Table 1 Clinical trials of MSCs and MSC-sEVs against COVID-19
From: Mesenchymal stem cells and their derived small extracellular vesicles for COVID-19 treatment
Study Phase and Type | Severity of COVID-19 | Number Enrolled | MSC/MSC-sEV source | Dosage | Frequency | Assessment of the efficacy | Adverse Primary Safety Outcome | Refs. |
|---|---|---|---|---|---|---|---|---|
A case report | Critical | 1 | UC-MSCs | 1 × 106 cells/kg | Days 0 and 3 | Inflammation-related indicators significantly improved; the cytokine storm was dampened and the NK cells were modulated | No infusion or allergic reactions, secondary infections, or treatment-related adverse events were found | [21] |
A case report | Severe | 1 | WJ-MSCs | 1 × 106 cells/kg | Single dose | The pulmonary function and symptoms were significantly improved | No acute infusion-related or allergic reactions were observed | [22] |
A case report | Critical | 1 | UC-MSCs | 1 × 106 cells/kg | Single dose | Inflammatory reaction was improved, and lung function and multiple organ functions were improved | No obvious side effects were observed | [23] |
A small sample, single arm, pilot trial | Severe 9; critical 7 | 16 | UC-MSCs | 1 × 108 cells | Single dose | The oxygenation index was improved, mortality relatively lowered; radiological presentations improved, lymphocyte count recovered and cytokine levels decreased | No infusion-related or allergic reaction | [24] |
A Phase 1 parallel non-randomized assigned, controlled, trial | Moderate 9; severe 9 | 18 | UC-MSCs | 3 × 107 cells | Days 0, 3, and 6 | The levels of cytokine reduced; symptoms improved | No serious UC-MSC infusion-associated adverse events were observed | [25] |
A Phase 2 randomized, double-blind, placebo-controlled trial | Severe | 101 | UC-MSCs | 4 × 107 cells | Days 0, 3, and 6 | Accelerated resolution of lung solid component lesions and the integrated reserve capability improved | No MSC infusion-related adverse events | [26] |
A prospective cohort follow-up study | Severe | 28 | UC-MSCs | 2 × 106 cells/kg | Single dose | Accelerated partial pulmonary function recovery and improved HRQL | No obvious adverse effects were observed in the UC-MSC group after 3 months | [27] |
A Phase 1/2 trial | Severe 111; critical 99 | 210 | UC-MSCs | 1–2 × 106 cells/kg | Single dose | The SaO2 parameter tended to improve; significantly higher survival was observed in patients who underwent UC-MSCs | No adverse effects were observed related to infusion or allergic reactions, secondary infection, or life-threatening adverse events | [28] |
A Phase 1 double-blind, multi-center, randomized controlled trial | Critical | 40 | UC-MSCs | 1 × 106 cells/kg | Single dose | The survival rate increased; there was no significant difference regarding the period of intubation and the period from intubation | MSCs were well tolerated with no life-threatening complications or acute allergic reactions during the administration | [29] |
A Phase 1/2a double-blind randomized controlled trial | Mild-to-moderate 6; moderate-to-severe 18 | 24 | UC-MSCs | 100 ± 20 × 106 cells | Days 0 and 3 | The levels of key inflammatory molecules were reduced; time to recovery was significantly shorted | No serious adverse events related to MSC infusion were observed | [30] |
Phase 1 | Severe | 5 | WJ-MSCs | 150 × 106cells | Days 0, 3, and 6 | Inflammation was reduced; COVID-19 antibody tests rose the total score of zonal involvement in both lungs was improved | No serious complications were observed except the headache in one of them | [31] |
A case series | Critical | 11 | PL-MSCs, UC-MSCs | 200 × 106 cells | Days 0, 2, and 4 | Respiratory symptoms improved and inflammatory conditions reduced | No serious adverse events were reported 24–48 h after the cell infusions | [32] |
A non-randomized assigned, controlled trial | Severe | 23 | BMMSCs | 1 × 106 cells/kg | 2–3 times | Pulmonary function and overall outcome improved | No significant side effects after MSC infusion | [33] |
2 case reports | Severe | 2 | MenSCs | 1 × 106 cells/kg | Days 0, 1, and 3 | Lung function improved | Not find obvious adverse reactions | [34] |
A Phase 1 multi-center, open-label, non-randomized, parallel, controlled trial | Severe 26; critical 18 | 44 | MenSCs | 9 × 107 cells | Days 0, 2, and 4 | The mortality significantly lowered; alleviating the breathing difficulties and reducing the symptoms of ARDS or expiratory dyspnea | The incidence of most adverse events did not differ between the groups, experimental group, and control group | [35] |
A case | Severe | 1 | UC-MSCs | 1.1 × 106 cells/kg | Days 0, 2, and 8 | Inflammatory, respiratory, thrombotic, and renal parameters improved | No adverse events occurred | [41] |
A prospective double phase 1/2 controlled trial | Moderate 10; critical 20 | 30 | WJ-MSCs | 3 × 106 cells/kg | Days 0, 3, and 6 | All the indicators of anti-inflammation, antifibrosis signs in the lungs, and immune-modulatory markers improved | No adverse or serious adverse events occurred related to the MSC therapy | [42] |
A case series | Severe 23; critical 8 | 31 | UC-MSCs | 1 × 106 cells/kg | 1–3 times | SARS-CoV-2 PCR results of 30 patients (96·8%) became negative after a mean time of 10·7 days; laboratory parameters, hypoxia, immune reconstitution, and cytokine storms improved | No adverse events were attributable to intravenous transplantation of UC-MSCs | [43] |
A Phase 1/2a randomized controlled trial | Severe | 24 | UC-MSCs |  | 1–3 times | Survival, serious adverse events-free survival, and time to recovery significantly improved | Serious adverse events-free | [44] |
A Phase 1, single-arm, non-randomized, parallel trial | Healthy | 24 | ADMSC-sEVs | 2–16 × 108 particles | Once inhalation | Improved survival rate to 80% at 96 h in P. aeruginosa-induced murine lung injury model by decreasing lung inflammation and histological severity | No serious adverse events were observed within 7 days | [78] |
A prospective nonblinded non-randomized trial | Mild 1; severe 20; critical 3 | 24 | BMMSC-sEVs | 15 mL | Single dose | Patients’ clinical status and oxygenation improved, laboratory values revealed significant improvements in absolute neutrophil count, and acute phase reactants declined | No adverse events were observed within 72 h of ExoFlo administration | [79] |