Table 2.
Results of published clinical studies based of UC-MSCs and WJ-MSCs (or derived exosomes) therapy administered to COVID-19 patients.
| Type of Study | Phase | Number of Patients | COVID Symptoms | Treatment | Outcomes | Ref. |
|---|---|---|---|---|---|---|
| Pilot trial | Early 1 | 7 | Mild 5 Severe 2 |
Nebulization ranged from 7.66 × 100.8 to 7.00 × 100.7 WJ-MSCs-derived exosomes/mL, twice a day, up to discharge. | Reduction of pulmonary lesions and period of hospitalization in mild cases and reduction in cellular residue in severe cases. No adverse events were observed. | Chu et al., 2022 [228] |
| Parallel assigned controlled, nonrandomized trial | 1 | 18 | Moderate 10 Severe 8 |
Moderate = 5; Severe = 4; Infusion of 3 × 107 UC-MSCs for 3 times on days 0, 3, and 6. |
Reduced trend in plasma levels of inflammatory cytokines IFN-γ, TNF-α, MCP-1, IP-10, IL-1RA, IL-6, IL-8, IL-18, IL-22 and MIP-1. No serious adverse events were observed. | Meng et al., 2020 [229] |
| Double-blind, multicenter, randomized controlled trial | 1 | 40 | Critical | N = 20 patients; Infusion of 1 × 106 UC-MSCs/kg in single dose. | Increased survival rate. Decrease trend in IL-6 levels and increase trend in IL-10, LIF and VEGF levels in plasma. No adverse events were observed. | Dilogo et al., 2021 [230] |
| Single-center open-label, individually randomized, standard treatment-controlled trial | 1 | 41 | Severe | N = 12 patients; Infusion of 2 × 106 UC-MSCs/kg in single dose. |
No progression from severe to critical illness. Reduction of weakness, fatigue, shortness of breath, and low oxygen saturation. Significant decreased in CRP and IL-6 plasma levels. Faster normalization in lymphocyte count and reduction of lung inflammation. No adverse events were observed. A 3-month follow-up of 28 patients (treated = 8, control = 20) revealed reduction of partial pulmonary function recovery time, ameliorated HRQL, and no adverse events were observed after 3 months. | Shu et al., 2020 [231] and Feng et al., 2021 [232] |
| Open-label, single-center trial | 1 | 5 | Severe | Injection of 150 × 106 WJ-MSCs for 3 times on days 0, 3, and 6. | Increase in IL-10 and SDF-1 and decrease of VEGF, TGF-β, IFN-γ, IL-6, and TNF-α plasma levels. Improvement in hematology, myocardial enzyme, inflammation, and biochemical tests. No adverse events were observed. | Saleh et al., 2021 [233] |
| Single-center, open-label, placebo-controlled trial | 1 | 20 | Mild-to-moderate | N = 10 patients; Infusion of 1 × 106 UC-MSCs/kg for 3 times on days 1, 3 and 5. |
Significant improvement in SpO2/FiO2 ratio. Significant reduction in cytokine IL-6, IFN-γ, TNF-α, IL-17 A, and CRP levels and increase in cytokine levels of TGF-β, IL-1B, and IL-10. No serious adverse events were observed. | Kaffash Farkhad et al., 2022 [234] |
| Single-arm, pilot trial | 2 | 16 | Severe 9 Critical 7 |
Infusion of 1 × 108 UC-MSCs for 4 rounds of transplantation. | Amelioration of oxygenation index. Increase of CD4+ T, CD8+ T, and NK lymphocytes. IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and CRP have returned in the normal range. No adverse events were observed. | Feng et al., 2020 [235] |
| Single-blind, randomized, placebo-controlled trial | 2 | 58 | Mild 31 Severe 21 Critical 6 |
N = 29 patients; Mild 15 Severe 11 Critical 3 Infusion of 1 × 106 UC-MSCs/kg in single dose. |
Shorter hospital stay and symptoms remission. Improved CT scans. Reduction of CD14+ monocytes, CRP, NETs and proinflammatory cytokines IL-1RA, IL-18, IL-27, IL-17E/IL-25, IL-17F, GRO-alpha (CXCL-1), and IL-5. High expression of genes involved in chemotaxis, telomerase assembly and maturation, angiopoiesis, HSCs mobilization, and fetal extramedullary hematopoiesis, including VNN2. Stimulation of SARS-CoV-2 specific antibodies production. No adverse events were observed. | Zhu et al., 2021 [236] |
| Double-blind, randomized, placebo-controlled trial | 2 | 100 | Severe | N = 65 patients; Infusion of 4 × 107 UC-MSCs for 3 times on days 0, 3, and 6. |
Improvement in lung lesion volume, improved restoration of the integrated reserve capability, and normal CT scans after 1 year. Similar incidence of adverse events and tumor markers to placebo group after 1 year. | Shi et al., 2021 [237] and Shi et al., 2022 [238] |
| Multicenter, double-blind, randomized, placebo-controlled trial | 2 | 45 | Mild 31.1%; Moderate 48.9%; Severe 20% |
N = 21 patients; Infusion of 0.9 ± 0.1 × 106 UC-MSCs/kg per dose over 5 days (on day 1, day 3 ± 1, and day 5 ± 1) N = 17 − 3 doses N = 2 − 2 doses N = 2 − 1 dose. |
UC-MSC-treated patients’ greater PaO2/FiO2-ratio increased between D0 and D7, with lack of statistically significant differences, compared to controls. No adverse events were observed. | Monsel et al., 2022 [239] |
| Double-blind, randomized, controlled trial | 1–2 | 24 | Mild-to-moderate 6; Moderate-to-severe 18 |
N = 12 patients; Mild-to-moderate 3 Moderate-to-severe 9 Infusion of 100 ± 20 × 106 UC-MSCs for 2 times on days 0 and 3. |
Significantly improved SAE-free survival and time to recovery. Significant reduction in plasma levels of inflammatory cytokines, chemokines, and growth factors GM-CSF, IFN-γ, IL-5, IL-6, IL-7, TNFα, TNF-β, PDGF-BB, RANTES, and sTNFR2. No difference in adverse events among both groups. | Lanzoni et al., 2021 [240] and Kouroupis et al., 2021 [241] |
| Randomized trial | 1–2 | 210 | Severe 111; Critical 99 |
Infusion of 1–2 × 106 UC-MSCs/kg in single dose. | After 2–3 weeks after transplantation, improvement oxygen saturation and high survival rate, especially before intubation. No adverse events observed. | O Ercelen et al., 2021 [242] |
| Prospective double controlled trial | 1–2 | 30 | Moderate 10; Critical 20 |
N = 10 critical patients; Infusion of 3 × 106 WJ-MSCs/kg for 3 times on days 0, 3, and 6. |
Decrease in proinflammatory and profibrotic factors IL-6, CRP, IFNγ, IL-2, IL-12, IL-17A, MMP-9, and MMP-3 plasma levels. Increase in anti-inflammatory and angiogenesis promoting factors IL-10, TGF-β, VEGF, KGF, and NGF plasma levels. Reduction of the mechanical ventilation period and high survival rate. No adverse events were observed. | Adas et al., 2021 [243] |
| Prospective, single-center, randomized, double-blind, placebo-controlled trial | 1–2 | 17 | Critical | N = 11 patients; Infusion of 5 × 105 UC-MSCs/kg every 48 h for 3 times. |
Decrease in ferritin, IL-6 and MCP-1-CCL2, CRP, D-dimer, and neutrophils levels and reduction of lung damage. Increase in the numbers of lymphocytes T CD3+, CD4+ and NK. All these values are maintained until 4 months. No serious adverse events were observed. | Rebelatto et al., 2022 [244] |
| Primary report of a two-center, open-label, single-arm trial | 2–3 | 11 | Critical | Infusion of 200 × 106 UC-MSCs (N = 6) and PL-MSCs (N = 5) every other day for 3 times. | Increased of SpO2. Significant reductions in serum levels of TNF-α, IL-8, and CRP. No adverse events were observed. | Hashemian et al., 2021 [245] |
| Case report | N/A | 1 | Severe | Infusion of 5 × 107 UC-MSCs for 2 times on days 30 and 32. | Increased PaO2/FiO2 ratio. Decrease of inflammatory monocytes and increase of patrolling monocytes, CD4+ T lymphocytes, and cDC2. Reduction of lung infiltrates and fibrosis. No adverse events were observed. | da Silva et al., 2021 [246] |
| Case report | N/A | 1 | Critical | Infusion of 1 × 106 UC-MSCs/kg in single dose. | Increase of SpO2 and absolute number of the lymphocytes. Reduction of GGO, lung infiltration, and plasma levels of CRP and D-dimer. No adverse events were observed. | Zhu et al., 2020 [247] |
| Case report | N/A | 1 | Severe | Infusion of 1 × 106 WJ-MSCs/kg in single dose. | Reduction of GGO, lung infiltration and plasma levels of CRP, IL-6 and TNF-α. Increase of CD3+, CD4+, and CD8+ T lymphocytes. No adverse events were observed. | Zhang Y. et al., 2020 [248] |
| Case report | N/A | 1 | Critical | Infusion of 1 × 106 UC-MSCs/kg for 8 times divided in 3 rounds. | Reduction of fiber strands and GGO. Reduction in IL-6, IL-10, WBCs, CRP, and D-dimer levels. Increase of CD4+ T lymphocytes and decrease of NK cells. No adverse events were observed. | Zhang Q. et al., 2021 [249] |
| Case report | N/A | 1 | Critical | Infusion of 5 × 107 UC-MSCs for 3 times on days 13, 16, and 19. | Reduction of GGO, D-dimer, WBCs, neutrophils, and lymphocytes/neutrophils ratio. Increase of CD3+, CD4+, and CD8+ T lymphocytes. No adverse events were observed. | Liang et al., 2020 [250] |
| Case report | N/A | 1 | Severe | Infusion of 0.5 × 106 UC-MSCs/kg for 3 times. | Reduction of GGO, plasmablasts, creatinine, GOT, ferritin, D-dimer, and CRP levels. Increase in the absolute number of total lymphocytes, CD4+ T, and Treg lymphocytes. No adverse events were observed. | Senegaglia et al., 2021 [251] |
CRP: C-reactive protein; CT: computed tomography; GGO: ground-glass opacity; HRQL: health-related quality of life; HSCs: hematopoietic stem cells; NETs: neutrophil extracellular traps; PaO2/FiO2: partial pressure arterial of oxygen to fractional inspired oxygen; PL-MSCs: placental MSCs; SAE: serious adverse event; SDF-1: stromal cell-derived growth factor 1; KGF: keratinocyte growth factor; NGF: nerve growth factor; SpO2/FiO2: peripheral arterial oxygen saturation to FiO2; GOT: glutamic-oxaloacetic transaminase; VNN2: vascular noninflammatory molecule 2; WBCs: white blood cells.