the role of mesenchymal stromal cells in immune modulation of … · 2020. 9. 18. · exercise...

REVIEW Open Access

The role of mesenchymal stromal cells inimmune modulation of COVID-19: focus oncytokine stormMaria Kavianpour1,2, Mahshid Saleh1* and Javad Verdi1

Abstract

The outbreak of coronavirus disease 2019 (COVID-19) pandemic is quickly spreading all over the world. This virus,which is called SARS-CoV-2, has infected tens of thousands of people. Based on symptoms, the pathogenesis ofacute respiratory illness is responsible for highly homogenous coronaviruses as well as other pathogens. Evidencesuggests that high inflammation rates, oxidation, and overwhelming immune response probably contribute topathology of COVID-19. COVID-19 causes cytokine storm, which subsequently leads to acute respiratory distresssyndrome (ARDS), often ending up in the death of patients. Mesenchymal stem cells (MSCs) are multipotential stemcells that are recognized via self-renewal capacity, generation of clonal populations, and multilineage differentiation.MSCs are present in nearly all tissues of the body, playing an essential role in repair and generation of tissues.Furthermore, MSCs have broad immunoregulatory properties through the interaction of immune cells in bothinnate and adaptive immune systems, leading to immunosuppression of many effector activities. MSCs can reducethe cytokine storm produced by coronavirus infection. In a number of studies, the administration of these cells hasbeen beneficial for COVID-19 patients. Also, MSCs may be able to improve pulmonary fibrosis and lung function. Inthis review, we will review the newest research findings regarding MSC-based immunomodulation in patients withCOVID-19.

Keywords: Mesenchymal stromal cells, COVID-19, Immune regulatory, Cytokine storm

IntroductionThe city of Wuhan was the origin of coronavirus disease(COVID-19), a severe acute respiratory syndrome withSARS-CoV-2 as its causative agent. Presently, COVID-19 infection has spread to all continents of the world [1].Due to unknown reasons, COVID-19 infection has beenwidely distributed in various geographical regions withhigh population densities [2]. Moreover, the profile ofsymptoms and severity of COVID-19 infection show ex-tensive variation in different parts of the world [3].

Worldwide assessments suggest that only 3.4% of thoseinfected with SARS-CoV-2 have perished as a result ofCOVID-19, which also shows high difference in variousparts of the world [4].Constant fever, non-productive cough, dyspnea, myal-

gia, fatigue, normal or reduced WBC counts, hyperferri-tinemia, and radiographic evidence of pneumonia areamong the clinical signs of patients with COVID-19,which are similar to the symptoms of infection by othermembers of this family, namely SARS-CoV and the Mid-dle East respiratory syndrome-related coronavirus(MERS-CoV) [5–7]. The mortality rate of the new cor-onavirus, known as SARS-CoV-2, is high because of in-sufficient knowledge about the pathogenesis of COVID-19, and no specific treatment has been recognized for it

© The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License,which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you giveappropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate ifchanges were made. The images or other third party material in this article are included in the article's Creative Commonslicence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commonslicence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtainpermission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to thedata made available in this article, unless otherwise stated in a credit line to the data.

* Correspondence: [email protected] of Tissue Engineering and Applied Cell Sciences, Faculty ofAdvanced Technologies in Medicine, Tehran University of Medical Sciences,Tehran, IranFull list of author information is available at the end of the article

Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 https://doi.org/10.1186/s13287-020-01849-7

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[8]. On the other hand, the response to COVID-19 in-fection can be overwhelmed in many patients. WhenSARS-CoV-2 enters into the lungs, it unleashes an im-mune response, attracting immune cells to the regionattacked by the virus and resulting in localized inflam-mation [9]. In some cases, excessive or unchecked levelsof cytokines are released that can be fatal due to anoverreaction of the immune system, which is referred toas a cytokine storm [10]. The cytokine storm can triggerorgan injury and cause edema, gas exchange dysfunction,acute respiratory distress syndrome (ARDS), acute car-diac injury, and secondary infection, which can be po-tentially fatal [11].Consequently, the inhibition of cytokine storm is a

main factor in the treatment of patients who are infectedwith SARS-CoV-2. Currently, available therapies forCOVID-19 include non-specific antiviral drugs, antibi-otics used for the treatment of secondary bacterial infec-tions, sepsis, and reduction of inflammation [12]. A largenumber of anti-inflammatory medications have been de-veloped, including NSAIDs, glucocorticoids, chloro-quine/hydroxychloroquine, antagonists of inflammatorycytokines (such as IL-6R monoclonal antibodies, TNFinhibitors, IL-1 antagonists), and Janus kinase JAK inhib-itors [13, 14]. However, in severe cases of ARDS, it is adifficult task to treat the cytokine storm induced by thevirus. The findings suggest that stem cell-based therapyis applicable to treat infected patients.

Mesenchymal stromal cells and their featuresMesenchymal stromal cells (MSCs) are the cells with theunique ability to exert suppressive and regulatory effectson the immune system [15]. MSCs have been the focusof research because evidence has indicated that MSCsare able to migrate to and return from damaged tissues,exercise potent anti-inflammatory and immune regula-tory activities, support the regeneration and repair of tis-sues, resist against apoptosis, inhibit tissue fibrosis, anddecrease tissue injury [16]. MScs are able to migrate tosite of lesion and differentiate into tissue-specific activecells such as lung, smooth muscle, and nerve cells [17].Following intravenous or intra-arterial infusion of MSCs,these cells are primarily trapped in capillary beds of theliver and lungs [18]. MSC homing processes are not fullyrealized but are known to involve a variety of moleculessuch as chemokine receptors, including CCR2, CCR4,CCR7, CCR10, CXCR5, CXCR6, and CXCR4, adhesionproteins, and matrix metalloproteinase (MMPs), namelymolecules also implicated in the well-known process ofleukocyte extravasation [19, 20]. Hypoxia and inflamma-tion are frequent indications of an injured tissue capableof affecting paracrine features of MSCs, which aremainly mediated via VEGF, FGF2, IGF-1, and HGF [21].

When MSCs are trapped in the lungs, a wide range ofsoluble mediators are secreted by them, including anti-microbial peptides, anti-inflammatory cytokines, extra-cellular vesicles, and angiogenic growth factors [22]. Therelease pattern of anti-inflammatory mediators is uniqueto the inflammatory lung environment, which is adjustedby differential damage and pathogen-associated molecu-lar receptors that are expressed on MSCs [23], namelyTLRs (toll-like receptors). As for COVID-19, TLRs arestimulated by viral unmethylated CpF-DNA (TLR9) aswell as viral RNA (TLR3), leading to sequential cellularsignaling pathways and the activation of MSCs [24].On the other hand, inflammation leads to nuclear

factor-kappa B (NF-κB) and c-Jun NH2-terminal kinase(JNK) signaling, which is also controlled through the fac-tors secreted by MSCs. In addition, lung damage im-proves during the response of MSCs to oxidative stress,cytoprotection, and phosphoinositide 3-kinase/proteinkinase B (P13K / Akt) signaling pathway [25]. Adminis-tration of BM-MSCs alleviated lung injury in a preclin-ical study via potentiating the PI3K/Akt signalingpathway [26, 27].For example, the release of IL-1ra through MSCs in-

hibits IL-α/β activity via generating TSG-6, which isfollowed by the downregulation of NF-κB signaling andreduced production of inflammatory cytokines. Secretionof prostaglandin E2 (PGE2) is another efficient way todecrease inflammation by MSCs, which is a function ofIL-10 production as a strong anti-inflammatory cytokine.Khakoo et al. showed that MSCs prevent PKB signalingof target cells via a contact-dependent way [28].MSCs encounter a complex setting specified by vari-

ous chemical and physical stimuli while moving towardan injured tissue and the microenvironment impactsMSCs’ behavior [29]. MSCs are able to release manytypes of cytokines through paracrine release or directinteraction with immune cells, which leads to immuno-modulation [30]. These cells have the capacity to inter-act with immune cells in innate and adaptive immunesystems [31]. Besides, MSC-mediated immunosuppres-sion depends on the combined reaction of chemokines,inflammatory cytokines, and effector factors, as alongwith the microenvironment and the rate of inflammatorystimulus [32]. Owing to their powerful immunomodula-tory ability, MSCs might have beneficial effects for pre-venting or attenuating the cytokine storm of SARS-CoV-2 infection [33, 34]. This paper tries to explain the sig-nificant role of MSCs in secreting important factors forimmune regulation in COVID-19.

The SARS-CoV-2 infection and cytokine stormARDS caused by cytokine storm is the main mortalityfactor in COVID-19 [35]. The lethally uncontrolled sys-temic inflammatory response is stimulated by the

Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 2 of 19

secretion of a large number of pro-inflammatory cytokinessuch as interleukin (IL)-1β, IL-2, IL-6, IL-7, IL-12, IL-18,IL-33, interferon (IFN)-α, IFN-γ, tumor necrosis factor-α(TNFα), granulocyte colony-stimulating factor (GSCF),interferon-γ inducible protein 10 (IP10), monocytechemoattractant protein 1 (MCP1), macrophage inflam-matory protein 1-α (MIP1A), and transforming growthfactor-beta (TGF-β) such as chemokines by immune ef-fector cells within coronavirus infection (Fig. 1) [36–38].Huang et al. reported the level of inflammatory factors

among patients with COVID-19. They measured cyto-kines of patients with COVID-19 and indicated increas-ing levels of IL-1B, IL-1RA, IL-7, IL-8, IL-9, IL-10,fibroblast growth factor (FGF), granulocyte-macrophagecolony-stimulating factor (GM-CSF), IFN-γ, G-CSF,IP10, MCP1, MIP1A, PDGF, TNFα, and vascular endo-thelial growth factor (VEGF) in their specimens, amongwhich TNFα levels were higher in patients with severedisease. Remarkably, no significant difference was ob-served in serum IL-6 levels between ICU and non-ICUadmitted patients [8]. Nevertheless, in a retrospective,multicenter cohort study, the same research group re-ported a significant elevation of IL-6 levels in patientsnot surviving COVID-19 as compared with survivors[39]. Several other reports have also confirmed increas-ing IL-6 levels among critically ill COVID-19 patients[24, 40]. Moreover, the result of another study demon-strated that a majority of severe COVID-19 patients inICU had persistently elevated levels of ESR and CRP, aswell as high levels of IL-6, TNFα, IL-1β, IL-8, and IL2R,and experienced ARDS, hypercoagulation, and dissemi-nated intravascular coagulation (DIC) [13].The cytokine storm was followed by ARDS and mul-

tiple organ failure, which causes death in severe cases ofCOVID-19. For example, the findings of Huang et al.showed that out of 41 infected patients who were admit-ted in the early stages, 6 patients died as a result ofARDS [8]. Like common acute viral infections, bothhumoral and cellular immunity are activated in COVID-19. Therefore, inhibition of cytokine storm may be thekey to the treatment of COVID-19 patients.

Immunomodulatory effects of MSCsMSCs show remarkable immunomodulatory capacityand are implicated in both innate and adaptive immunesystems. Former investigations on immune regulation ofMSCs have concentrated on interactions of MSCs and Blymphocytes, natural killer (NK) cells, and dendritic cells(DC) [41]. Lately, the application of MSCs in repairingdamaged tissue and adjustment of inflammatory reac-tions have become noticed considering macrophage andT lymphocyte regulation (Fig. 1) [16]. Interaction mech-anisms have been shown to be dependent upon cell-cellcontact along with the release of soluble immune factors

to induce MSC-regulated immunosuppression [42]. Thecells that express immunosuppressive ligands like pro-grammed death-ligand 1 (PD-L1) and Fas ligand (Fas-L)on their surface bind receptors present on the surface ofimmune cells, which leads to loss of function in immunecells [43, 44].Several studies have revealed that the anti-

inflammatory effect of MSCs can alleviate virus-inducedlung injury and mortality in mice [45, 46]. Research hasindicated that MSCs are able to significantly reduceacute lung injury by H9N2 and H5N1 viruses in mice bydecreasing levels of pro-inflammatory cytokines and che-mokines as well as diminishing the recruitment of in-flammatory cells into the lungs [47, 48]. Applying MSCsto interfere in endotoxin (LPS)-induced acute lung in-jury of mice proved that MSCs can remarkably lead toreduction of inflammatory cell infiltration in lung tissue,alleviate inflammation, and improve the lung tissue fromendotoxin-induced damage [49, 50].Intravenous infusion of MSCs normally results in their

accumulation within lungs, whereby they secrete manyparacrine factors [51]. Evidence suggests that MSCs bindactivated immune cells, which could keep them in closeproximity and hence potentiate immunosuppressive ef-fects [52]. Moreover, MSCs can also prevent the func-tion of immune cells via releasing cytokines such asTGF-β, HGF, and prostaglandin E2 (PGE2), as alongwith other anti-inflammatory factors [53]. For example,MSCs secrete TGF-β and other factors promoting theinduction of regulatory T lymphocytes (Tregs) and M2macrophages, transmitting the immunosuppressive ef-fects to other cells in order to activate various immuno-suppressive mechanisms [54]. MSCs express TNFα-stimulated gene/protein 6 (TSG-6) that mediates theregulation of immune inflammation (Fig. 1) [55]. TSG-6is another key factor with a crucial role in tissue re-pair activity of human MSCs that has been proven inmouse models of myocardial infarction, peritonitis,and acute corneal and lung injury [23, 56]. TSG-6 an-tagonizes the binding of CXCL8 to heparin via inter-action with the GAG-binding site of CXCL8, whichinhibits CXCL8-mediated chemotaxis of neutrophils.Furthermore, TSG-6 can prevent the extravasation ofleukocytes (especially neutrophils and macrophages)at the inflammation site [57].In COVID-19 cases, MSCs are able to increase the

lymphocyte count and regulatory DCs to raise their anti-viral characteristic which results in the decreased level ofC-reactive protein and pro-inflammatory cytokines (IL-6, TNFα, IL-8, and so on) that are the main markers ofinflammation and ROS to diminish the inflammationand oxidative stress [58]. On the other hand, MSCs canincrease the level of IL-10 as an anti-inflammatory pro-tein activating regulatory cells such as Tregs (Fig. 1)


Fig. 1 Immunomodulation effect of mesenchymal stem cells on cytokines storm led by COVID-19. When SARS-CoV-2 enters the lungs, it attractsimmune cells to infection areas and localizes inflammation. The lethal unchecked systemic inflammatory response is caused by the secretion oflarge levels of pro-inflammatory cytokines such as interleukin, interferons, chemokines, and other factors by immune effector cells in this infection.After MSC therapy, these cells reach the lung tissue and secrete factors that can modulate the immune system; they also can prevent ROS andeven fibrosis of the lung tissue. Abbreviation: ARDS: acute respiratory distress syndrome, COVID-19: coronavirus disease 2019, CCL: chemokine (C-C motif) ligand, CXCL: chemokine (C-X-C motif) ligand, C3: Complement component 3, CRP: C-reactive protein, DC reg: regulatory dendritic cells,GSCF: granulocyte colony-stimulating factor, HO-1: Heme oxygenase-1, HLA-G5: human leukocyte antigen-G, IL: interleukin, IFN: interferon, IP10:IFN-γ-Inducible Protein 10, IL-1RA: interleukin-1 receptor antagonist, LIF: leukemia inhibitory factor, IDO: Indoleamine 2,3-dioxygenase, MSCs:mesenchymal stem cells, MIP1A: Macrophage Inflammatory Protein 1 Alpha, MCP1: monocyte chemoattractant protein 1, NKCs: natural killer cells,NO: nitric oxide, PERIF: peripheral, PGE2: Prostaglandin E2, ROS: reactive oxygen species, SARS-CoV: severe acute respiratory-associated coronavirus,SOD-3: superoxide dismutase, TSG-6: TNFα-stimulated gene-6, TGF-β: transforming growth factor, Treg: regulatory T


[59]. Therefore, MSCs play a central role in immunehomeostasis by interacting with cytokines, chemokines,and cell surface molecules. Put together, all these immu-nomodulatory features contribute to the extensive po-tential of MSCs in clinical therapies.

MSC-based therapy in COVID-19 patientsThe capacity of MSCs in multilineage differentiation andimmunomodulation signifies that these somatic progeni-tor cells are extremely versatile in many therapeutic appli-cations [60]. In fact, as of April 2016, more than 500MSC-related clinical trials have been recorded on the NIHClinical Trial Database (https://clinicaltrials.gov/) [61].The safety and efficacy of transplanted MSCs for the

alleviation of inflammatory lung diseases appears to bedemonstrated in experimental models [62]. MSCs havebeen extensively used in cell-based therapies from basicresearch to clinical trials [63–65]. Inflammation has beenrecognized to affect several morbid processes in the pul-monary system, which include obstructive diseases suchas chronic obstructive pulmonary diseases (COPD) andasthma, along with restrictive diseases such as idiopathicpulmonary fibrosis (IPF) and (ARDS). The acute andchronic lung injury observed in these diseases always in-volves abnormal immune activity and fibrosis either as acause or a consequence [66, 67]. Similar to most celltherapies, MSC therapy could be useful in lung diseasebecause it has been demonstrated that many intraven-ously delivered MSCs (80–90%) will rapidly reach thelungs when delivered through intravenous injection [68].Following systemic administration, a majority of MSCslodge in the pulmonary vascular bed through unknowninteractions with the capillary endothelial cells. Trackingstudies using labeled MSCs demonstrate that mostMSCs are cleared within 24–48 h although there can belonger persistence of them in injured or inflamed lungs[69]. Several phase I/II clinical trials have been done todetermine the safety of MSC infusions in patientsafflicted with ARDS. In China, Zheng et al. observed noserious adverse events associated with MSC administra-tion in 12 patients with ARDS [70]. Besides, Wilsonet al. showed that a single intravenous MSC infusion upto 106 cells/kg was well tolerated in nine patients withmoderate to severe ARDS [71]. Matthay and colleaguesreported a prospective, double-blind, randomized clinicaltrial evaluating the effect of a single systemic dose ofallogeneic bone marrow-derived MSCs (107 cells/kg) incomparison with placebo (2:1 ratio). This research dem-onstrated that no hemodynamic or respiratory abnormalevents associated with MSC infusion were seen over afollow-up period of 60 days and that the 28-day deathrate was higher in the MSC group relative to the pla-cebo, which was not remarkably different between thegroups [72]. Furthermore, the novel avian-origin

influenza A (H7N9) virus with single-stranded RNA seg-ments and COVID-19 has comparable complications(e.g., ARDS and lung failure), as well as correspondingmulti-organ dysfunction together with inflammatorylung lesions and structural damage [73, 74]. Thus, ad-vances in finding a therapeutic approach for H7N9 in-fection in human beings would be essential for treatingCOVID-19, especially severe ARDS-induced pneumoniathat has presently provoked panic in every corner of theworld [8, 75, 76]. Wilson et al. [71] have recently foundthat the administration of allogeneic MSCs for nine pa-tients with ARDS did not lead to any particular adverseevents such as cardiac arrhythmia, hypoxemia, and ven-tricular tachycardia. MSCs taken from menstrual bloodhave recently become attractive because of easy access,high rate of proliferation, and a non-invasive procedurelacking ethical issues [77–79]. Chen et al. argue thatMSCs are capable of reducing inflammatory effects andavoiding cytokine storm. MSCs are an encouraging toolfor treatment of acute pneumonia for prospective clin-ical application [14]. A recent study in China revealedthat administration of intravenous injection of MSCssignificantly improved the inflammation situation in se-vere COVID-19 patients. Ultimately, the patients withsevere COVID-19 pneumonia survived the worst condi-tion and entered recovery. Also, they said that the levelof TNFα was significantly decreased, while IL-10 in-creased in MSC treatment group [80].It should be mentioned that just a few cell therapy

studies for ARDS and sepsis have reached their primarygoals in randomized investigations [81, 82]. Scientistsapprove that targeted clinical research is essential whilstthe first reports of MSC use for COVID-19 over theearly phase of COVID-19 breakout in China have pre-sented valuable clues that the therapeutic measurescould be rather safe and efficient [83–85]. Few conclu-sions can be derived from these early studies because ofthe low number of subjects (typically ≤ 10) and the ab-sence of adequate control groups [58, 80, 86]. Proper de-sign of clinical trials and the observation of qualityfactors such as the documentation of patients, inclusion/exclusion criteria, classification of treatment approaches,primary and secondary statistics, timing and dosing oftreatments, and comedication are immediately needed[85, 87]. While preliminary results may appear to bepromising, the previous failures of innovative clinical re-search with MSCs as well as the low number of regis-tered MSC products should be kept in mind [88–92].Several problems have been identified in this respect, in-cluding failed upscaling of the product to large-scalesupply and the absence of translation to efficient clinicalapplication (e.g., cell expansion from the starting mater-ial, cell viability problems after thawing, and suboptimaldelivery route) [82, 93–96], which could account for the


https://clinicaltrials.gov/

failure of different studies [88, 89]. A key issue for sustain-able marketing would be the technological adequacy of theproducts and manufacturers in case some of the advancedphase II/III clinical studies show solid evidence supportingthe approval of product in future (as discussed below) [90,91]. The unprecedented dynamics of COVID-19 pandemicas well as the high number of deaths all over the world in-dicate that large-scale manufacturing and comprehensivelogistic capacity are required to supply enough doses ofhigh-quality cellular products in a reproducible andchronological manner [97]. SARS-CoV-2 enters into cellsthrough the recognition of cellular transmembrane proteaseserine 2 (TMPRSS2) and angiotensin I converting enzyme2 receptor (ACE2). ACE2 receptors have been detected inthe heart (endothelium of coronary arteries, myocytes, fi-broblasts, epicardial adipocytes), blood vessels (vascularendothelial and smooth cells), gut (intestinal epithelialcells), lung (tracheal and bronchial epithelial cells, type 2pneumocytes, macrophages), kidney (luminal surface oftubular epithelial cells), brain, and testis [98]. In the humanlung, the wide surface area of alveolar epithelial cells couldaccount for the vulnerability of this organ to negative se-quelae of COVID-19 infiltration. A main point is thatACE2 receptors are largely expressed in type II pneumo-cytes, i.e., small cylinder-shaped cells representing 5% of allpneumocytes [99] that are responsible for the generation ofalveolar surfactant while acting as “stem” cells and progeni-tors of type I pneumocytes (95% of pneumocytes) perform-ing gas exchanges in lungs [100–102].SARS-Cov and SARS-CoV2 bind ACE2 receptors,

leading to membrane fusion and virus penetration intothe cell, thereby causing the downregulation of these re-ceptors [98, 103]. In other words, the virus seems toenter into the cell together with the membrane receptor,which is subsequently removed from the external surfaceof the membrane.The ACE2 gene lies on X chromosome and it has been

shown that potential functional variants of ACE2 genealter its transcriptional activity. Nevertheless, the patternof population distribution influencing differential suscepti-bility to SARS-CoV-2 and the genetic origin of differentialACE2 expression and its functional implications amongdifferent populations are barely known [104]. Hyperten-sion and diabetes mellitus (DM) are the most frequent co-morbid conditions in COVID-19 and both are modulatedby ACE2. Loss of ACE2 disturbs the balance of renin-angiotensin system, impairing vascular function and ex-acerbating cardiovascular complications of diabetes [105].It appears that higher severity of COVID-19 among thosesuffering from high blood pressure and DM could bedriven at least partially by pathological deviations fromthe ACE2 pathway. Accordingly, ACE2 appears to be cru-cial in the outcome of COVID-19as well as the role itplays in susceptibility [106].

A major function of ACE2 has also been proven in in-flammatory processes [107]. Genetic deficiency of ACE2leads to upregulated expression of cytokines, inducingvascular inflammation in ApoE knockout mouse models[108]. In a recent research, ACE2 expression was relatedwith several immune signatures such as markers of Tcells, B cells, and NK cells, as well as interferon responsein various human tissues [109]. These results suggestthat ACE2 not only acts as a receptor of SARS-CoV-2but takes part in mediation of post-infection down-stream processes, including inflammatory responses.Furthermore, the gene expression profile of MSCs showsthat ACE2 and TMPRSS2 are not expressed in thesecells, so MSCs are not infected by a coronavirus. RNA-seq survey to identify 12,500 transplanted MSC duringfollow-up revealed that the cells had not been differenti-ated and remained ACE2 negative. ACE2 expression isobserved in other tissues like the heart, liver, kidney, anddigestive organs [80].Such an expression pattern explains the reason why

infected ICU patients are afflicted not only with ARDSbut also other complications of multiple organ dysfunc-tion syndromes [110]. The mechanisms that account forthe improvement observed following MSC infusion inCOVID-19 patients seem to be indicative of the stronganti-inflammatory activity of these cells [80]. Two recentstudies from China on COVID-19 patients reveal amarked reversal of symptoms even in severe and criticalconditions [58, 80]. Consequently, their clinical re-searches recognize a new remedial strategy and the pres-ence of natural mechanisms capable of defeating acuteinflammatory pneumonia. One study was a case reportof a critically ill COVID-19 patient on a ventilator withprogressive disease despite undergoing intensive therapywith markers showing liver injury. The patient wastreated using allogeneic human umbilical cord MSC(hUC-MSC) and three intravenous infusions of 5 × 107

hUC-MSC 3 days later. Within 4 days of the first cell in-fusion, the patient was detached from the ventilator andwas able to walk. All the parameters under study such ascirculating T lymphocytes returned to normal. Lowlevels of lymphocytes could be due to their sequestrationwithin the inflamed lungs and tissues. No noticeable sideeffects were observed [58].The second study [80] by Leng et al. demonstrated

that intravenous MSC infusion prevents the immunesystem from overactivation and repairs the lung micro-environment affected by SARS-CoV-2 infection even inolder patients. Intravenous infusion of MSCs normallyresults in the accumulation of these cells in the lungsand release of several paracrine factors [111]. MSC infu-sion is useful especially in older people infected withSARS-CoV-2 because this group is more susceptible topneumonia from SARS-CoV-2, resulting in severe


Table

1Overview

ofplanne

dor

ongo

ingstud

iesof

celltherapyforthetreatm

entof

COVID-19

NO

Title

andspon

sor

TrialID

Locatio

nDesign

Prim

aryou

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entstatus

Phase

1.ARand

omized

,Dou

ble-Blind,

Placeb

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ntrolledClinical

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Hop

eBioscien

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neic

Mesen

chym

alStem

Cell

Therapy(HB-ADMSC

s)to

ProvideProtectio

nAgainstCOVID-19

Spon

sor:

Hop

eBioscien

ces

NCT

04348435

Texas,USA

Rand

omized

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-controlled,

doub

le-

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assess

effectiven

essof

HB-alloge

neicadipose-

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mesen

chym

alstem

cells

tosupp

lyim

mun

esupp

ort

againstcoronavirus

illne

ss.N:100.

•Incide

nceof

hospitalization

forCOVID-19

•Incide

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symptom

sassociated

with

COVID-19

Enrolling

byinvitatio

nApril16,2020

Phase2

2.AClinicalTrialtoDetermine

theSafety

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Hop

eBioscien

cesAutolog

ous

Mesen

chym

alStem

Cell

Therapy(HB-ADMSC

s)to

ProvideProtectio

nAgainst

COVID-19

Spon

sor:

Hop

eBioscien

ces

NCT

04349631

Texas,USA

Ope

nlabe

l,sing

le-

center,and

clinicaltrial

toassess

effectiven

ess

ofHB-ADMSC

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prod

uceim

mun

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coronavirusillne

ss.N:56.

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nceof

hospitalization

forCOVID-19

•Incide

nceof

symptom

sassociated

with

COVID-19

Enrolling

byinvitatio

nApril16,2020

Phase2

3.NaturalKillerCell(CYN

K-001)

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Adu

ltsWith

COVID-19(CYN

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COVID-19)

(CYN

K001CO

VID)

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CellularityIncorporated

NCT

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?Ope

nlabe

l,rand

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,ph

aseIcan

assess

the

safety

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ofmultip

ledo

sesof

CYN

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in14

patients.

PhaseIIcanutilize

arand

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,ope

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;multip

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ofCYN

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comparedto

the

controlg

roup

.Upto

72patientsare

enclosed

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inthe

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portionof

thestud

ywith

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omizationratio

.

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ts(AE)

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gApril28,2020

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Phase2

4.Treatm

entof

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iaWith

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(COVID_M

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NCT

04361942

Vallado

lid,Spain

Dou

ble-blind,

placeb

o-controlled,

N:24,

mesen

chym

alstromal

cells,evaluatesafety

andefficacyof

mesen

chym

alstromal

cells

from

alloge

nic

tissuefortreatm

ent

ofacuterespiratory

failure

inpatients

with

COVID-19.

•Prop

ortio

nof

patientswho

have

achieved

with

draw

alof

invasive

mechanical

ventilatio

n•Rate

ofmortality

Recruitin

gApril24,2020

Phase2


Table

1Overview

ofplanne

dor

ongo

ingstud

iesof


entof

COVID-19(Con

tinued)

NO

Title

andspon

sor

TrialID

Locatio

nDesign

Prim

aryou

tcom

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entstatus

Phase

5.Safety

andEffectiven

essof

Mesen

chym

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theTreatm

entof

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iaof

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aviru

sDisease

2019

Spon

sor:

Fuzhou

Gen

eralHospital

NCT

04371601

Fuzhou

,Fujian,China

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nlabe

l,rand

omized

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controlg

roup

:standard

symptom

atic

treatm

entslikeantiviral

(Oseltamivir),hormon

es,

oxygen

therapy,

mechanicalven

tilation,

anddifferent

accessory

therapies;Expe

rimen

tal

grou

p:Onthebasisof

theabove-named

standard

symptom

atic

treatm

entand

supp

ortivemed

ical

aid,

UC-M

SCswere

givenat

106/kg

weigh

t/tim

e,on

ceeach

4days

forfour

times.ivinfusion

was

givenat

intervals

3days

of1stadmission

.

•Chang

esof

oxygen

ation

inde

x(PaO

2/FiO2),blood

gastest

Active,no

trecruitin

gMay

1,2020

Early

Phase1

6.NovelAdo

ptiveCellular

TherapyWith

SARS-CoV

-2SpecificTCellsin

Patients

With

Severe

COVID-19

Spon

sor:

KKWom

en’sandChildren’s

Hospital

NCT

04351659

Sing

apore

Observatio

nal,no

vel

adop

tivecellular

therapywith

SARS-

CoV

-2-spe

cific

Tcells

inpatientswith

severe

COVID-19,N:8

•Successrate

inprod

uctio

nof

SARS-CoV

-2specificT

cells

from

convalescent

dono

r

Recruitin

gApril17,2020

….

7.Bo

neMarrow-Derived

Mesen

chym

alStem

Cell

Treatm

entforSevere

Patients

With

Coron

aviru

sDisease

2019

(COVID-19)

Spon

sor:

Guang

zhou

Institu

teof

Respiratory

Disease

NCT

04346368

Guang

zhou

,Guang

dong

,China

Rand

omized

controlledtrial,

parallel,N=20,

BM-M

SCsin

severe

patientswith

coronavirus

disease19.

•Chang

esof

oxygen

ation

inde

x(PaO

2/FiO2)

•Side

effectsin

theBM

-MSC

streatm

entgrou

p

Not

yetrecruitin

gApril15,2020

Phase1

Phase2

8.Mesen

chym

alStromalCells

fortheTreatm

entof

SARS-

CoV

-2Indu

cedAcute

Respiratory

Failure

(COVID-19

Disease)

Spon

sor:

Baylor

College

ofMed

icine

NCT

04345601

Hou

ston

,Texas,U

SAPilotstud

y,N=30,,BM

-MSC

sforthe

treatm

entof

SARS-CoV

-2indu

cedacute

respiratory

failure

•Incide

nceof

unexpe

cted

adverseeven

ts•Im

proved

oxygen

saturatio

ns≥93%

Not

yetrecruitin

gApril20,2020

Early

Phase1

9.Ph

aseI/

IIClinicalStud

yof

Immun

othe

rapy

Basedon

Ado

ptiveCellTransferas

aTherapeutic

Alternativefor

NCT

04344548

Bogo

ta,C

undinamarca,

Colom

bia

Ope

nlabe

l,sing

legrou

passign

men

t,N=10,alloge

neic

NKtransfer

•Adverse

effectsandsafety

Not

yetrecruitin

gApril14,2020

Phase1

Phase2


Table

1Overview

ofplanne

dor

ongo

ingstud

iesof


entof

COVID-19(Con

tinued)

NO

Title

andspon

sor

TrialID

Locatio

nDesign

Prim

aryou

tcom

eRecruitm

entstatus

Phase

PatientsWith

COVID-19in

Colom

bia

Spon

sor:

Universidad

Nacionald

eColom

bia

10.

NKCellsTreatm

entfor

COVID-19

Spon

sor:

Xinxiang

med

icalun

iversity

NCT

04280224

Xinxiang

,Hen

an,C

hina

Ope

nlabe

l,rand

omized

,N=30,natural

killercells

treatm

entin

pneumon

iapatientsinfected

with

2019

novel

coronavirus

•Im

provem

entof

clinical

symptom

sinclud

ing

duratio

nof

fever

•Im

provem

entof

clinical

symptom

sinclud

ing

respiratory

frequ

ency

Recruitin

gFebruary

21,2020

Phase1

11.

CellThe

rapy

Using

Umbilical

Cord-de

rived

Mesen

chym

alStromalCellsin

SARS-CoV

-2-relatedARD

S(STROMA-CoV

2)Spon

sors:

AssistancePu

blique

-Hôp

itaux

deParis

NCT

04333368

Paris,France

Triple,rando

mized

N=60

patients,20

patientswillbe

cell-

treatedwhe

reas

the

remaining

40patients

willbe

injected

with

aplaceb

oin

additio

nto

thestandard

ofcare.

•Respiratory

efficacy

evaluatedby

theincrease

inPaO2/FiO2ratio

from

baselineto

day7in

the

expe

rimen

talg

roup

comparedwith

the

placeb

ogrou

p[tim

eframe:fro

mbaselineto

day7]

Not

yetrecruitin

gApril3,2020

Phase1

Phase2

12.

ASC

TherapyforPatientsWith

Severe

Respiratory

COVID-19

(ASC

COVID-19)

Spon

sors:

Rigsho

spitalet,Den

mark

NCT

04341610

Cop

enhage

n,Den

mark

Dou

ble-blind

placeb

o-controlled,

rand

omized

,N=40

participants,

alloge

neicadipose-

derived

,mesen

chym

alstem

cells

orplaceb

owillbe

injected

toCOVID-19patients

having

severe

pulm

onarydysfun

ction.

•Chang

esin

clinicalcritical

treatm

entinde

x[tim

eframe:day7fro

mrand

omization]

Not

yetrecruitin

gApril10,2020

Phase1

Phase2

13.

Safety

andEfficacyof

CAStem

forSevere

COVID-19Associated

With

/With

outARD

SSpon

sors:

Chine

seAcade

myof

Sciences

NCT

04331613

Beijing

,China

Ope

nlabe

l,sing

legrou

p,CAStem

will

beinjected

tosevere

COVID-19associated

with

orwith

outacute

respiratory

distress

synd

rome(ARD

S),

CAStem

willbe

administeredivroute.

•Adverse

reactio

n(AE)

and

severe

adversereactio

n(SAE)

•Freq

uencyof

adverse

reactio

n(AE)

andsevere

adversereactio

n(SAE)

with

in28

days

after

treatm

ent

•Chang

esof

lung

imaging

exam

inations

•Evaluatio

nby

chestCT

Recruitin

gApril3,2020

Phase1

Phase2

14.

APh

aseI/IIStudy

ofUniversal

Off-the-shelfNKG

2D-ACE2

CAR-NKCellsforTherapyof

NCT

04324996

Cho

ngqing

,China

Interven

tional,

quadruple,rand

omized

,aph

aseI/IIstudy

of

•Clinicalrespon

se[tim

eframe:up

to28

days]

•Side

effectsin

the

Recruitin

g,March

27,2020

Phase1

Phase2


Table

1Overview

ofplanne

dor

ongo

ingstud

iesof


entof

COVID-19(Con

tinued)

NO

Title

andspon

sor

TrialID

Locatio

nDesign

Prim

aryou

tcom

eRecruitm

entstatus

Phase

COVID-19

Spon

sors:

Cho

ngqing

PublicHealth

Med

icalCen

ter

universalo

ff-the-shelf

NKG

2D-ACE2

CAR-NK

cells

secretingIL15

supe

ragon

istand

GM-CSF-neutralizing

scFv

fortreatm

entof

COVID-19

treatm

entgrou

p[tim

eframe:up

to28

days]

15.

ClinicalResearch

ofHum

anMesen

chym

alStem

Cellsin

theTreatm

entof

COVID-19

Pneumon

iaSpon

sors:

PurenHospitalA

ffiliatedto

Wuh

anUniversity

ofScience

andTechno

logy

NCT

04339660

Wuh

an,H

ubei,C

hina

Triple,rando

mized

,N=30

Hum

anmesen

chym

alstem

cells

inthe

treatm

entof

COVID-19

pneumon

ia

•Theim

mun

efunctio

n(TNFα,IL-1β

,IL-6,TG

F-β,

IL-8,PCT,CRP)

•Bloo

doxygen

saturatio

n

Recruitin

gApril9,2020

Phase1

Phase2

16.

Stem

CellEdu

catorTherapy

TreattheViralInflammation

Causedby

Severe

Acute

Respiratory

Synd

rome

Coron

aviru

s2

Spon

sor:

Tianhe

Stem

Cell

Biotechn

olog

iesInc.

NCT

04299152

?Rand

omized

=20

Two-arm,p

artially

masked,

sing

lecenter

clinicalstud

yto

assess

thesafety,feasibility,

andefficacyof

SCE

therapyforthe

treatm

entof

patients

with

SARS-CoV

-2.

•Determinethenu

mbe

rof

COVID-19patients

who

wereun

ableto

completeSC

Etherapy

Not

yetrecruitin

gMarch

6,2020

Phase2

17.

Treatm

entWith

Mesen

chym

alStem

CellsforSevere

Coron

aVirusDisease

2019(COVID-19)

Spon

sors:

Beijing

302Hospital

NCT

04288102

Hub

ei,C

hina

Prospe

ctive,do

uble-

blind,

multicen

ter,

rand

omized

trial

N=60

severe

COVID-19patients

rand

omized

2:1to

3ivdo

sesof

mesen

chym

alstem

cells

(MSC

s)or

placeb

o(saline).

•Im

provem

enttim

eof

clinicalcriticaltreatmen

tinde

xwith

in28

days

•Side

effectsin

theMSC

streatm

entgrou

p

Recruitin

g;Aug

ust31,2020/

Decem

ber31,2020

Phase2

18.

TherapyforPn

eumon

iaPatientsinfected

by2019

NovelCoron

aviru

sSpon

sors:

PurenHospitalA

ffiliatedto

Wuh

anUniversity

ofScience

andTechno

logy

NCT

04293692

China,H

ubei

Triple-blinde

dRC

T.N=48

with

mod

erateto

severe

COVID-19

rand

omized

toUC-

MSC

sor

placeb

o

•Size

oflesion

area

bychestim

aging

•Bloo

doxygen

saturatio

n

Recruitin

g;May

12,020/Feb

1,2021

Not

App

licable

19.

ClinicalTrialfor

Hum

anMesen

chym

alStem

Cellsin

theTreatm

entof

Severe

NovelCoron

aviru

sPn

eumon

ia(COVID-19)

Spon

sor:

Chine

sePLAGen

eralHospital

ChiCT

R2000030138

Hainan,China

Rand

omized

,dou

ble-

blind,

placeb

o-controlledtrial

N=60

rand

omized

tohu

man

umbilical

cord

mesen

chym

alstem

cells

(UC-M

SC),

•Clinicalinde

xNot

yetrecruitin

g;From

2020-02-24

to2020-05-31

Phase2


Table

1Overview

ofplanne

dor

ongo

ingstud

iesof


entof

COVID-19(Con

tinued)

NO

Title

andspon

sor

TrialID

Locatio

nDesign

Prim

aryou

tcom

eRecruitm

entstatus

Phase

orplaceb

oin

COVID-19.

20.

Mesen

chym

alStem

Cell

Treatm

entforPn

eumon

iaPatientsInfected

With

2019

NovelCoron

aviru

sSpon

sors:

Beijing

302Hospital

NCT

04252118

China

Ope

n-labe

l,no

n-rand

omized

interven

tionstud

yN=20

patientswith

COVID-19

Treatm

ent:N=10

treatedwith

MSN

N=10

treatedwith

conven

tionaltreatmen

t.

•Size

oflesion

area

bychestradiog

raph

orCT

(tim

eframeday28)

•Side

effectsday(tim

eframeday180)

Recruitin

g;Dec

2020/

Decem

ber,2021

Phase1

21.

APilotClinicalStud

yon

Inhalatio

nof

Mesen

chym

alStem

CellsExosom

esTreatin

gSevere

NovelCoron

aviru

sPn

eumon

iaSpon

sors:

RuijinHospital

NCT

04276987

China

Ope

n-labe

lpilotstud

yN=30

with

severe

COVID-19,

Sing

legrou

passign

men

t

•Adverse

reactio

ns•Timeto

clinical

improvem

ent(28days)

Not

yetrecruitin

g;Estim

ated

stud

ycompletion:

July31,2020

Phase1

22.

Stud

yof

Hum

anUmbilical

CordMesen

chym

alStem

Cells

intheTreatm

entof

Novel

Coron

aviru

sSevere

Pneumon

iaSpon

sor:

Wuh

anUnion

Hospital,China

NCT

04273646

China,H

ubei

Ope

n-labe

l,rand

omized

stud

yN=48

with

severe

COVID-19;

Rand

omized

tostem

celltherapy

orplaceb

o

•Pn

eumon

iaseverity

inde

x•Oxyge

natio

ninde

x(PaO

2/FiO2)

Not

yetrecruitin

g;June

302,020/Feb

15,2022

Not

App

licable

23.

Safety

andefficacyof

umbilical

cord

bloo

dmon

onuclear

cells

cond

ition

edmed

ium

inthe

treatm

entof

severe

and

critically

novelcoron

aviru

spn

eumon

ia(COVID-19):a

rand

omized

controlledtrial

Spon

sor:

Xiangyang1stPeop

le’sHospital

ChiCT

R2000029569

China,H

ubei

Ope

nlabe

lN=30

with

severe

andcriticalC

OVID-

19.Rando

mized

tostem

cellor

conven

tional

treatm

ent.

•PSI

Not

recruitin

gFrom

2020-02-05

to2021-04-30

0

24.

UmbilicalCord(UC)-Derived

Mesen

chym

alStem

Cells(M

SCs)

Treatm

entforthe2019-novel

Coron

aviru

s(nCOV)

Pneumon

iaSpon

sor:

ZhiYon

gPeng

NCT

04269525

China,H

ubei

Ope

nlabe

lN=10,serious

orcriticalC

OVID-19

•Oxyge

natio

ninde

xday14

•Partialarterialo

xyge

npressure

(PaO

2)/oxygen

concen

tration(FiO2)

Recruitin

g;April30,2020/

Sept

30,2020

Phase2

25.

ClinicalStud

yforHum

anMen

strualBloo

d-Derived

Stem

Cellsin

theTreatm

entof

Acute

NovelCoron

aviru

sPn

eumon

ia(COVID-19)

Spon

sor:

TheFirstAffiliatedHospital,

College

ofMed

icine,Zh

ejiang

ChiCT

R2000029606

Zhejiang

,China

Ope

n-labe

l,5-arm

stud

y.Criticallyillpatients

treatedwith

stem

cells,con

ventional

treatm

ent,artificial

liver

therapy,artificial

liver

therapy+stem

•Mortalityin

patients

Recruitin

g;From

2020-01-15

to2022-12-31

0


Table

1Overview

ofplanne

dor

ongo

ingstud

iesof


entof

COVID-19(Con

tinued)

NO

Title

andspon

sor

TrialID

Locatio

nDesign

Prim

aryou

tcom

eRecruitm

entstatus

Phase

University

cells,o

rconven

tional

treatm

ent

26.

Canceledby

theinvestigator

ClinicalStud

yforUmbilical

CordBloo

dMon

onuclear

Cellsin

theTreatm

entof

Acute

NovelCoron

aviru

sPn

eumon

ia(COVID-19)

Spon

sor:

Guang

zhou

rebo

rnhe

alth

managem

entconsultatio

nco.,LTD

ChiCT

R2000029812

Guang

dong

,China

Ope

nlabe

l,N=60

patientswith

COVID-19rand

omized

toum

bilicalcord

bloo

dmon

onuclear

cells

orconven

tional

treatm

ent

•Timeto

disease

recovery

Not

recruitin

g;From

2020-02-20

to2021-02-20

0

27.

ClinicalStud

yof

CordBloo

dNKCellsCom

bine

dwith

CordBloo

dMesen

chym

alStem

Cellsin

theTreatm

ent

ofAcute

NovelCoron

aviru

sPn

eumon

ia(COVID-19)

Spon

sor:

Guang

zhou

Rebo

rnHealth

Managem

entCon

sultatio

nCo.,LTD

ChiCT

R2000029817

Guang

dong

,china

Ope

nlabe

l,N=60

patientswith

COVID-19rand

omized

tohigh

-doseNKcells,

andmesen

chym

alstem

cells,con

ventional

dose

NKcells

and

mesen

chym

alstem

cells,o

rpreven

tive

dose

NKcells

and

mesen

chym

alstem

cells.

•Timeto

disease

recovery

Not

recruitin

g;From

2020-02-20

to2021-02-20

0

28.

Canceledby

theinvestigator

ClinicalStud

yforUmbilical

CordBloo

dPlasmain

the

Treatm

entof

Acute

Novel

Coron

aviru

sPn

eumon

ia(COVID-19)

Spon

sor:

Guang

zhou

rebo

rnhe

alth

managem

entconsultatio

nco.,LTD

ChiCT

R2000029818

Guang

dong

,china

Ope

nlabe

l,N=60

patientswith

COVID-19rand

omized

tohigh

-doseNKcells,

andmesen

chym

alstem

cells,

conven

tionald

ose

NKcells

and

mesen

chym

alstem

cells,o

rpreven

tive

dose

NKcells

and

mesen

chym

alstem

cells.

•Timeto

disease

recovery

Not

recruitin

g;From

2020-02-20

to2021-02-20

0

29.

Clinicaltrialsof

mesen

chym

alstem

cells

forthetreatm

ent

ofpn

eumon

itiscaused

byno

velcoron

aviru

spn

eumon

ia(COVID-19)

Spon

sor:

Institu

teof

BasicMed

ical

Sciences,C

hine

seAcade

my

ofMed

icalSciences

ChiCT

R2000029990

Beijing

,Hub

ei,Shang

hai

N=120,severe

COVID-19

rand

omized

toMSC

sor

saline

•Im

proved

respiratory

system

functio

n(blood

oxygen

saturatio

n)recovery

time

Recruitin

g;From

2020-01-30

to2020-03-31

Phase1–2

30.

Umbilicalcord

Wharton

’sJelly

derived

mesen

chym

alstem

ChiCT

R2000030088

Beijing

,China

Type

ofstud

yno

tstated

.Blinding

not

•Thenu

cleicacid

ofthe

novelcoron

aviru

sis

Not

yetrecruitin

g;From

2020-03-01

to0


Table

1Overview

ofplanne

dor

ongo

ingstud

iesof


entof

COVID-19(Con

tinued)

NO

Title

andspon

sor

TrialID

Locatio

nDesign

Prim

aryou

tcom

eRecruitm

entstatus

Phase

cells

inthetreatm

entof

severe

novelcoron

aviru

spn

eumon

ia(COVID-19)

Spon

sor:

TheSixthMed

icalCen

terof

PLAGen

eralHospital

stated

N=40

with

criticalC

OVID-19.

Treatm

ent:stem

cells

(n=20)

40mlsaline(n=20)

negative

•CTscan

ofgrou

nd-glass

shadow

disapp

eared

2021-12-31

31.

Safety

andeffectiven

essof

human

umbilicalcord

mesen

chym

alstem

cells

inthetreatm

entof

acute

respiratory

distress

synd

romeof

severe

novelcoron

aviru

spn

eumon

ia(COVID-19)

Spon

sor:

TheFirstAffiliatedHospitalo

fNanchangUniversity

ChiCT

R2000030116

Jiang

xi,C

hina

N=16

with

criticalC

OVID-19;

different

stem

cell

doses

•Timeto

leaveventilator

onday28

afterreceiving

MSC

sinfusion

Recruitin

g;From

2020-02-01

to2020-08-31

N/A

32.

Canceledby

theinvestigator

Clinicalstud

yof

mesen

chym

alstem

cells

intreatin

gsevere

novelcoron

aviru

spn

eumon

ia(COVID-19)

Spon

sor:

TheFirstAffiliatedHospital

ofNanchangUniversity

ChiCT

R2000030224

Hub

ei,C

hina

Clinicalstud

y,op

enlabe

lSevere

orcritical

COVID-19patients;

N=32

stratified

severityand

rand

omized

tostem

cells

orinjectionwith

saline

•Severalp

rimary

endp

oints—

notspecified

Not

yetrecruitin

g;From

2020-02-14

to2020-05-31

N/A

33.

Umbilicalcord

mesen

chym

alstem

cells

(hUC-MSC

s)in

the

treatm

entof

high

riskno

vel

coronaviruspn

eumon

ia(COVID-19)

patients

Spon

sor:

NanjingSecond

Hospital

ChiCT

R2000030300

Jiang

su,C

hina

Asing

le-cen

ter,

sing

le-arm

,prospe

ctive,op

enclinicalstud

yN=9.UC-M

SCswill

beinjected

toCOVID-19patients.

•Timeto

diseaserecovery;

•Exacerbatio

n(transferto

RICU)tim

e

Recruitin

g;From

2020-02-19

to2021-02-20

Phase1

34.

Stem

CellEdu

catorTherapy

TreattheViralInflammation

Causedby

Severe

Acute

Respiratory

Synd

rome

Coron

aviru

s2

Spon

sor:

Tianhe

Stem

Cell

Biotechn

olog

iesInc.

NCT

04299152

?Thisisaprospe

ctive,

two-arm,p

artially

masked,

sing

le-

center

clinicalstud

y.N=20

patientswith

SARS-CoV

-2un

dergoing

either

stem

celltherapy

orconven

tional

treatm

ent

•Determinethenu

mbe

rof

COVID-19patientswho

wereun

ableto

complete

SCEtherapy

•Thefeasibility

willbe

evaluatedby

thenu

mbe

rof

COVID-19patientswho

wereun

ableto

complete

SCEtherapy

Not

yetrecruitin

g;Nov

2020

Phase2

35.

NovelCoron

aviru

sIndu

ced

Severe

Pneumon

iaTreated

byDen

talP

ulpMesen

chym

alStem

Cells

Spon

sor:

CAR-T(Shang

hai)

Biotechn

olog

yCo.,Ltd.

NCT

04302519

?Sing

le-arm

stud

yN=24.Patients

with

severe

COVID-19assign

edto

stem

celltherapy.

•Disappe

artim

eof

grou

nd-

glassshadow

inthelung

s[tim

eframe:14

days]

Not

yetrecruitin

g,July2021

phase1


Table

1Overview

ofplanne

dor

ongo

ingstud

iesof


entof

COVID-19(Con

tinued)

NO

Title

andspon

sor

TrialID

Locatio

nDesign

Prim

aryou

tcom

eRecruitm

entstatus

Phase

36.

Treatm

entof

COVID-19

PatientsUsing

Wharton

’sJelly-M

esen

chym

alStem

Cells

Spon

sor:

Stem

CellsArabia

NCT

04313322

Jordan

Sing

le-arm

stud

yN=5with

COVID-19

•Im

provem

entof

clinical

symptom

s;•Adverse

even

ts;

•ViralR

NA

Recruitin

g.Sept

2020

Phase1

37.

NestCell®Mesen

chym

alStem

CelltoTreatPatientsWith

Severe

COVID-19Pn

eumon

ia(HOPE)

Spon

sor:

Azidu

sBrazil

NCT

04315987

Not

stated

N=24

patients

•Disappe

artim

eof

grou

nd-

glassshadow

inthelung

sNot

yetrecruitin

g.June

2020

Phase1–2

38.

Stud

ytheeffect

ofintraven

ous

injectionof

dentalpu

lpmesen

chym

alstem

cells

intreatm

entof

patientswith

COVID-19pn

eumon

iaSpon

sor:

Kerm

anUniversity

ofMed

ical

Sciences

IRCT

20140911019125N6

Iran,Kerm

anClinicaltrialw

ithou

tcontrolg

roup

,commun

itybased,

notblinde

d,no

n-rand

omized

controlledstud

y.Den

talp

ulp

mesen

chym

alstem

cells

willbe

injected

intraven

ouslyat

one

time.

•Pu

lmon

arycond

ition

•Expression

ofnu

cleicacid

ofvirus

•Lymph

ocytecoun

t•Patientsclinicalsign

s

Recruitin

g,2020-04-04,

Phase2

39.

Evaluatio

nof

theefficacyand

safety

ofcord-derived

mesen

chym

alstem

cell

transplantationin

the

treatm

entof

COVID-19

Spon

sor:

MOM

research

and

inno

vatio

ncenter

IRCT

20140528017891N8

Iran,Tehran

Thisstud

ywas

aparallelrando

mized

controlledclinicaltrial

stud

yde

sign

.The

samplesize

ofthe

stud

yis10

corona

viruspatientsthat

willbe

assign

edto

interven

tionand

controlg

roup

susingsimple

rand

omization

metho

d.

•Death

•Evaluatio

nof

Pneumon

iaSeverityInde

x•Evaluatio

nof

oxygen

supp

lyinde

x•C-Reactiveprotein

•Pro-calcito

nin

•Lymph

ocytecoun

t•Cou

ntingof

CD3+,

CD4+andCD8+Tcells

•+CD4+/CD8ratio

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provepn

eumon

iaevaluatedby

CTscan

Recruitm

entcomplete,

2020-03-24

Phase3

40.

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chym

alstem

cellutilizatio

nin

redu

cing

complications

and

enhancingpn

eumon

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aling

inpatientsinfected

with

2019-

nCoV

(phase

Iclinicaltrial)

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sor:

Bagh

eiatallahUniversity

ofMed

icalSciences

IRCT

20200325046860N2

Iran,Tehran

Expe

rimen

tal:

mesen

chym

alstem

cell(M

SC)treatm

ent

grou

pconven

tional

treatm

entplus

MSC

participantswill

receiveconven

tional

treatm

entplus

3tim

esof

MSC

s(7.0×10E7

MSC

sintraven

ouslyat

day

0,day3,day6),5

•Respiratory

functio

nof

patients

Recruitm

entcomplete,

2020-04-01

Phase1


Table

1Overview

ofplanne

dor

ongo

ingstud

iesof


entof

COVID-19(Con

tinued)

NO

Title

andspon

sor

TrialID

Locatio

nDesign

Prim

aryou

tcom

eRecruitm

entstatus

Phase

patients,clinical

trialp

hase

INo

interven

tion:

conven

tional

controlg

roup

with

outMSC

therapybu

tconven

tional

treatm

entshou

ldbe

received

.

41.

ACom

parison

Stud

yon

Safety

&Efficacyof

Repe

ated

Intraven

ousInfusion

ofAlloge

neicMesen

chym

alStem

Cellfrom

Differen

tSources

inARD

SPatients:ARand

omized

,Dou

bleBlind,

ClinicalTrialP

hase

IISpon

sor:

Bagh

eiatallahUniversity

ofMed

icalSciences

IRCT

20080901001165N44

Iran,Tehran

Aun

controlled,

parallel,do

uble-

blind,

rand

omized

,clinicaltrial,ph

ase

II4grou

ps,3

patientsin

each

grou

p,totally

12patients4cell

interven

tional

grou

ps12

mon

ths

follow-up

•Num

bersof

patients

occurred

anyun

expe

cted

severe

adverseeven

ts(includ

ingall-cause

deaths)

Recruitin

g,2020-03-29

Phase1–2

42.

Mesen

chym

alStem

CellThe

rapy

forAcute

Respiratory

Distress

Synd

romein

Coron

aviru

sInfection:APh

ase2–3Clinical

Trial

Spon

sor:

Iranian

academ

iccenter

for

educationcultu

reandresearch

IRCT

20200217046526N2

Iran,Tehran

Acontrolled

rand

omized

clinical

trialp

hase

2–3

•Adverse

even

tsassessmen

t•Bloo

doxygen

saturatio

nRecruitin

g,2020-04-05

Phase2–3

43.

Cellthe

rapy

inpatientswith

coronavirus19using

mesen

chym

alstem

cells

Spon

sor:

BarekatPh

armaceuticalGroup

IRCT

20190717044241N2

Iran,Tehran

One

grou

pwith

10un

controlled

patients,Ph

aseI

clinicaltrial

•Clinicalrespon

se•partialarterialo

xyge

npressure

(PaO

2)&

oxygen

concen

tration

(FiO2)

Recruitin

g,2020-04-20

Phase1


respiratory distress and mortality because of immunose-nescence [112–114]. It is proved that the intravenous in-fusion of MSCs is a safe and efficient orientation fortreating patients infected by COVID-19 pneumonia, in-cluding older people with severe pneumonia [115].Nowadays, several clinical trials using stem cell therapy

to treat the coronavirus have been recorded from China,Iran, USA, Columbia, France, Denmark, Jordan, and SaudiArabia, which are listed at www.clinicaltrials.gov, www.chictr.org, www.irct.ir and summarized in Table 1.

Concussion and future perspectiveGiven the prevalence of COVID-19 and its complica-tions such as cytokine storm, which is followed by ARDSand death of patients, finding a way to treat and improvethe patients is of high importance [116]. As mentionedin this paper, there is no specific therapy for this virusand supportive therapies as well as non-specific antiviraldrugs are mainly used for this purpose. Today, cell ther-apy is a modern method for treating a variety of diseasesand several studies have been conducted in recentmonths to treat the SARS-CoV-2 virus using stem cells,suggesting the application of MSCs or immune cellssuch as NK cells [33, 117, 118]. According to researchon MSC-based therapy, the safety and immunomodula-tory role of MSCS in ARDS have been approved [82].MSCs can secrete factors that improve the lung micro-environment, inhibit immune system overactivation,promote tissue repair, rejuvenate alveolar epithelial cells,inhibit pulmonary counteracting fibrosis, or improvefunction in damaged lung tissue because of SARS-CoV-2infection [119, 120].Many issues related to the application of MSCs, in-

cluding the ideal dose and optimum timing of MSC de-livery, should be further explored. In several animalmodels of human diseases, the use of secretory exo-somes from MSCs has been claimed to mimic the bene-ficial effects of MSCs in antiviral therapy for influenzavirus, reducing virus replication in lungs and virus-induced release of pro-inflammatory cytokines [121,122]. Experimental studies and ongoing randomized tri-als will play an essential role in the clarification of thetherapeutic potential of MSCs, which further our under-standing of how MSCs interact with lung tissue infectedby SARS-CoV-2.

AcknowledgementsNot applicable.

Authors’ contributionsMK, JV, and MS contributed to the concept of the review. MK, JV, and MSwere responsible for the reference selection and writing of the manuscript.MK and MS contributed to the critical review of the manuscript. All authorsread and approved the final manuscript.

FundingThis work was supported by the Tehran University of Medical Sciences.

Availability of data and materialsNot applicable.

Ethics approval and consent to participateNot applicable.

Consent for publicationNot applicable.

Competing interestsThe authors declare that they have no competing interests.

Author details1Department of Tissue Engineering and Applied Cell Sciences, Faculty ofAdvanced Technologies in Medicine, Tehran University of Medical Sciences,Tehran, Iran. 2Cell-Based Therapies Research Center, Digestive DiseaseResearch Institute, Tehran University of Medical Sciences, Tehran, Iran.

Received: 7 May 2020 Revised: 30 June 2020Accepted: 23 July 2020

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