Mesenchymal stem cells and their derived exosomes for the treatment of COVID-19

Table 5 Efficacy of mesenchymal stem cells and their derived exosomes in clinical trials for the treatment of coronavirus disease 2019 patients

No.	Study title	Trial ID	Phase	Indications	Source	Route and time of administration	Dose	Effectiveness of treatment			Number of patients	Ref.
								Clinical symptoms	Cytokine storm biomarkers	Lung image
1	Effectiveness and safety of normoxic allogenic umbilical cord mesenchymal stem cells administered as adjunctive treatment in patients with severe COVID-19	NCT04333368	Phase 1	Severe COVID-19	NA-UC-MSC	Intravenous infusions, 3 rounds (at days 0, 3, and 6)	1 × 106/kg	Improved the oxygenation index, oxygen saturation	↓ESR, CRP		42	[104]
2	Repair of acute respiratory distress syndrome in COVID-19 by stromal cells (REALIST-COVID Trial): A multicenter, randomized, controlled clinical trial	NCT03042143	Phase 2	Moderate and severe ARDS in COVID-19	ORBCEL-C	Intravenous infusions, 1 round	400 × 106 cells	Prolonged duration of ventilation, modulated the peripheral blood transcriptome			60	[157]
3	Human placenta-derived mesenchymal stem cells transplantation in patients with acute respiratory distress syndrome (ARDS) caused by COVID-19 (phase I clinical trial): Safety profile assessment	IRCT20200621047859N4	Phase 1	ARDS in COVID-19	PL-MSC	Intravenous infusions, 1 round	1 × 106 cells/kg	Not show any adverse events			20	[153]
4	Bone marrow-derived mesenchymal stromal cell therapy in severe COVID-19: Preliminary results of a phase I/II clinical trial	NCT04445454	Phase 1/2	Severe COVID-19	BM-MSC	Intravenous infusions, 3 rounds (1, 4 ± 1, 7 ± 1)	(1.5-3) × 106 cells/kg	The higher survival rate in the MSC group at both 28 and 60 d	↓D-dimer		32	[158]
5	Mesenchymal stromal cell therapy for COVID-19-induced ARDS patients: A successful phase 1, control-placebo group, clinical trial	IRCT20160809029275N1	Phase 1	ARDS in COVID-19	UC-MSC	Intravenous infusions, 3 rounds (1, 3, 5)	1 × 106 cells/kg	Improved the SpO2/FiO2 ratio	↓CRP, IL-6, IFN-γ, TNF-α, and IL-17A; ↑TGF-β, IL-1β, IL-10		20	[159]
6	Safety of DW-MSC infusion in patients with low clinical risk COVID-19 infection: A randomized, double-blind, placebo-controlled trial	NCT04535856	Phase 1	Low clinical risk COVID-19	UC-MSC	Intravenous infusions, 1 round	High dose: 1 × 108 cells or low dose: 5 × 107 cells				9	[160]
7	Safety and long-term improvement of mesenchymal stromal cell infusion in critically COVID-19 patients: A randomized clinical trial	U1111-1254-9819	Phase 1/2	Critical COVID-19	UC-MSC	Intravenous infusions, 3 rounds (at days 1, 3, and 5)	5 × 105 cells/kg/round		↓Ferritin, IL-6, MCP1-CCL2, CRP, D-dimer, and neutrophil levels; ↑TCD3, TCD4, and NK lymphocytes	A decrease in the extent of lung damage was observed in the fourth month	17	[161]
8	Treatment of COVID-19-associated ARDS with mesenchymal stromal cells: A multicenter randomized double-blind trial	NCT04333368	Phase 2	ARDS in COVID-19	UC-MSC	Intravenous infusions, 3 rounds (at days 1, 3 ± 1, and 5 ± 1)	1 × 106 cells/kg/round	Significant increase in PaO2/FiO2 ratios			47	[162]
9	Clinical experience on umbilical cord mesenchymal stem cell treatment in 210 severe and critical COVID-19 cases in Turkey		Phase 1	Severe/critical COVID-19	UC-MSC	Intravenous infusions, 1 round	(1-2) × 106/kg	Significantly lower mortality, improvements in SaO2			210	[163]
10	Cell therapy in patients with COVID-19 using Wharton’s jelly mesenchymal stem cells: A phase 1 clinical trial	IRCT20190717044241N2	Phase 1	Severe COVID-19	UC-MSC	Intravenous infusions, 3 rounds (at days 0, 3, and 6)	1.5 × 108 cells/round		↓Ferritin		5	[70]
11	The systematic effect of mesenchymal stem cell therapy in critical COVID-19 patients: A prospective double controlled trial	NCT04392778	Phase 1/2	Critical COVID-19	UC-MSC	Intravenous infusions, 3 rounds (at days 0, 3, and 6)	3 × 106 cells/kg/round		↓Ferritin, fibrinogen, and CRP		30	[164]
12	Umbilical cord mesenchymal stromal cells as critical COVID-19 adjuvant therapy: A randomized controlled trial	NCT04457609	Phase 1	ARDS in COVID-19	UC-MSC	Intravenous infusions, 1 round	1 × 106 cells/kg/round	Survival rate was 2.5 times higher in the UC-MSC group than in the control group	↓IL-6		40	[165]
13	Evaluation of the safety and efficacy of using human menstrual blood-derived mesenchymal stromal cells in treating severe and critically ill COVID-19 patients: An exploratory clinical trial	ChiCTR2000029606	Phase 1	Severe and critical COVID-19	Allogenic menstrual blood-derived MSCs	Intravenous infusions, 3 rounds (1, 3, 7)	Total 9 × 107 cells	Significant improvement in dyspnea on days 1, 3, and 5 and significant improvements in SpO2 and PaO2		Improved the lung condition	44	[166]
14	Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: A randomized, double-blind, placebo-controlled phase 2 trial	NCT04288102	Phase 2	Severe COVID-19	UC-MSC	Intravenous infusions, 3 rounds (at days 0, 3, and 6)	4 × 107 cells/round			Significant reduction in the proportions of solid component lesion volume	100	[147]
15	Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: A case series	IRCT20200217046526N2	Phase 1	ARDS in COVID-19	UC-MSC	Intravenous infusions, 3 rounds (at days 0, 2, and 4)	2 × 108 cells/round	Reduced dyspnea and increased SpO2 within 2-4 d	↓TNF-α, IL-8, and CRP. There is no significant difference between the two groups (P > 0.05)	Reduction in ground-glass opacities or consolidation	11	[106]
16	Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial	NCT04355728	Phase 1/2a	ARDS in COVID-19	UC-MSC	Intravenous infusions, 2 rounds (at days 0 and 3)	(10 ± 2) × 107 cells/round	Improved patient survival and a shorter time to recovery	↓GM-CSF, IFN-γ, IL-5, IL-6, IL-7, TNF-α, and TNF-β		24	[167]
17	Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: A phase 1 clinical trial	NCT04252118	Phase 1	Moderate and severe COVID-19	UC-MSC	Intravenous infusions, 3 rounds (at days 0, 3, and 6)	3 × 107 cells/round		↓IL-6, IFN-γ, TNF-α, MCP-1, IP-10, IL-22, IL-1RA, IL-18, IL-8, and MIP-1	Complete fading of lung lesions within 2 wk	18	[168]
18	Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells	ChiCTR2000031494	Phase 1	Severe/critical COVID-19	UC-MSC	Intravenous administration, 1 round	2 × 106 cells/kg	Improved the weakness, fatigue, shortness of breath, and oxygenation index as early as the third day	↓CRP, IL-6	Shorter lung inflammation absorption	41	[49]
19	Nebulization therapy with umbilical cord mesenchymal stem cell-derived exosomes for COVID-19 pneumonia	ChiCTR2000030261	Phase 1	Moderate COVID-19	MSCs-Exo	Nebulized, twice a day (am 8:30, pm 16:00) for 10 min each	1 million cells/kg predicted body weight		↓CRP, IFN-γ, IL-17, ATH 19; ↑NK	Absorption of pulmonary lesions	7	[115]
20	Nebulized exosomes derived from allogenic adipose tissue mesenchymal stromal cells in patients with severe COVID-19: A pilot study	NCT 04276987	Phase 2	Severe COVID-19	HAMSCs-Exo	Nebulized, consecutively 5 d	2.0 × 108 nanovesicles		↓CRP, IL-6, lymphocyte counts, and LDH	Massive infiltration and ground-glass opacity disappeared	7	[114]

CRP: C-reactive protein; ESR: Erythrocyte sedimentation rate; HAMSCs-Exo: Human adipose mesenchymal stem cells-derived exosomes; IP-10: Interferon gamma-induced protein 10; LDH: Lactate dehydrogenase; MCP-1: Monocyte chemoattractant protein-1; MCP1-CCL2: Monocyte chemoattractant protein-1/c-c motif chemokine ligand 2; MIP-1: Macrophage inflammatory protein-1; NA-UC-MSC: Normoxic-allogenic umbilical cord mesenchymal stem cell; ORBCEL-C: CD362-enriched, umbilical cord-derived mesenchymal stem cells; COVID-19: Coronavirus disease 2019; NK: Natural killer; IL: Interleukin; IFN-γ: Interferon-γ; TNF-α: Tumor necrosis factor-α; MSCs-Exo: Mesenchymal stem cells derived exosomes; TGF-β: Transforming growth factor β; MSCs: Mesenchymal stem cells; ARDS: Acute respiratory distress syndrome; PL-MSCs: Placenta-derived mesenchymal stem cells.