotal case reports, small-scale non-randomized or open-label studies, and only 2 recent, single-center, double-blind, Placebo-Controlled Trials (PCTs) have been published thus far in studies investigating UC-MSCs in COVID-19 patients. Overall, the results of those studies corroborated the great tolerance of IV MSC infusions and showed improved clinical outcomes (COs), even though they were small-scale non-randomized or open-label studies, with just 2 contemporary, single-center, double-blind, PCTs. Overall, the findings of those investigations supported the high tolerability of IV MSC infusions and suggested improved COs.⁸⁶

So far, the evidence suggests that allogeneic UC-MSC TX is safe for a wide range of diseases.⁹⁴ These cells can be generated from UC that have been discarded after birth and rapidly grown to clinically significant amounts. They display low amounts of human leukocyte antigen (HLA) class-I and class-II, which may diminish alloreactivity.⁹⁵

Menstrual Blood-MSCs (MB-Derived MSCs)

Considering SC-based TX is dose-dependent, and human clinical research normally necessitates millions of SC, a high proliferation rate is critical in therapeutic trials. MB-derived MSCs double in approximately 20 hours, while BM-derived MSCs double in around 40–45 hours. Thus, MSCs obtained from MB had a higher output in a shorter amount of time at early passages.^96,97 More significantly, MB-derived MSCs provide a painless solution that is devoid of the ethical problems that may come with BM-MSC contributions.⁹⁸ Thus, MSC-based therapy produced from MB may be a potential TX for COVID-19, especially in fighting the inflammatory CS shown in severe and critical patients.¹²

This is an exploratory trial to determine whether MB-derived MSCs may benefit COVID-19 patients who are severely and chronically unwell. To that effect, researchers evaluated the safety, therapeutic effectiveness, and tolerability of transplanted MSCs during a one-month follow-up following SARS-CoV-2 infection. The research specifically looked at any improvements in pulmonary function. The findings of the study not only shed light on MSCs’ potential to cure COVID-19 patients but also imply that MSCs are a promising method for treating acute or chronic pneumonia in future clinical applications.¹¹ MB-derived MSCs have lately gained a lot of interest due to their exceptional proliferation capacity and absence of ethical issues.¹²

MSC transplantation from MB considerably reduces the death rate of severe and critical SARS-CoV-2-induced patients with COVID-19.¹⁴ MSC-based therapy might be used as an alternate TX for COVID-19 in the future. MB-derived MSCs have been viewed in numerous pre-clinical and clinical studies, including the TX of pulmonary illnesses, in recent decades due to their unique features, such as high proliferation rate, low immunogenicity, and non-invasive periodical acquisition.^99,100

Bone Marrow MSCs (BM-Derived MSCs)

In children, allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a Human Leukocyte Antigen (HLA) identical family donor is the initial therapy.¹⁰¹ BM-MSCs have been found to promote lung repair following ventilator-induced LD, to aid in inflammation resolution, and to restore lung function and structure in ARDS patients.¹⁰²

Adipose Tissue-Derived MSCs (AT-Derived MSCs)

Sanchez-Guijo et al revealed the effects of IV injection of AT-derived MSCs in 13 severe COVID-19 pneumonia cases on mechanical ventilation (MV), and the patients were followed up on 16 days following the infusions.⁹³ The advantages of perinatal MSCs over adult MSCs include their ease of availability, lack of donor site morbidity, cell naivety, the quantity of SC in the main tissue, and a high potential for proliferation.¹⁰³

Given the global severity of COVID-19, one research study evaluated the safety of aerosol inhalation of exosomes derived from human AT-derived MSCs-Exo in the TX of patients with severe COVID-19-related pneumonia, intending to determine the optimal dosage and delivery route of MSCs-based therapy for acute respiratory diseases (ARD). Research utilizing a mouse model of occupational bronchial asthma found that TX of AT-derived MSCs dramatically lowers lung neutrophilic infiltrates and immunoglobulin-E (IgE) levels.¹⁰⁴ AT-derived SC, a common kind of MSCs, has been offered as a therapy option for COVID-19 to minimize morbidity and mortality. AT-derived MSC therapies have the potential to alleviate the strain on crucial hospital resources⁴¹ (Table 1).

Table 1 Search Databases and Strategies About the Stem Cell Applications Among the COVID-19 Population

Research Questions

1. What is the pooled effectiveness of MSC applications among the COVID-19 population?
2. What are the study characteristics of MSC applications among the COVID-19 population?

Methods

This systematic review (SR) included studies from all across the world. This study was registered in the PROSPERO (CRD42022380088).

Search Strategies

Scopus, Web of Science, PUBMED, EMBASE, Science Direct, Cochrane Library, and Google Scholar were utilized to search for relevant literature. During this time, papers published until December 31, 2022, were sought with key terms on COVID-19, SARS-CoV-2, Novel Coronavirus, nCoV, and Severe Acute Respiratory Syndrome, coronavirus-2, Coronavirus Disease-2019 Virus, 2019-nCoV, 2019 New Coronavirus, Coronavirus, Stem Cells, Stem Cell Management, Therapeutic Stem Cell Management, Stem Cell Applications, Mesenchymal Stem Cell Applications, Mesenchymal Stem Cell Management, Therapeutic Mesenchymal Stem Cell Applications”, and Boolean operators were employed.

Eligibility Criteria

Inclusion Criteria

Studies were included in the SR if they fulfil: Studies that reported outcome variables on SC management on COVID-19 patients, studies reported on RCTs, articles published in the English language, and articles published up to December 31, 2022, across all countries.

Exclusion Criteria

Articles that did not assess the outcome variables, articles that were not fully accessible, articles published in a non-English language, articles with non-RCTs, observational studies, case studies, editorials, perspectives, commentary, and poor quality studies were excluded from this SR.

Outcome Interest

In this SR, the primary outcome was the effectiveness of MSCs applications among COVID-19 patients. Effectiveness refers to studies that explained positive results on MSC applications among COVID-19 patient studies which were included in this SR.

The secondary outcome was study characteristics that reported on MSC applications among the COVID-19 population.

Data Extraction and Quality Assessment

The retrieved articles from all databases were exported to “Thomson Reuters EndNote version-8”. The titles and abstracts of all possible articles to be included in this SR were checked. The standardized data extraction format prepared in a Microsoft Excel worksheet was used to extract the data from the selected articles according to the present inclusion criteria. Author name, publication year, study period, study country, participants, sample size, study design, type of intervention, outcome measurement, study findings, and conclusion of the study were used for the extraction of data from each article.

This SR has included 14 RCTs. The CASP, a critical appraisal tool for SR that could be RCTs on MSC applications among COVID-19 patients was used to assess the included articles, and the CASP for RCTs was used to include the articles in this SR, whereas all articles fulfilling CASP criteria are considered high-quality RCTs and included in this SR and given as a Supplementary 1 File. The CASP methodological quality assessment checklist has been included for each article.

Data Processing and Analysis

This SR adopted a narrative synthesis of the RCTs pooling evidence on MSC therapeutic applications among COVID-19 patients during the epidemic. The data are prepared in the tabular column which includes

Author, Year, Country, Study Design, Study Duration, Setting of The Study, Population, Sample Size, Sampling Technique, Method of Randomization, Type of SC Applied, Type of Intervention, Duration of Intervention, Study Outcome Measurement, Study Characteristics, Results and Conclusion of the Studies.

Data Synthesis and Reporting

This SR was conducted on the effectiveness of pooling evidence on MSC’s therapeutic applications during the COVID-19 epidemic. During this, PRISMA 2020 flowchart diagram and PRISMA 2020 checklist were used for the study screening, selection, and inclusion into this SR. PRISMA 2020 checklist is given in (the Supplementary 2 Files).

Results

Search Results

All related studies done across the world were identified by using diverse databases. From the search made through the mentioned databases, 12,567 studies were found. From this, only 14 studies were meeting the predefined eligibility criteria and were included in this SR (Figure 1).¹⁰⁵

Figure 1 PRISMA flowchart diagram of the study selection for a systematic review on Mesenchymal stem cell therapeutic applications during the COVID-19 epidemic.

Study Characteristics

This SR focused on the studies conducted on MSC applications among COVID-19 patients. In this SR, a total of 14 studies were included, comprising studies done on MSC applications on COVID-19 patients.

Results

The study overall records (12,567) are extracted from various databases (Scopus, Web of Science, PUBMED, EMBASE, Science Direct, Cochrane Library, and Google Scholar), and 14 RCTs were included in this SR,^{1,58,83,86,88,93,106–113} whereas remaining records were excluded with various reasons and are explained in Figure 1 in detailed. The CASP checklist criteria were considered for inclusion of the studies and considered as high-quality studies (CASP check attached as Supplementary File 1).

Effectiveness of RCTs on MSC Applications Among COVID-19 Patients

In this systematic review, the included studies conducted on MSC therapeutic applications among COVID-19 patients with RCT clinical trials. The outcome of the each included study was clearly evidenced with positive outcome of the patient prognosis. The RCTs on MSC therapies among COVID-19 patients was progressing and showing promising results with no complication, and these study effective results may evidence early patient recovery with harmful ailments (Table 2).

Table 2 RCTs Pooled Evidence on Stem Cell Applications During the COVID-19 Epidemic

Demographic Characteristics

The studies were conducted by

Murdani Abdullah, Hamid Reza Aghayan, Najmeh Kafash Farkhad, Rodrigo Pinheiro Araldi, Muhammad Karyana, Antoine Monsel, Carmen Lucia Kuniyoshi Rebelatto, Ayca Sultan Sahin, G Adas, Smail Hadisoebroto Dilogo, Giacomo Lanzoni, Lei Shi, Lei Shi, Fanping Meng.^{1,58,83,86,88,93,106–113}

RCT published studies included in the year 2022 were 8; ^{58,86,106–111} in 2021 were 5; ^{1,83,93,112,113} in 2020 one study.⁸⁸ The RCTs published from different countries were Indonesia-3; ^106,109,112 Iran-2; ^58,107 Brazil −2; ^108,110 Turkey-2; ^83,111 China-2; ^1,113 Florida-1; ⁹³ UK-1.⁸⁸

The total pooled sample size was 574 (treatment group (318), control group (256)).^{1,58,83,86,88,93,106–113} The highest sample size was reported from China, ie, 100 (100 severe COVID-19 patients with lung damage with UC-MSCs (n = 65) or placebo (n = 35)).¹ The lowest sample size was recorded from Jakarta, Indonesia, ie, 9 patients with low clinical risk COVID-19 infection, and 9 subjects were enrolled and randomly assigned to 1 of the 3 groups: TL, TH, and C.¹⁰⁹

The reported highest age of the patient category was 69 years,¹⁰⁸ and the lowest age category was 18 years,¹⁰⁶ and the identified age (mean ± SD) is intubated/no comorbidity (48 ± 10.8781), intubated/with comorbidity (62.2857 ± 8.2606), no intubated (56.8571 ± 13.2718); UC-MSC group (n = 65) 60.72 (9.14), placebo group (n = 35) 59.94 (7.79).^111,113 The recorded BMI (body mass index), Kg/m2, of the patient is UC-MSC group (n = 65) 24.71 (3.19), placebo group (n = 35) 25.01 (3.12); UC-MSC (n = 12) 34.5 ± 4.5, control (n = 12) 29.6 ± 3.5; UC-MSC (n = 21) 28.6 (3.5), placebo (n = 24) 28 (5.5).^1,86,93

Different study measurements were recorded on comorbidities; ^{1,58,88,93,106,107,110,112,113} SOFA score; ⁸⁶ PaO₂/FiO₂ ratio; ^86,93 laboratory values; ^{1,88,106,107,109–111,113} mechanical ventilation; ^86,88 clinical symptoms; ^88,110 inflammatory markers; ^{83,106,111,112} body mass index; ^1,86,93,113 concomitant treatment; ^1,93,110,113 adverse events.^1,86,113

The type of MSCs applied in the studies was MSCs-secretome (1); ¹⁰⁶ MSCs (1); ¹¹¹ PL-MSCs; ¹⁰⁷ human immature dental pulp stromal cells (hIDP-SCs) (1);¹⁰⁸ DW-MSC infusion (1); ¹⁰⁹ WJ-MSCs (1); ⁸³ majority of the studied transfused UC-MSCs (8).^{1,58,86,88,93,110,112,113} The transfused interventional dosage was 1 × 10⁶ cells/kg (6); ^{58,83,86,93,107,112} 1 × 10⁷ cells/kg (4); ^1,88,108,109 1 × 10⁵ cells/kg (1);¹¹⁰ 1 million cells/kg (1).¹¹¹

The reported laboratory measurements are haemoglobin, haematocrit, white blood cells (WBC), platelets, erythrocyte, basophils, eosinophils, neutrophils, lymphocytes, monocytes, neutrophils lymphocytes ratio, ureum, creatinine, aspartate transaminase (AST), alanine transaminase (ALT), total bilirubin, direct bilirubin, indirect bilirubin, procalcitonin, C-reactive protein (CRP), albumin, glomerular filtration rate (GFR), D-dimer, sodium (Na+), potassium (K+), chloride, ferritin, troponin-I.^1,106,110

The recorded clinical symptoms are fever, fatigue, cough, shortness of breath (SOB), nausea or vomiting, diarrhea, loss of taste or smell, disorientation, and confusion.^88,110 The documented inflammatory markers are interleukin (IL)-6, IL-10, LIF, VEGF, and ferritin.^1,106,113 The findings on the Sepsis-related Organ-Failure Assessment score (SOFA) are UC-MSC (n = 21) 5.5 (2.7) and placebo (n = 24) 5.9 (2.7).⁸⁶ The used concomitant medications are antiviral drugs, immunomodulatory drugs, steroids treatment, antibiotics, corticosteroids, heparin (anticoagulant), only prophylactic dose heparin, therapeutic dose heparin, remdesivir, convalescent plasma, corticosteroids, tocilizumab, hydroxychloroquine, alteplase.^{1,86,88,93,110,113}

The observed comorbidities are obesity, diabetes mellitus (DM), heart disease, hypertension (HTN), atrial fibrillation, coronary artery disease (CAD), dyslipidemia, encephalitis, stroke, asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, tuberculosis (TB), stress ulcer, dyspepsia syndrome with alarm sign, kidney disease, sepsis, autoimmune diseases, adenomyosis, mild anemia, fatty liver disease, schizophrenia, cancer^{1,86,93,106,110,113} (Table 2 and Table 3).

Table 3 Demographic Factors of MSC Applications on COVID-19 Patients

Discussion

COVID-19, caused by SARS-CoV-2, was first identified in December 2019 as the source of a cluster of respiratory infections.^4,114 There is currently no viable TX for COVID-19.¹⁴ MSC-based therapy might be a potential alternative TX for severe and serious COVID-19.¹² The number of ventilator-free and organ-failure-free days in patients with ARDS was statistically lower in the MSC group than in the placebo group.^75,79 MSCs have been studied in various clinical trials; however, they face hurdles such as carcinogenic risk and particular storage conditions, as well as limited evidence regarding their mode of action. The core of MSCs’ distinctive features is attributable to their paracrine activity, notably their exosomes.⁵³

The aim of the study was “to identify the effectiveness of RCTs pooling evidence on MSC therapeutic applications during the COVID-19 epidemic”. The articles were extracted around 12,567 from the different databases from 1st December 2022 to 31st December 2022. As per the PRISMA checklist, the articles were screened, and find 14 relevant RCTs which reported on MSC applications among COVID-19 patients during the pandemic. The articles were evaluated by the CASP quality assessment tool. The included articles were published between the years 2019–2022.

The included 14 RCTs, the highest 8 studies were conducted in the year 2022 and one study was conducted in the year 2020, and 5 studies were published in the year 2021 with a pooled sample size of n = 574 (treatment group (n = 318) + control group (n = 256) in different countries). The majority of 3 studies were recorded from Indonesia, 2 studies from Iran, 2 studies from Brazil, 2 studies from Turkey, 2 studies from China, 1 study from Florida, 1 study from the UK, and 1 study from France.

The application of MSCs by the different studies among 14 RCTs was that the majority 8 studies experimented on UC-MSCs among COVID-19 patients and MSC secretome, MSCs, PL-MSCs, hIDPSC, DW-MSC infusion, and WJ-MSCs were experimented by another study. The highest studies’ interventional dosage of 1 × 10⁶ cells/kg was used by 6 studies, 1 × 10⁷ cells/kg was used by 4 studies, 1 × 10⁵ cells/kg was used by one study, and 1 million cells/kg was applied by one study. The studies focused on DV, CS, LT, comorbidities, RM, CT, SOFA score, MV, BMI, AEs, IMs, and PaO₂/FiO₂ ratio were all recorded as study characteristics. There is a promising result on pooled evidence of RCTs on MSC applications among COVID-19 patients and may be used in the management of severe infectious disease.

Limitations of the Study

The studies included in this SR were RCT studies published on MSC applications among COVID-19 patients, studies limited to the English language, from the year 2019–2022, and full-text articles.

Conclusion

COVID-19, caused by SARS-CoV-2, was discovered in December 2019 and has since expanded globally. ARDS is a catastrophic consequence of the new COVID-19 pandemic, and it is directly connected to high levels of inflammatory cytokines. MSCs offer a viable therapy against this illness due to their IDM properties. Clinical evidence presented on MSC’s therapeutic applications during the COVID-19 pandemic has proven to be a promising therapy for COVID-19 patient recovery with no side consequences, and it may be applied as a routine TX for the prevention of challenging disorders. The study results were explained the good progress of the patient condition during the COVID-19 pandemic times with MSC application with RCT trials. These methods are dramatically brought the progressed effective results among patients with COVID-19.