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

Table 1 Advantages and disadvantages of existing coronavirus disease 2019 treatment approaches

Treatment categories	Classification	Application examples	Countries and regions	Advantages	Disadvantages
Targeting the host response	Inflammation	Dexamethasone reduces overreaction of the immune system and lowers inflammation[118]	Widely used globally	Reduces the immune system’s overreaction and lowers inflammation, decreasing mortality rates	There are uncertainties and individual variabilities, which may entail potential risks and are constrained to early disease intervention
	Thrombosis	Heparin is used to prevent thrombosis and protect the cardiovascular system[119,120]		Reduces the risk of thrombosis and improves the prognosis of patients	Blood clotting needs to be carefully monitored to reduce the risk of bleeding
	Acute respiratory distress syndrome	Oxygen therapy aids in supporting respiratory function and enhancing oxygenation[121,122]		Improves severe hypoxemia	There are side effects on healthy organs and tissues
	Activation of the renin-angiotensin-aldosterone system	ACE inhibitors alter ACE2 expression or activity[123,124]		Reduces the viral invasion by SARS-CoV-2, thus improving survival and reducing lung inflammation and injury	There is a potential risk of causing or exacerbating hypotension, hyperkalemia, or kidney damage
	Multi-targeted stem cell therapy	Stem cell therapy promotes the repair of damaged tissue, regulates immune responses, and reduces inflammation[125]		Decreases the inflammatory response, lowers the risk of cytokine storms, and promotes the repair of damaged tissues, thereby improving outcomes in severe cases	Further research is necessary to ascertain the safety, efficacy, optimal timing for administration, and appropriate dosages
Targeting viruses	Blocking viral replication	Artemisia annua, through its direct inhibition of viral RNA polymerase[5]	Madagasca (Africa)	Offers a potential for shorter hospitalization	The use of unproven artemisinin therapy raises concerns about the emergence of drug-resistant malaria. For drugs currently in use, there should also be extensive randomized controlled trials to assess their effectiveness and safety in the population
		The active metabolite of remdesivir reduces genome replication by inhibiting RNA-dependent RNA polymerase[4]	Widely used globally
	Blocking viral access to host cells	Plasma from convalescent patients containing antibodies against SARS-CoV-2[126-128]	United States, United Kingdom, Germany, China, Brazil, Africa, etc.	Provides immediate immune support and benefits critically ill patients who do not have other appropriate treatment options. Early administration of recombinant monoclonal antibody is effective in preventing hospitalization	However, challenges include high variability in antibody levels and quality, the need to match blood types, and the risk of transmission of other pathogens. The neutralizing activity of recombinant monoclonal antibodies is readily lost as new virus variants emerge
		Passive administration of pathogen-specific antibodies has been employed to control viral infections[129-132]
Targeting improves immunity	Nutritional supplement	Vitamin C enhances immunity by stimulating interferon production and lymphocyte proliferation and enhancing neutrophil phagocytosis[133]	Widely used globally	Enhances immunity	Further research is needed to fully understand its safety, efficacy, optimal administration timing, and dosage

SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; ACE2: Angiotensin-converting enzyme 2.

Table 2 Coronavirus disease 2019 causes primary pathological changes

Organ system	Primary change
Lung tissue	Acute interstitial pneumonia occurs along with diffuse alveolar damage. The lung tissue shows macrophage infiltration, hyaline membrane formation, and alveolar wall edema. Microvascular involvement includes hyaline thrombosis, hemorrhage, vascular endothelial edema, and immune cell infiltration[134]	+
Cardiovascular system	Degeneration and necrosis of some cardiomyocytes, interstitial congestion and oedema, and infiltration by a few monocytes, lymphocytes, and neutrophils are observed. The nucleic acid test for novel coronavirus is occasionally positive. Endothelial cell detachment and endothelial or whole-layer inflammation are present in small blood vessels in significant parts of the body, accompanied by mixed intravascular thrombosis, thromboembolism, and infarction in the corresponding areas. The microvessels of major organs are prone to hyaline thrombosis[135]	+
Liver	The liver is enlarged with dark red hepatocyte degeneration and focal necrosis with neutrophil infiltration; hepatic sinusoids are congested, and lymphocyte and monocyte infiltration and microthrombosis are observed in the confluent area[136]	+
Gallbladder	The gallbladder is highly filled, and the mucosal epithelium is detached[137]	+
Kidney	The renal glomeruli exhibit congestion and occasional segmental fibrinoid necrosis; proteinaceous exudates can be observed within the glomerular lumens. Proximal renal tubular epithelial degeneration, partial necrosis, and desquamation are present, while casts can be found in the distal tubules. The renal interstitium is congested, with microthrombi formation noted[138]	+
Brain	Congestion, oedema, degeneration of some neurons, ischaemic changes and detachment, phagocytosis, and satellite phenomena are found. Infiltration of monocytes and lymphocytes in the perivascular space is observed[139]
Testicle	Varying degrees of reduction in the number of spermatogenic cells and degeneration of Sertoli and Leydig cells are observed[140]	+
Adrenal gland	Cortical cell degeneration, focal hemorrhage, and necrosis are observed[141]
Esophageal, gastric, and intestinal mucosal epithelium	There is variable degeneration, necrosis, and detachment observed, accompanied by the infiltration of monocytes and lymphocytes in the lamina propria and submucosa[142,143]	+

+: The nucleic acid test for novel coronavirus was positive.

Table 3 Coronavirus disease 2019 causes secondary pathological changes

Organ system	Secondary change
Spleen	The spleen shrinks. The white marrow is atrophic, with a decreased number of lymphocytes and some cell necrosis; the red marrow is congested and focally hemorrhagic, macrophages are proliferated, and phagocytosis is observed in the spleen; anemic infarcts of the spleen are easily found. Immunohistochemical staining shows decreased spleen CD4+ T and CD8+ T cells[144]	+
Lymph nodes	The lymphocyte count is reduced, and necrosis is found. Immunohistochemical staining shows decreased CD4+ T and CD8+ T cells in the spleen and lymph nodes. Lymph node tissues may be positive for novel coronavirus nucleic acid detection in macrophages[145]	+
Bone marrow	Hematopoietic cells are either hyperplastic or reduced in number, with an increased granulocyte-red ratio[146]

+: The nucleic acid test for novel coronavirus was positive.

Table 4 Comparison of different sources of mesenchymal stem cells for treatment of coronavirus disease 2019

Types	Advantages	Disadvantages
UC-MSCs	Prevent fibrosis and restore the oxygenation index and down-regulated CS in critically ill COVID-19 hospitalized patients; readily available and rapidly expanded to clinically required numbers without raising ethical issues and with minimal allograft rejection[147,148]	More extensive randomized trials and phase III clinical trials of UC-MSCs are still needed to investigate the exact molecular mechanisms of UC-MSCs in treating COVID-19 patients
BM-MSCs	Inhibit CS[149]	Adverse events such as low cryopreservation survival, cell product heterogeneity, immunogenicity, and thrombus generation, which have been observed with BM-MSCs products, as well as the low number of MSCs in bone marrow aspirates and the invasive nature of the process of obtaining MSCs have also prevented the generalization of BM-MSCs[150-152]
PL-MSCs	Higher amounts of CD106 are expressed because surface markers such as CD106 and CD54 are important for immunizing MSCs through cell-to-cell contact[153]	Differences in autologous or allogeneic preparation protocols and ethical concerns about PL-MSCs[154]
ADSCs	Rich tissue sources and tissue collection methods are simple[155]	Some severe side effects have been shown, such as three cases of vision loss after patients with AMD received bilateral intravitreal injections of autologous adipose tissue-derived stem cells at a stem-cell clinic[156]

ADSCs: Adipose-derived mesenchymal stem cells; AMD: Age-related macular degeneration; BM-MSCs: Bone marrow-derived mesenchymal stem cells; PL-MSCs: Placenta-derived mesenchymal stem cells; UC-MSCs: Umbilical cord mesenchymal stem cells; MSC: Mesenchymal stem cell; COVID-19: Coronavirus disease 2019; CS: Cytokine storm.

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.