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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: m_saleh@razi.tums.ac.ir1Department 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
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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)
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 3 of 19
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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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 4 of 19
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[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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 5 of 19
https://clinicaltrials.gov/
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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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 6 of 19
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Table
1Overview
ofplanne
dor
ongo
ingstud
iesof
celltherapyforthetreatm
entof
COVID-19
NO
Title
andspon
sor
TrialID
Locatio
nDesign
Prim
aryou
tcom
eRecruitm
entstatus
Phase
1.ARand
omized
,Dou
ble-Blind,
Placeb
o-Co
ntrolledClinical
TrialtoDeterminetheSafety
andEfficacyof
Hop
eBioscien
cesAlloge
neic
Mesen
chym
alStem
Cell
Therapy(HB-ADMSC
s)to
ProvideProtectio
nAgainstCOVID-19
Spon
sor:
Hop
eBioscien
ces
NCT
04348435
Texas,USA
Rand
omized
,placebo
-controlled,
doub
le-
blinde
d,clinicaltrialto
assess
effectiven
essof
HB-alloge
neicadipose-
derived
mesen
chym
alstem
cells
tosupp
lyim
mun
esupp
ort
againstcoronavirus
illne
ss.N:100.
•Incide
nceof
hospitalization
forCOVID-19
•Incide
nceof
symptom
sassociated
with
COVID-19
Enrolling
byinvitatio
nApril16,2020
Phase2
2.AClinicalTrialtoDetermine
theSafety
andEfficacyof
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
sto
prod
uceim
mun
esupp
ortagainst
coronavirusillne
ss.N:56.
•Incide
nceof
hospitalization
forCOVID-19
•Incide
nceof
symptom
sassociated
with
COVID-19
Enrolling
byinvitatio
nApril16,2020
Phase2
3.NaturalKillerCell(CYN
K-001)
Infusion
sin
Adu
ltsWith
COVID-19(CYN
K-001-
COVID-19)
(CYN
K001CO
VID)
Spon
sor:
CellularityIncorporated
NCT
04365101
?Ope
nlabe
l,rand
omized
,ph
aseIcan
assess
the
safety
andeffectivity
ofmultip
ledo
sesof
CYN
K-001(days1,4,and7)
in14
patients.
PhaseIIcanutilize
arand
omized
,ope
n-labe
lde
sign
;multip
ledo
ses
ofCYN
K-001are
comparedto
the
controlg
roup
.Upto
72patientsare
enclosed
with
inthe
phaseIIclinicaltrial
portionof
thestud
ywith
a1:1
rand
omizationratio
.
•Freq
uencyandseverityof
adverseeven
ts(AE)
•Timeto
clearanceof
SARS-CoV
-2
Not
yetrecruitin
gApril28,2020
Phase1
Phase2
4.Treatm
entof
Severe
COVID-19
Pneumon
iaWith
Alloge
neic
Mesen
chym
alStromalCells
(COVID_M
SV)(COVID_M
SV)
Spon
sor:
Redde
TerapiaCelular
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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 7 of 19
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Table
1Overview
ofplanne
dor
ongo
ingstud
iesof
celltherapyforthetreatm
entof
COVID-19(Con
tinued)
NO
Title
andspon
sor
TrialID
Locatio
nDesign
Prim
aryou
tcom
eRecruitm
entstatus
Phase
5.Safety
andEffectiven
essof
Mesen
chym
alStem
Cellsin
theTreatm
entof
Pneumon
iaof
Coron
aviru
sDisease
2019
Spon
sor:
Fuzhou
Gen
eralHospital
NCT
04371601
Fuzhou
,Fujian,China
Ope
nlabe
l,rand
omized
,N:60,
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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 8 of 19
-
Table
1Overview
ofplanne
dor
ongo
ingstud
iesof
celltherapyforthetreatm
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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 9 of 19
-
Table
1Overview
ofplanne
dor
ongo
ingstud
iesof
celltherapyforthetreatm
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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 10 of 19
-
Table
1Overview
ofplanne
dor
ongo
ingstud
iesof
celltherapyforthetreatm
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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 11 of 19
-
Table
1Overview
ofplanne
dor
ongo
ingstud
iesof
celltherapyforthetreatm
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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 12 of 19
-
Table
1Overview
ofplanne
dor
ongo
ingstud
iesof
celltherapyforthetreatm
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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 13 of 19
-
Table
1Overview
ofplanne
dor
ongo
ingstud
iesof
celltherapyforthetreatm
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
•Im
provepn
eumon
iaevaluatedby
CTscan
Recruitm
entcomplete,
2020-03-24
Phase3
40.
Mesen
chym
alstem
cellutilizatio
nin
redu
cing
complications
and
enhancingpn
eumon
iahe
aling
inpatientsinfected
with
2019-
nCoV
(phase
Iclinicaltrial)
Spon
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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 14 of 19
-
Table
1Overview
ofplanne
dor
ongo
ingstud
iesof
celltherapyforthetreatm
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
Kavianpour et al. Stem Cell Research & Therapy (2020) 11:404 Page 15 of 19
-
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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