Table 1.

Clinical and study characteristics.

Author	Disease	Cell type and administration	Number of patients	Inclusion criteria	Evaluated parameters	Main outcomes	Adverse effects	Study design/evidence level
Shi L.et al.19.	COVID-19	UC-MSC IV	100	- Severe COVID-19 - CT confirmed pneumonia and any of the following: (1) Noninvasive ventilation, shock, or other organ failures (2) RR ≥30 times/min; (3) O2 of 93% (4) PaO2/FiO2 ≤300 mmHg; (5) CXR/CT evidence of progression >50% in 24–48 h	Clinical outcomes Biomarker response inflammatory factors Leukocytes count	↓ Pro-inflammatory factors improvement on CT	Pneumothorax Not related	Phase 2 clinical trial: multicenter, double-blind, randomized, controlled. 1 A: high
Matthay MA. et al.27.	ARDS	BM-MSCs IV	60	(1) Endotracheally intubated (2) ↓ PaO2/FiO2 (3) Positive pressure ventilation (4) Bilateral infiltrates on CXR (5) No clinical evidence of left-heart failure or volume overload	Hospital indexes SOFA score Angiopoietin-2 Respiratory parameters Inflammatory factors Alveolar epithelial injury	↓ Angiopoietin-2 The results had no statistical relevance	Cardiopulmonary arrest Not related	Phase 2 clinical trial: multicenter, double-blind, randomized, controlled. 1 A: high
Zheng G. et al.31.	ARDS	AD-MSCs IV	12	ARDS diagnostic criteria according to the New Berlin definition	PaO2/FIO2 Hospital indexes Inflammatory factor biomarker responses	↑ PaO2/FIO2	Diarrhea and rash in chest area related	Clinical trial: single-center, randomized, double-blind, controlled. 1B: moderate
Lanzoni G. et al.14.	COVID-19	UC-MSC IV	24	(1) Hospitalized patient ≥18 years (2) SpO2 ≤94% (3) PaO2/FiO2 <300 mmHg (4) Bilateral infiltrates CXR or bilateral ground-glass opacities on a CT	Survival Inflammatory factors	↓ Pro-inflammatory factors ↑Survival/↓Mortality Improvement on hospital discharge ↓Biomarker responses	Bradycardia Related Acute respiratory failure not related	Phase 1 clinical trial: a single-center, double-blinded, randomized, controlled. 1B: moderate
Bellingan G. et al.33.	ARDS	BM-MAPC IV	30	(1) PaO2/FiO2 above or below 150 mmHg (2) Need for vasopressors (3) 96-h of moderate-to-severe ARDS onset	Clinical outcomes PaO2/FIO2 Hospital indexes Biomarker responses	↑ PaO2/FIO2 ↑Survival/↓Mortality Clinical improvement Improvement on hospital discharge Discontinuation of oxygen support ↓Biomarker responses	Single CTCAE grade 1 Related	Phase 1 clinical trial: multicenter, open-label, randomized, controlled. 1B: moderate
Meng F. et al.17.	COVID-19	UC-MSC IV	18	(1) Patients aged 18–70 years old. (2) Confirmed COVID-19 (3) Pneumonia evidenced by CXR or CT	inflammatory factor biomarker responses PaO2	↓ Pro-inflammatory factors ↑ PaO2/FIO2 Improvement on CT	Transient facial flushing Fever Related Hypoxemia Not related	Phase 1 clinical trial: a single-center, open-label, non- randomized, controlled. 2B: low
Shu L. et al.18.	COVID-19	UC-MSC IV	41	- PCR COVID-19 - CT indicators of pneumonia and any of the following: (1) respiratory distress, RR ≥30 times/min; (2) O2 saturation ≤93%; (3) PaO2/FiO2 ≤300 mmHg	Biomarker responses Inflammatory factors Leukocytes count	↓ Pro-inflammatory factors ↑ Lymphocyte count ↑ O2 saturation Improvement on CT Clinical improvement	None	Clinical trial: single-center open-label, randomized, controlled. 2B: low
Feng Y.et al.21.	COVID-19	UC-MSC IV	16	Severe COVID-19 using the Clinical classification by the National Health Commission of China	Biomarker responses Inflammatory factors Leukocytes count EKG CT	↓ Pro-inflammatory factors ↑ Lymphocyte count Clinical improvement ↑ PaO2/FIO2	Bacterial pneumonia Septic shock Not related	Pilot trial: multicenter, open-label, non- randomized, noncontrolled. 2B: low
Wilson J. et al.26.	ARDS	BM-MSCs IV	9	(1) Positive pressure ventilation ↓ PaO2/FiO2 (2) Bilateral infiltrates on CXR (3) No clinical evidence of left atrial hypertension (4) Criteria 1–3 must be present within a 24 h period and at the time of enrollment	Lung injury score (LIS) Angiopoietin-2 Alveolar epithelial injury Inflammatory factors SOFA score Biomarker responses	LIS improved ↓ SOFA The results had no statistical relevance	Respiratory arrest Sepsis Embolic infarcts Not related	Phase 1 clinical trial: multicenter, open-label, non- randomized, noncontrolled 2B: low
Sánchez-Guijo F. et al.32.	COVID-19	AD-MSCs IV	13	- PCR COVID-19 - Pneumonia diagnosed by CXR or CT requiring mechanical ventilation in the ICU and any of the following: (1) RR 30 times/min (2) finger O2 saturation 93% (3) PaO2/FiO2 <300 mmHg (4) CXR/CT evidence of progression >50% in 24–48 h (5) SOFA score >3 points (6) WHO OSCI level 6 (7) No evidence of multiorgan failure Compassionate use	Safety EKG CXR Biomarker responses Inflammatory factors Leukocytes count Clinical outcomes Hospital indexes	↓ Pro-inflammatory factors ↑ Lymphocyte count Improvement on CT/CXR Clinical improvement Discontinuation of oxygen support	Massive gastrointestinal bleeding Hypotension Tachycardia Pneumonia Fungal infection by Candida spp. Not related	Clinical trial: multicenter, open-label, non- randomized, noncontrolled. 2B: low
Leng Z. et al.34.	COVID-19	ACE2-MSCs IV	10	No improvement under the standard treatments	Biomarker responses Inflammatory factors Clinical outcomes Leukocytes count CT RR	↓ Pro-inflammatory factors ↑ Lymphocyte count ↑ O2 saturation Improvement on CT Clinical improvement	None	Pilot trial: a single-center, open-label, non- randomized, controlled. 2B: low
Tang L. et al.36.	COVID-19	Menstrual blood-derived SC IV	2	Not applicable	Hospital indexes Biomarker responses Inflammatory factors CT	↓ Pro-inflammatory factors ↑ Lymphocyte count Clinical improvement Improvement on CT	None	Pilot trial: multicenter, open-label, non- randomized, noncontrolled. 2B: low
Hashemian S. et al.38.	COVID-19	P-MSCs IV	11	(1) Patients with 18–70 years (2) Evidence of pneumonia in CXR or CT and/or COVID-19 positive by RT-PCR (3) ARDS diagnosed (4) SpO2/FiO2 ≤315 (5) SOFA score between 2 and 13 (6) Required mechanical ventilation and/or supplemental O2	Clinical outcomes Leukocytes count SOFA PaO2/FIO2 RR	↓ Pro-inflammatory factors Improvement on CT/CXR Clinical improvement ↓Biomarker responses	Transient shivering Related Cardiac arrest Not related	Phase 1 clinical trial: multicenter, open-label, non- randomized, noncontrolled 2B: low
Iglesias M. et al.16.	COVID-19	UC-MSC IV	5	(1) Severe ARDS -Berlin definition (2) PCR COVID-19 (3) No clinical improvement after standard management (4) Persistent fever (5) D-dimer by at least 50% up from the baseline value and/or ferritin concentrations >1000 ng/mL (6) CT with ground-glass opacity and bilateral pneumonia (7) SOFA <11 Compassionate use	Biomarker responses Inflammatory factors Leukocytes count CT RR, HR PaO2/FIO2	↓ Pro-inflammatory factors ↑ PaO2/FIO2 Improvement on CT ↑Survival/↓Mortality Discontinuation of oxygen support	Hypoxemia Hypotension and/or hypertension Muscle spasms Related Acute Kidney Injury Cardiomyopathy and Liver Failure Bacterial Pneumonia Bleeding Lower-extremity arterial thrombosis Epistaxis and hematuria Not related	Pilot trial: single-center, open-label, non- randomized, noncontrolled. 2 C: low
Singh S. et al.22.	COVID-19	CDC IV	6	(1) RT-PCR COVID-19; (2) severe COVID-19, requiring supplemental oxygen and/or shock requiring inotropes; (3) not enrolled in another clinical trial; Compassionate use	Inflammatory factors Leukocytes count Biomarker responses	↓ Pro-inflammatory factors ↑ Lymphocyte count ↑Survival/↓Mortality Clinical improvement Discontinuation of oxygen support Improvement on hospital discharge	None	Clinical trial: a single-center, open-label, non- randomized, noncontrolled. 2 C: low
Chen X. et al.23.	COVID-19	BM-MSCs IV	25	(1) Diagnosis of severe COVID-19; (2) age ≥18 years; (3) Receiving MSCs therapy	Clinical outcomes CT Leukocytes count Inflammatory factors Biomarker responses	Clinical improvement Improvement on CT ↑Survival/↓Mortality LAC, cTnT, and CK-MB elevated	Liver dysfunction Heart failure Allergic rash Related	Clinical trial: a single-center, open-label, non- randomized, noncontrolled. 2 C: low Retrospective
Helene H. et al.28.	COVID-19	BM-MSCs IV	23	(1) Confirmed COVID-19 (2) Horovitz index <100 on admission.	Biomarker responses Inflammatory factors Leukocytes count	↓ Pro-inflammatory factors ↓ Neutrophil count ↑ Lymphocyte count ↑ PaO2/FIO2 ↑Survival/↓Mortality Improvement on hospital discharge Discontinuation of oxygen support	None	Clinical trial: a single-center, open-label, non- randomized, noncontrolled. 2 C: low
Sengupta V. et al.29.	COVID-19	BM-MSCs IV	24	(1) RT-PCR COVID-19; (2) Fever and/or dyspnea for more than 72 h (3) ↓ PaO2/FiO2 ratio Compassionate use	PaO2/FIO2 Oxygen support requirements Inflammatory factors CXR; EKG Cultures	↓ Pro-inflammatory factors ↑ Lymphocyte count ↓ Neutrophil count ↑Survival/↓Mortality ↑ PaO2/FIO2 Clinical improvement Improvement on hospital discharge Discontinuation of oxygen support	Hypoxic respiratory failure Pulmonary embolism Acute renal failure Expiration Not related	Clinical trial: a single-center, open-label, non- randomized, noncontrolled. 2 C: low
Zhinian G. et al.11.	COVID-19	UC-MSC IV	31	Severe COVID-19 pneumonia	Inflammatory factors PaO2/FIO2 Leukocytes count MSCs regulation Biomarker responses	↓ Pro-inflammatory factors ↑ Lymphocyte count ↑ PaO2/FIO2	None	Clinical trial: a single-center, open-label noncontrolled, non- randomized. 2 C: low
Zhang Y. 1et al.12.	COVID-19	UC-MSC IV	1	Not applicable	Clinical outcomes Lung function Leukocytes count Inflammatory factors Biomarker responses	↓ Pro-inflammatory factors ↑ O2 saturation Improvement on CT Clinical improvement Improvement on hospital discharge	None	Case Report 4 C: very low
Chang Y. et al.13	ARDS	UC-MSC IT	1	Compassionate use	PaO2/FIO2 CT Mental status Lung compliance	↑ PaO2/FIO2 Clinical improvement Discontinuation of oxygen support His mental status, lung compliance, P/F ratio improved	Repeated pulmonary infections Septic shock empyema Not related	Case Report 4 C: very low
Liang B. et al.15.	COVID-19	UC-MSC IV	1	Not applicable	Leukocytes count Biomarker responses Inflammatory factors	↓ Pro-inflammatory factors ↑ Lymphocyte count ↓Biomarker responses ↓ Neutrophil count	None	Case Report 4 C: very low
Peng H. et al.20.	COVID-19	UC-MSC IV	1	No improvement under the standard treatments	Clinical outcomes Biomarker responses Inflammatory factors CT PaO2	↓ Pro-inflammatory factors ↓ Neutrophil count ↑ Lymphocyte count Clinical improvement Discontinuation of oxygen support Improvement on CT	None	Case Report 4 C: very low
Simonson O. et al.24.	ARDS	BM-MSCs IV	2	Two patients with severe ARDS treated on a compassionate use	Physical capacity HRQoL Lung function DECT	Improvement on CT Discontinuation of oxygen support Clinical improvement	None	Cohort: 5-year follow-up. 4 C: very low
Simonson O. et al.25.	ARDS	BM-MSCs IV	2	Refractory ARDS	BALF Inflammatory factors CXR and CT Clinical outcomes Respiratory measurements Biomarker responses	↓ Pro-inflammatory factors Discontinuation of oxygen support Improvement on CT Clinical improvement	Nosocomial pneumonia Not related	Case Series 4 C: very low
Jungebluth P. et al.30.	ARDS	PBMCs IT	1	Refractory ARDS	Gene expression Bronchoscopy Clinical outcomes Inflammatory factors	↓ Pro-inflammatory factors ↑ PaO2/FIO2 Improvement on CT Clinical improvement Discontinuation of oxygen support	Disseminated fungal infection Intra-abdominal sepsis Not related	Case Report 4 C: very low
Lu J. et al.35.	COVID-19	Menstrual blood-derived SC IV	1	No improvement under the standard treatments	CT Inflammatory factors	↓ Pro-inflammatory factors Improvement on CT	None	Case Report 4 C: very low
Wu J. et al.37.	COVID-19	IMRCs IV	1	No improvement under the standard treatments Compassionate use	Clinical outcomes CT Inflammatory factors Blood pressure, O2 saturation Leukocytes count	↓ Pro-inflammatory factors Clinical improvement	None	Case Report 4 C: very low
Tao J. et al.63.	COVID-19	UC-MSC IV	1	No improvement under the standard treatments Compassionate use	Blood gas analysis Clinical outcomes Biomarker responses	↓ Pro-inflammatory factors ↑ Lymphocyte count Clinical improvement ↓Biomarker responses ↑ PaO2/FIO2	Lung transplant rejection	Case Report 4 C: very low

All studies required informed consent. All studies availed safety. Hospital indexes: length of hospital stay, ventilator-free days and ICU-free days, length of time from admission to the start of mechanical ventilation, the time between the latter, and extubation or death.

START stem cells for ARDS treatment, ATMP advanced therapy medicinal product, ACE2-MSC angiotensin-converting enzyme 2 mesenchymal stem cells, hESC human embryonic stem cells, UC-MSC umbilical cord-derived mesenchymal stem cells, CDC cardiosphere-derived cells, BM-MCSs bone marrow-derived mesenchymal stem cells, PBMCs peripheral blood mononuclear cells, AD-MSCs adipose-derived mesenchymal stem cells, BM-MAPC bone marrow-derived multipotent adult progenitor cells, IMRCs- immunity and matrix-regulatory cells, IV intravenous, P-MSC perinatal tissues mesenchymal stem cells, RT-PCR real-time polymerase chain reaction, PaO2/FiO2 arterial oxygen partial pressure/fractional inspired oxygen, CRP C-reactive protein, ECMO extracorporeal membrane oxygenation, SOFA Score sequential organ failure score, CXR chest X-ray, CT computed tomography, ICU intensive care unit, RR respiratory rate, SpO2 oxygen saturation, WHO OSCI WHO-ordinal scale for clinical improvement, DECT dual-energy computed tomography, BALF bronchoalveolar lavage fluid, EKG electrocardiogram, HR heart rate.