Mesenchymal stromal cells as potential immunomodulatory players in severe acute respiratory distress syndrome induced by SARS-CoV-2 infection

Table 1 Most common therapeutic compounds used for the treatment of coronavirus disease-19

	Agents	Mechanism of action	Approval
Antimalarial agent	Chloroquine/hydroxychloroquine	Inhibition of RNA-dependent RNA polymerase, Increase of endosomal and lysosomal pH	FDA approved (under investigation for COVID-19)
Antiviral agent	Ribavirin	Inducing mutations in RNA-dependent replication in RNA viruses, stop viral RNA synthesis	FDA approved (under investigation for COVID-19)
	Nelfinavir	Inhibitor of viral proteases	FDA approved (under investigation for COVID-19)
	Remdesivir	Inhibition of viral RNA-dependent RNA polymerase and proofreading	FDA approved (for COVID-19)
Anti-rheumatic agent	Baricitinib/ruxolitinib	JAK inhibitor/suppression of immune cells	Clinical Trial phase III
Monoclonal antibody	Tocilizumab	Humanized monoclonal antibody against the interleukin-6 receptor (IL-6R) and IL-6	FDA approved (under investigation for COVID-19)
	Anakinra	Humanized monoclonal antibody against IL-1R	FDA approved (under investigation for COVID-19)
Vaccination	Ad5-nCoV	Recombinant adenovirus type 5	Clinical Trials Phase II
	ChAdOx1 nCoV-19	Adenovirus vector	Clinical Trials Phase I-II
	INO-4800	DNA plasmid delivered by electroporation	Clinical Trials Phase I-II
	NVX-CoV2373	Recombinant S protein of SARS-CoV-2	Clinical Trial Phase I
	LV-SMENP-DC	Minigene vaccination in combination with modified DCs	Clinical Trial Phase I
Human antibodies	Convalescent plasma	Plasma enriched with antibodies specific to SARS-CoV-2, derived from convalescent patients	Clinical Trials Phase I
Stem cells	MSCs and derivatives (exosomes)	Suppression of the overactivated immune response through cell-cell contact and secretion of soluble factors	Clinical Trials Phase I

COVID-19: Coronavirus disease-19; MSCs: Mesenchymal stromal cells; SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2; DCs: Dendritic cells; FDA: Food and Drug Administration.

Table 2 Immunomodulation mechanisms of mesenchymal stromal cells

	Implicated biomolecules	Mechanism of action	Implicated immune cells	Result
Cell-cell contact	Fas/fas ligand	Fas/fas ligand death signaling pathway/FADD/caspases activation or TRAIL signaling pathway	Macrophages, DCs, T and B cells	Apoptosis
	PD-L1/ PD-1	PD-L1 induced death through binding with the inhibitory checkpoint protein PD-1	T and B cells	Reducing cell proliferation, reducing apoptosis of T reg
	HLA-G/LIRB2 (ILT4/CD85d) and KIR2DL4 (CD158d)	HLA-G/LIRB2 interaction /phosphorylation of TIMS/SHP phosphatases activation/ MAPK downregulation	DCs, NK cells and T cells	Inhibition of cellular proliferation
Soluble factors	PGE2	PGE2/cAMP production/ downregulation of IL-2, IL-2R expression. PGE2/ downregulation of PtdIn/ suppression of T cell receptor signaling	Macrophages, DCs, T and B cells	M2 macrophages switching; Prevention of DCs maturation, T and B cell inactivation
	IDO	IDO blocks the conversion of tryptophan to kyneurenin/in combination with TGF-β1 and HGF	DCs NK cells, T and B cells	G0/G1 cell cycle arrest
	NO	NO/suppression of STAT5 phosphorylation	Macrophages, T and B cells	Inhibition of cellular proliferation
	Galectins	Crosslinking with TCR/clustering prevention	T and B cells	Inhibition of T and B cell proliferation
	Soluble HLA-G isoforms	Similar interaction mechanism as membrane bound HLA-G isoforms	DCs, NK cells and T cells	Inhibition of cellular proliferation
ΕVs	miR-21-5p, miR-142-3p, miR-223-3p, and miR-126-3p	Interaction with JAG1, PDCD4, IL-12p35, downregulation of IL-6 expression	DCs	Inhibition of DC maturation
	miR-145, miR-146 and miR-155	Suppression of TRAF6 and IL-1 IRAK1 expression/down-regulation of NF-κB p65 phosphorylation/decrease in TNF- α, ΙL-1β and IL-6 production	Macrophages, T cells	Inactivation of M1 macrophages; Switching from Th1 to Th2 responses

FADD: Fas-associated death domain; PtdIn: Phosphatidylinositol; DCs: Dendritic cells; NK cells: Natural killer cells; PGE2: Prostaglandin E2; IL: Interleukin; TNF: Tumor necrosis factor; NO: Nitric oxide; STAT5: signal transducer and activator of transcription 5; TCR: T cell receptor; TRAIL: TNF-related apoptosis-inducing ligand; IDO: Indoleamine-2,3-dioxygenase; EVs: Extracellular vesicles; SHP: Src-homology 2 domain-containing protein tyrosine phosphatases; TRAF6: TNF receptor-associated factor 6; IRAK1: IL-1 receptor-associated kinase 1.

Table 3 Clinical trials associated with the use of mesenchymal stromal cells in coronavirus disease-19

NCT number	Title	Status	MSCs origin	Route of infusion
NCT04252118	Mesenchymal stem cell treatment for pneumonia patients infected with COVID-19	Recruiting	Not specified	Intravenously
NCT04313322	Treatment of COVID-19 patients using Wharton's Jelly-mesenchymal stem cells	Recruiting	Wharton’s Jelly MSCs	Intravenously
NCT04336254	Safety and efficacy study of allogeneic human dental pulp mesenchymal stem cells to treat severe COVID-19 patients	Recruiting	Allogeneic human dental pulp stem cells	Intravenously
NCT04288102	Treatment with mesenchymal stem cells for severe COVID-19	Recruiting	Not specified	Intravenously
NCT04346368	Bone marrow-derived mesenchymal stem cell treatment for severe patients with COVID-19	Not yet recruiting	BM-MSCs	Intravenously
NCT04366323	Clinical trial to assess the safety and efficacy of intravenous administration of allogeneic adult mesenchymal stem cells of expanded adipose tissue in patients with severe pneumonia due to COVID-19	Not yet recruiting	Allogeneic and expanded adipose tissue-derived MSCs	Intravenously
NCT04276987	A pilot clinical study on inhalation of mesenchymal stem cells exosomes treating severe novel coronavirus pneumonia	Not yet recruiting	MSCs-derived exosomes	5 times aerosol inhalation of MSCs derived exosomes
NCT04269525	Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) treatment for the 2019-novel coronavirus (nCOV) pneumonia	Recruiting	UC-MSCs	Intravenously
NCT04348461	Battle against COVID-19 using mesenchymal stromal cells	Not yet recruiting	Allogeneic and expanded adipose tissue-derived MSCs	Intravenously
NCT03042143	Repair of acute respiratory distress syndrome by stromal cell administration (REALIST) (COVID-19)	Recruiting	Human umbilical cord derived CD362 enriched MSCs	Intravenously
NCT04333368	Cell therapy using umbilical cord-derived mesenchymal stromal cells in SARS-CoV-2-related ARDS	Recruiting	Umbilical cord Wharton's jelly-derived human	Intravenously
NCT04352803	Adipose mesenchymal cells for abatement of SARS-CoV-2 respiratory compromise in COVID-19 disease	Not yet recruiting	Autologous adipose MSC's	Intravenously

COVID-19: Coronavirus disease-19; MSCs: Mesenchymal stromal cells; SARS-CoV-2: Severe acute respiratory syndrome coronavirus-2; ARDS: Acute respiratory distress syndrome; UC-MSCs: Umbilical cord-derived mesenchymal stem cells; BM-MSCs: Bone marrow-derived mesenchymal stem cells.