Since 2020, the relentless grip of the coronavirus disease 2019 (COVID-19) has profoundly shaped people’s lives worldwide, causing extensive global devastation ^[1][2][1,2]. As of 13 September 2023, 770,563,467 cases of COVID-19 have been confirmed and countless lives lost ^[3][4][3,4]. The COVID-19 virus (SARS-CoV-2) primarily spreads through large respiratory droplets, airborne particles, and fecal–oral and surface contact ^[5][6][5,6]. These modes of transmission significantly contribute to the rapid and difficult-to-control spread of the virus, despite the implementation of various government response policies in many countries. Consequently, the global community has actively dedicated itself to identifying effective methods for preventing and treating the disease. COVID-19 vaccines have been developed to prevent the spread of the disease and end the pandemic [7]. Significant progress has also been made in developing antiviral drugs, which have proven instrumental in treating the disease ^[8][9][8,9]. However, their effectiveness against COVID-19 has declined with the emergence of new virus variants [10]. COVID-19 can be categorized into mild, moderate, severe, and critical [11]. In mild and moderate COVID-19 cases, supportive care, oxygen therapy, and antiviral treatment are important for treatment ^[12][13][12,13]. However, in patients with severe and critical COVID-19, hyperinflammation and a cytokine storm resulting from a dysregulated host innate immune response often occurs ^[14][15][14,15], leading to the potential development of acute respiratory distress syndrome, septic shock, multiple organ damage, and even death ^{[16][17][18][19][20]}[16,17,18,19,20]. In addition to the traditional supportive care for viral diseases, various strategies have been proposed to address the dysregulated immune response and mitigate the inflammatory cascade of COVID-19.

Immunotherapy-related agents, such as glucocorticoids and anti-interleukin-6 (IL-6) receptor antibodies, have effectively modulated the immune response and reduced excessive inflammation in these patients [21]. These treatments have demonstrated promising results in reducing mortality among individuals affected by the disease ^{[22][23][24][25]}[22,23,24,25]. However, it is important to consider the potential risk of secondary infections associated with these therapies ^[26][27][26,27].

Unlike immunosuppressants, mesenchymal stem cells (MSCs) possess a unique combination of properties, including the ability to reduce inflammation, immunomodulation, and regenerative capabilities [28]. COVID-19 primarily affects the respiratory tract and can potentially lead to the development of acute respiratory distress syndrome (ARDS), cardiac injury, acute kidney injury, and multi-organ failure, often triggered by a cytokine storm ^[29][30][29,30]. MSC-based therapy has been proposed as a promising option for managing COVID-19 due to its ability to significantly suppress cytokine storms, leading to improved clinical symptoms and higher survival rates [31].

2. MSCs in COVID-19 Treatment

2.1. Source and Immunomodulation of MSCs

MSCs, a type of versatile stem cells, can be sourced from various tissues of both adult and neonatal origin. These tissues include the bone marrow (BM), adipose tissue (AT), and peripheral blood ^[32][91] from adults, as well as neonatal birth-associated tissues, such as the umbilical cord (UC), cord blood (CB), and placenta (PL) ^[33][141]. Derived from the ethereal realm of fetal tissues, particularly the umbilical cord, MSCs have emerged as a true spectacle and have the advantage of rapid proliferation and enhanced immunomodulatory properties. This sets them apart from other sources, sidestepping any inconveniences that might arise while procuring MSCs from the bone marrow or adipose tissue ^[34][142]. MSCs possess differentiative and regenerative attributes and can secrete factors, such as hepatocyte growth factor, vascular endothelial growth factor, and keratinocyte growth factor. These molecules play crucial roles in regenerating type II alveolar epithelial cells ^[35][143]. Moreover, MSCs can be drawn to sites of inflammation through diverse chemokines and can regulate the activities of various immune cells, including NK cells, dendritic cells, B cells, T cells, neutrophils, and macrophages. This modulation occurs via direct and paracrine mechanisms. The major effectors of this process include indoleamine 2,3-dioxygenase, transforming growth factor β, human leukocyte antigen isoforms, and prostaglandin E2 ^[36][144]. Thus, MSCs possess immunomodulatory properties, can reduce immunity, and may offer a therapeutic option for patients with severe or critical COVID-19 to suppress overactivated inflammatory responses.

2.2. Effectiveness of MSC Treatment in Other Diseases

MSCs have demonstrated significant clinical efficacy in the treatment of various immune disorders. In animal studies, human umbilical cord-derived MSCs have shown promising results in alleviating cytokine storms and reducing lung damage in mice with LPS-induced acute lung injury (ALI) ^[37][145]. Furthermore, a review highlighted the positive impact of MSC therapy on survival rates, hematopoietic reconstitution, and the recovery of peripheral blood cells in animal models of aplastic anemia ^[38][146]. In clinical practice, MSCs have been successfully used to treat numerous immune disorders ^[39][147], including inflammatory bowel disease ^[40][41][42][148,149,150], systemic lupus erythematosus ^[43][44][45][151,152,153], graft-versus-host disease ^[46][47][154,155], or multiple sclerosis ^[48][49][50][156,157,158]. MSCs exert significant effects on tumor growth and treatment response, making them promising candidates for cancer treatment, either alone or in combination with other therapies ^[51][52][159,160]. MSCs have the potential to effectively treat severe COVID-19 and its complications.

2.3. Current Outcomes of Clinical Trials of MSCs in COVID-19 Treatment

2.3.1. Effectiveness of MSC Treatment in Clinical Symptoms

MSC therapy has shown promising outcomes in reducing clinical symptoms in patients with severe COVID-19. As stated by Shu et al. ^[53][163], individuals who underwent treatment with umbilical cord mesenchymal stem cells (UC-MSC) experienced enhancements in clinical symptoms, such as weakness, fatigue, shortness of breath, and improved oxygenation index as early as the third day of treatment. Prenatal MSCs derived from umbilical cord (UC-MSC) or placental (PL-MSC) tissues can be utilized to treat critically ill patients with COVID-19-induced ARDS, resulting in reduced dyspnea and increased SpO2 within 2–4 days after the initial infusion in 64% of patients ^[54][164]. A multicenter randomized, double-blind trial unveiled a significant increase in PaO2/FiO2 ratios in the UC-MSC group compared to the placebo group in COVID-19-associated ARDS ^[55][165]. In a clinical trial using human menstrual blood-derived mesenchymal stromal cells for the treatment of severe and critically ill COVID-19 patients, significant improvement in dyspnea after MSC infusion on days 1, 3, and 5 and significant improvements in SpO2 and PaO2 following MSC infusion were noted. Additionally, patients in the MSC group showed significantly lower mortality (7.69% in the experimental group vs. 33.33% in the control group; p = 0.048) ^[56][166]. Farkhad et al. demonstrated that mesenchymal stromal cell therapy could improve the SPO2/FIO2 ratio in COVID-19-induced ARDS patients ^[57][167]. Sadeghi et al. showed that in COVID-19-induced ARDS cases treated with placenta-derived decidual stromal cells, there was a noticeable improvement in oxygenation levels, with a median increase from 80.5% (range, 69–88) to 95% (range, 78–99) (p = 0.012) ^[58][168]. Lanzoni et al. ^[59][169] reported improved patient survival and a shorter time to recovery after administering two rounds of intravenous allogeneic UC-MSC to patients with ARDS. In a phase I/II study involving patients with severe COVID-19, survival rates were notably higher in the MSC group at both 28 and 60 days after BM-MSC treatment (both p values < 0.05) ^[60][170]. In Indonesia, a randomized controlled trial demonstrated a survival rate 2.5 times higher in the UC-MSC group than in the control group in critical COVID-19 cases ^[61][171]. Fathi-Kazerooni et al. demonstrated that the survival rate in severe COVID-19 patients treated with human Mesenchymal Stromal Cells was significantly higher than that of patients who received placebo treatment (p < 0.001) ^[62][172]. Following a 2-year monitoring period for severe COVID-19 patients subjected to UC-MSC treatment, a slightly smaller subset of individuals within the MSC-treated group exhibited a 6 min walking distance (6-MWD) falling below the lower boundary of the normal range in comparison to the placebo-administered group (OR = 0.19, 95% CI: 0.04–0.80, Fisher’s exact test, p = 0.015). Furthermore, at month 18, the MSC-treated group demonstrated a higher general health score on the Short Form 36 questionnaire than the placebo group (MSC group: 50.00, placebo group: 35.00) (95% CI: 0.00–20.00, Wilcoxon rank sum test, p = 0.018) ^[63][173].

2.3.2. Effectiveness of MSC Treatment in Biomarkers Related to Cytokine Storm

Many inflammatory biomarkers and cytokines are closely associated with severe and critical COVID-19. Notably, significant improvements in the levels of these biomarkers were observed after MSC treatment. Shu et al. ^[53][163] reported that CRP and IL-6 levels significantly decreased starting from day three, and the time required for lymphocyte counts to return to the normal range was notably shorter in patients with severe COVID-19 following UC-MSC infusion. In a study by Lanzoni et al. ^[59][169], significantly lower concentrations of GM-CSF, IFN-r, IL-5, IL-6, IL-7, TNF-a, and TNF-b were observed in COVID-19-related acute respiratory distress syndrome. Meng et al. ^[64][174] showed an improvement in the percentage of inspired oxygen (PaO2/FiO2) ratio and a declining trend in levels of inflammatory cytokines, including high levels of IL-6, IFN-γ, TNF-α, MCP-1, interferon-inducible cytokine IP-10 (IP-10), IL-22, interleukin 1 receptor type 1 (IL-1RA), IL-18, IL-8, and macrophage inflammatory protein 1-alpha (MIP-1), after three rounds of UC-MSC treatment. Fathi-Kazerooni et al. conducted a study that showed that in severe COVID-19 patients treated with human mesenchymal stromal cells, the levels of CRP on day five were notably lower than those in patients who underwent placebo treatment (p < 0.03). Additionally, within the treatment group of critical COVID-19 patients, significant reductions in CRP, LDH, D-dimer, and ferritin levels were observed after MSC treatment (all p < 0.05) ^[62][172]. Sadeghi et al. demonstrated that in cases of COVID-19-induced ARDS treated with placenta-derived decidua stromal cells, there were significant reductions in levels of IL-6, with a median decrease from 69.3 (range 35.0–253.4) to 11 (range 4.0–38.3) pg/mL, and CRP, with a median decrease from 69 (range 5–169) to 6 (range 2–31) mg/mL (p = 0.028) ^[58][168]. After aerosol inhalation of exosomes derived from human adipose-derived MSCs (haMSC-Exos) in COVID-19 patients, a pilot study reported an increase in lymphocyte counts and a decrease in CRP, LDH, and IL-6 levels ^[65][175]. In a case series study, considerable reductions in the serum levels of TNF-α, IL-8, and CRP were evident in all six critically ill COVID-19-induced ARDS survivors ^[54][164]. In a randomized clinical trial involving critically ill COVID-19 patients who underwent mesenchymal stromal cell infusion, the UC-MSC group exhibited reduced ferritin, IL-6, and MCP1-CCL2 levels on the fourteenth day. In the second month, decreases in reactive C-protein, D-dimer, and neutrophil levels were observed, along with increases in the numbers of TCD3, TCD4, and NK lymphocytes ^[66][176]. In a phase I/II clinical trial, patients with severe COVID-19 treated with BM-MSCs exhibited significantly lower D-dimer levels on day seven than control patients ^[60][170]. An Indonesian randomized controlled trial revealed that the infusion of UC-MSC led to a significant decrease in IL-6 levels in recovered COVID-19 patients with ARDS (p = 0.023) ^[61][171]. A randomized controlled trial showed that MSC infusion was associated with a decrease in inflammatory cytokines, such as IL-6 (p = 0.015), TNF-α (p = 0.034), IFN-γ (p = 0.024), and CRP (p = 0.041) in ARDS COVID-19 patient ^[67][177]. A prospective double-controlled trial revealed that after adding MSCs transplantation therapy to treat critical COVID-19 patients in the ICU, serum ferritin, fibrinogen, and CRP levels significantly decreased compared to conventional therapy alone ^[68][178]. In a successful phase 1 clinical trial with a control-placebo group, a noteworthy reduction (p < 0.05) was noted in biomarkers such as CRP, IL-6, IFN-γ, TNF-α, and IL-17A in COVID-19-induced ARDS patients. Conversely, there was a significant increase in the serum levels of TGF-B, IL-1B, and IL-10 ^[57][167]. In a phase 1 clinical trial, a generalized estimating equation analysis showed a significant decrease in ferritin levels (p = 0.008) after MSC treatment in COVID-19 patients ^[69][179].

2.3.3. Effectiveness of MSC Treatment in Lung Image

Among COVID-19 patients, the most frequently observed computed tomography (CT) findings include ground-glass opacification, infiltration, consolidation, pneumonia, and emphysematous changes ^[70][185]. After MSC treatment in COVID-19 patients, many clinical trials have shown improved lung change. Shu et al. ^[53][163] reported shorter lung inflammation absorption on CT imaging in patients with severe COVID-19 in the UC-MSC group than in the control group. In a clinical trial involving a case series, lung CT revealed remarkable indications for recovery, including a reduction in ground-glass opacities or consolidations, among patients with COVID-19-induced ARDS ^[54][164]. Chest CT images showed complete fading of lung lesions within 2 weeks in moderate COVID-19 patients after UC-MSCs transfusion in the study by Meng et al. ^[64][174]. In a randomized, double-blind, placebo-controlled phase 2 trial, UC-MSCs led to a significant reduction in the proportions of solid component lesion volume compared to the placebo group in patients with COVID-19-induced ARDS (p = 0.043) ^[71][180]. A decrease in the extent of lung damage was observed in the fourth month after three rounds mesenchymal stromal cell infusion in critical COVID-19 patients in a randomized clinical trial ^[66][176]. Different degrees of resolution of pulmonary lesions after aerosol inhalation of haMSC-Exos were observed in patients with COVID-19 in a pilot study ^[65][175]. Xu et al. demonstrated a noteworthy distinction between experimental and control groups concerning the improvement rate of chest CT findings during the initial month following MSC infusion in individuals with severe and critical COVID-19 ^[56][166]. Fathi-Kazerooni et al. showed that in severe COVID-19 patients treated with human mesenchymal stromal cells, the percentage of pulmonary involvement exhibited a significant improvement in the group receiving secretome treatment (p < 0.0001) ^[62][172]. Sadeghi et al. demonstrated that all pulmonary infiltrates disappeared in patients with COVID-19-induced ARDS treated with placenta-derived decidual stromal cells ^[58][168].

3. Conclusions

MSCs demonstrated significant therapeutic potential owing to their ability to attenuate inflammation, modulate immune responses, and facilitate tissue regeneration. MSCs have the potential to effectively treat severe COVID-19 and its complications. Clinical trials have generated evidence showcasing the effectiveness of MSCs in addressing various facets of severe COVID-19 and COVID-19-related ARDS. These trials have yielded positive outcomes by improving clinical symptoms, enhancing survival rates, optimizing oxygen saturation levels, influencing cytokine storm-related biomarkers, and positively affecting lung imaging results. In the future, there may be a need to delve deeper into several areas. Investigating optimal administration routes, determining appropriate cell dosages, defining treatment intervals for MSC therapy, understanding the impact of severe extrapulmonary damage treatment, and exploring the potential applications of MSCs in pediatric cases are important aspects that warrant further investigation. These research directions hold promise for refining our understanding and utilization of MSCs as a therapeutic approach against the multifaceted challenges posed by COVID-19.