Table 2.

Reports of clinical use of MSCs in COVID-19 patients

Study phase/type	Country	Sample size	Patient characteristics	Cell product	Dose and administration regimen	Main findings	Adverse events	References
Pilot study	China	10 patients, n = 7 included in the cell therapy arm	COVID-19 pneumonia confirmed by RT-PCR, with no improvement under standard treatment	Allogeneic, UC-MSC	Single dose of 1 × 106 MSCs/kg, i.v. infusion	Improvement of pulmonary function and symptoms, increase of peripheral lymphocytes, decrease in C-reactive protein, disappearance of overactivated cytokine-secreting immune cells, decrease of TNF-α levels and increase of IL-10 levels	No treatment-related adverse events	Leng et al, 2020 [66]
Phase 1, controlled, open label	China	41 patients, n = 12 included in the cell therapy arm	Severe COVID-19, clinical symptoms were not alleviated under standard treatment for 7 to 10 days	Allogeneic, UC-MSC	Single dose of 2 × 106 MSCs/kg, i.v. infusion	Relief of clinical symptoms, reduction of inflammatory factors, increase of lymphocytes, patients with diabetes used less exogenous insulin after hUC-MSC infusion than usual	No treatment-related adverse events	Shu et al, 2020 [139]
Primary safety trial, open-label cohort study	USA	27 patients	Severe or critical COVID-19 SpO2 < 94% on room air (RA), with fever and dyspnea (n = 2); patients with SpO2 < 90% on RA or patients who required supplemental oxygen to maintain SpO2 < 94% (n = 21), and patients with hypoxic respiratory failure on mechanical ventilation (n = 4)	Allogeneic, MSC-Exo	15 ml of ExoFlo was added to 100 mL of normal saline, i.v. infusion Quantification and characterization of exosomes were not provided	Reversal of hypoxia, immune reconstitution, modulation of cytokine storm	No treatment-related adverse events	Sengupta et al, 2020 [140]
Case series/Retrospective study	China	25 patients	Severe COVID-19 confirmed by real-time RT-PCR assay; patients in respiratory distress, with RR ≥ 30 beats/min, oxygen saturation level ≤ 93% in resting state and arterial partial pressure of oxygen (PaO2)/fraction of inspiration O2 (FiO2) ≤ 300 mmHg	MSCs of non-specified origin	1 × 106 MSCs/kg, i.v. infusion, single dose (n = 7), two doses (n = 7), three doses (n = 11)	Effectiveness, serum levels of LAC, cTnT and CK-MB were elevated significantly after MSCs therapy	Three cases experienced treatment-related side effects, specifically liver dysfunction, heart failure and allergic rash	Chen et al, 2020 [141]
Case report	China	1 patient	RT-PCR assay confirmed that the patient’s specimen tested positive for COVID-19, severe shortness of breath, SpO2 of 87.9%, computerized tomography evidences pneumonia and ground-glass opacity in bilateral lungs	Allogeneic, UC-MSC	Single dose of 1 × 106 MSCs/kg, i.v. infusion	Improvement of pulmonary function and symptoms, increase of lymphocyte subsets, decrease of IL-6, TNF-α, and C-reactive protein levels, safety and efficiency	No treatment-related adverse events	Zhang et al, 2020 [142]
Pilot study	China	2 patients	Severe COVID-19; patient 1 with increased leukocyte count and neutrophils, decreased hemoglobin and lymphocytes, X-ray indicates large, patchy, high-density lesions in bilateral lungs; patient 2 with increased neutrophils and decreased leukocyte counts and lymphocytes, chest X-ray indication of patchy high-density shadows in the lower lung fields and left middle lung	Allogeneic, menstrual blood–derived MSC	Three infusions of 1 × 106 MSCs/kg, i.v. infusion	MSC transplantation increases the immune indicators (including CD4 and lymphocytes) and decreases the inflammation indicators (interleukin-6 and C-reactive protein), improvement of dyspnea and lung function	No treatment-related adverse events	Tang et al, 2020 [143]
Proof of concept	Spain	13 patients	COVID-associated pneumonia requiring mechanical ventilation in the ICU	Allogeneic AT-MSC	Median number of AT-MSCs per dose was 0.98 (IQR 0.5) × 106/kg Single dose (n = 2), two doses (n = 10); three doses (n = 1), interval of 3 days	9 patients improved clinically and 7 were extubated with a median time from the first MSC dose to extubation of 7 days. Radiological improvement in sequential X-rays was confirmed in 40% of evaluable patients. A decrease in inflammatory parameters at day 5 after infusion with a decrease in C-reactive protein in 8 patients (88%), LDH in 9 (100%), and D-dimer and ferritin in 5 of 8 evaluable patients (63%), increase in the levels of total lymphocytes was observed in responders patients (B, CD4, CD8)	No treatment-related adverse events	Sánchez-Guijo et al, 2020 [130]
Case series	Brazil	10 patients, n = 7 in cell therapy arm	COVID-associated pneumonia, presenting severe acute respiratory syndrome	MSCs of non-specified origin	Single dose of 1 × 106 MSCs/kg, i.v. infusion	Improvement in symptoms, significant reduction ofchest infiltration, reduction of pro-inflammatory cytokines (TNF-α), increase of peripheral lymphocyte counts (CD4+ T cells and dendritic cells), increase of anti-inflammatory gene expression and trophic factors	No treatment-related adverse events	Mazzeo and Santos, 2020 [144]
Case report	China	1 patient	Severe COVID-19 confirmed by RT-PCR, SpO2 90%, P/F 243 mmHg, pulmonary exudative lesions in bilateral lungs showed in X-ray	Convalescent plasma + UC-MSC	Three infusions of 1 × 106 MSCs/kg, i.v. infusion	Restoration of lung diffusion, improvement of pulmonary function, increase of oxygenation index, PaO2 and absolute lymphocyte count, decline in absolute neutrophils count and IL-6	No treatment-related adverse events	Peng et al, 2020 [145]
Pilot study	China	31 patients	Severe (n = 23) or critical (n = 8) COVID-19	Allogeneic, UC-MSC	Single (n = 11), two (n = 9) or three (n = 11) infusions of 1 × 106 MSCs/kg BW, i.v. infusion	Restoration of oxygenation, downregulation of cytokine storm, improvement of lung function. Laboratory parameters tended to improve after UC-MSC therapy compared to the status before UC-MSC therapy, including elevated lymphocyte count, decreased C-reactive protein level and procalcitonin level, decreased D-Dimer levels	No treatment-related adverse events	Guo et al, 2020 [146]
Case report	China	1 patient	Severe COVID-19, SpO2 of 81%, chest tightness, blood pressure of 160/91 mmHg and X-ray showing ground-glass opacity in right lung	Allogeneic, UC-MSC	Three cycles (5 ×  107 cells each time) with a 3-day interval, i.v. infusion	Improvement of clinical indexes and symptoms, reversal of lymphopenia (increase in counts of CD3+ T cell, CD4+ T cell and CD8+ T cell)	No treatment-related adverse events	Liang et al, 2020 [147]
Phase 1, controlled, open label	China	18 patients; n = 9 included in the cell therapy arm	Moderate and severe COVID-19 confirmed by RT-PCR; pneumonia was evidenced using chest radiography or CT; moderate cases were defined as fever, respiratory symptoms and confirmed pneumonia; severe cases included symptoms of shortness of breath or dyspnea after activity	Allogeneic, UC-MSC	Three cycles of i.v. infusion of allogeneic UC-MSCs (3 × 107 cells each infusion) on days 0, 3, and 6	Decrease of serum IL-6 biomarker of disease progression, improvement of percentage of inspired oxygen ratio, faster absorption of lung lesions	Two patients developed transient facial flushing and fever, and one patient developed transient hypoxia at 12 h post UC-MSCs infusion	Meng et al, 2020 [148]
Case report	China	1 patient	COVID-19 confirmed by RT-PCR, acute respiratory distress, SpO2 90%, computerized tomography showed ground-glass opacity in both lungs, multiple organ injury (hepatic respiratory system), immunosuppression	Allogeneic, UC-MSC	Single infusion of 1 × 106 MSCs/kg BW, i.v. infusion	Patient’s SpO2 returned to the normal level 48 h after MSC infusion, non-invasive ventilator was successfully removed after 6 days. BUN, PCT, CRP, AST, and ALT levels decreased, leucocytes gradually recovered after 13 days	No treatment-related adverse events	Zhu et al, 2020 [149]
Phase 2, randomized, double-blind, placebo-controlled	China	101 patients; n = 65 included in the cell therapy arm; n = 45 control, n = 1 excluded	Severe COVID-19 confirmed by RT-PCR; pneumonia was evidenced using chest computed radiography (CT) imaging. Dyspnea (respiratory rate ≥ 30 times/min), oxygen saturation of 93% or lower on room air; arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen ≤ 300 mmHg; pulmonary imaging showing that the foci progressed by > 50% in 24–48 h	Allogeneic, UC-MSCs	Three cycles of i.v. infusions of UC-MSCs (4 × 107 cells) each on days 0, 3, and 6	UC-MSC administration was safe and accelerated resolution of lung solid component lesions and improvement in the integrated reserve capability after UC-MSC administration	Adverse events reported during the study was similar in the MSC group and the placebo group. All adverse events during the observation period were judged by the site investigators and found to be unrelated to UC-MSC intervention. No deaths were observed in this trial.	Shi et al, 2021 [150]
Phase 1	Iran	11 patients	COVID-19 confirmed by RT-PCR or chest X-ray; SpO2/FiO2 ≤ 315, SOFA score between 2 and 13 point, required mechanical ventilation and/or supplemental oxygen	(UC-MSC) or (PL-MSC)	Three i.v. infusions (200 × 106 cells) every other day for a total of 600 × 106 human umbilical cord MSCs (UC-MSCs; 6 cases) or placental MSCs (PL-MSCs; 5 cases)	MSCs from a prenatal source is relatively safe, tolerable, and could rapidly improve respiratory symptoms and reduce inflammatory conditions in some critically ill COVID-19 patients	Two patients developed shivering that occurred during the initial PL-MSC infusion, which was relieved by supportive treatment in less than 1 h. This shivering did not develop again during the second and third infusions.	Hashemian et al. 2021 [151]
Pilot study	China	17 patients, n = 9, severe and n = 7 critically severe, n = 1 excluded	Severe COVID-19 with respiratory distress, RR ≥ 30 min−1, oxygen saturation ≤ 93% at rest state, oxygenation index ≤ 300 mmHg, 1 mmHg = 0.133 kPa or critically severe with respiratory failure needs mechanical ventilation Shock, combined with other organ failure, patients need ICU monitoring and treatment	Allogeneic UC-MSCs	Four i.v. infusions of (1 × 108 cells) with 1-day intervals in between	UC-MSCs was safe in severe and critically severe COVID-19 pneumonia and that administration of UC-MSCs is associated with clinical benefit and changes in inflammatory and immune populations	There were two severe adverse events (SAE) during the trial. The two SAEs were considered to have no relationship with UC-MSCs transplantation.	Feng et al. 2020 [152]
Pilot study	China	7 patients, n = 2 severe cases, n = 5 mild cases	COVID-19 confirmed by RT-PCR	MSC-derived exosomes	Nebulization of MSC-derived exosomes. The concentration of exosomes for nebulization for each patient ranged from 7.66e+0.8 to 7.00e+0.7 particles/ml based on NanoSight.	The nebulization of MSC-derived exosomes is safe and beneficial for the absorption of pulmonary lesions in mild cases of COVID-19 pneumonia and in reducing cellular residue in severe cases.	No adverse events were reported	Chu et al. 2021 [153]
Phase I double-blind, randomized, controlled	USA	28 patients, n = 12 included in the cell therapy arm; n = 12 control, n = 4 excluded	COVID-19 confirmed by RT-PCR, peripheral capillary oxygen saturation (SpO2) ≤ 94% at room air, or requiring supplemental oxygen at screening, PaO2/FiO2 ratio < 300 mmHg, Bilateral infiltrates on frontal chest radiograph or bilateral ground-glass opacities on a chest CT scan	Allogeneic UC-MSC	Two i.v. infusions of (100 ± 20 × 106)	UC-MSC treatment was safe, reduced mortality and recovery time. Inflammatory cytokines were significantly decreased in UC-MSC-treated subjects at day 6.	In the UC-MSC treatment group, the only reported adverse event occurred in a subject with bradycardia required transient vasopressor treatment.	Lanzoni et al., 2021 [154]

MSCs, mesenchymal stem/stromal cells; UC-MSCs, umbilical cord-derived mesenchymal stem cells; AT-MSCs, adipose tissue-derived mesenchymal stem cells; MSCs-Exo, mesenchymal stem/stromal cell exosomes; ARDS, acute respiratory distress syndrome; BW, body weight; PL-MSC, placenta-derived mesenchymal stem cells