key: cord-0845507-kco6mouk
authors: Song, Na; Wakimoto, Hiroaki; Rossignoli, Filippo; Bhere, Deepak; Ciccocioppo, Rachele; Chen, Kok‐Siong; Khalsa, Jasneet Kaur; Mastrolia, Ilenia; Samarelli, Anna Valeria; Dominici, Massimo; Shah, Khalid
title: Mesenchymal stem cell immunomodulation: In pursuit of controlling COVID‐19 related cytokine storm
date: 2021-03-07
journal: Stem Cells
DOI: 10.1002/stem.3354
sha: 283071fdaac99ff4543819360e50528728a78939
doc_id: 845507
cord_uid: kco6mouk

The Coronavirus disease 2019 (COVID‐19) pandemic has grown to be a global public health crisis with no safe and effective treatments available yet. Recent findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the coronavirus pathogen that causes COVID‐19, could elicit a cytokine storm that drives edema, dysfunction of the airway exchange, and acute respiratory distress syndrome in the lung, followed by acute cardiac injury and thromboembolic events leading to multiorgan failure and death. Mesenchymal stem cells (MSCs), owing to their powerful immunomodulatory abilities, have the potential to attenuate the cytokine storm and have therefore been proposed as a potential therapeutic approach for which several clinical trials are underway. Given that intravenous infusion of MSCs results in a significant trapping in the lung, MSC therapy could directly mitigate inflammation, protect alveolar epithelial cells, and reverse lung dysfunction by normalizing the pulmonary microenvironment and preventing pulmonary fibrosis. In this review, we present an overview and perspectives of the SARS‐CoV‐2 induced inflammatory dysfunction and the potential of MSC immunomodulation for the prevention and treatment of COVID‐19 related pulmonary disease.

respiratory distress syndrome (ARDS), septic shock, and/or multiple organ failure. 1, 4 Therefore, a comprehensive understanding of how these severe symptoms develop could reveal promising strategies for therapeutic intervention.

Severe COVID-19 infection is characterized by pneumonia, lymphopenia, and a cytokine storm. 5 This latter phenomenon is characterized by an excessive inflammatory response, caused by a dysregulated immune system, which begins at a local site and then spills over to the systemic circulation, affecting multiple organs. Cytokine storm is not specific to SARS-CoV-2 infection; it has been also observed initially in the context of graft-vs-host disease, as well as other infectious diseases caused by cytomegalovirus, Epstein-Barr virus, streptococcus, influenza virus, variola virus, and SARS-CoV. 6 Moreover, it was also observed in noninfectious diseases and the corresponding therapeutic interventions. 7 SARS-CoV-2 infection induces the activation of both innate and adaptive immune responses, 5, 8 and tumor necrosis factor-α (TNF-α). 4, 5, 8, 9 A retrospective study of 150 COVID-19 patients indicated that elevated ferritin and IL-6 due to hyperinflammation might be involved in mortality risk. 11 Substantially, high levels of cytokines may lead to cytokine release syndrome (CRS), causing shock and tissue damage in vital organs. 5, 10 In particular, cytokine storm in COVID-19 patients has been shown to aggravate acute cardiac injury comprising of myocarditis, acute heart failure, and cardiac arrest. 12 These markers of inflammation detected in the serum, are most likely the end result of a chain of events starting in the lung itself. This local immunological cascade is generally crucial to immunopathology of other severe infections affecting deep tissues of the respiratory tract, such as avian influenza virus or severe primary influenza virus infections. 13, 14 Specifically, the cytokine storm in the lung is a hallmark of SARS-CoV-2 pathogenesis, resulting in extensive pulmonary pathology including increased permeability of lung endothelial and epithelial cells, interstitial edema, diffuse alveolar damage, dysfunction of air-exchange, and ARDS ( Figure 1 ). 5, 15, 16 Usually, CRS is initiated by macrophages, dendritic cells (DCs), natural killer (NK) cells and T cells, owing to pathogen-associated molecular pattern activation. 17 Indeed, it has been reported that bronchoalveolar fluid from patients 

This study provides the cutting edge knowledge on the emerging role of mesenchymal stem cell in our fight against COVID-19, and will have implications on developing innovative therapies for COVID-19 infected patients with severe COVID-19 had high concentrations of chemokines CCL2 and CCL7, which are potent monocyte recruiters, thus suggesting a role for those cells in the pathophysiology of the disease. Notably, mononuclear phagocytes represented 80% of bronchoalveolar fluid cells in severe COVID-19 cases, 60% in mild cases, and only 40% in healthy controls. In severe COVID-19 patients, there was also depletion of tissue macrophages, an increase in inflammatory monocyte derived macrophages 18, 19 and a general increment in the number of neutrophils and leukocytes. Moreover, the prominent lymphopenia, which develops in most COVID-19 patients, indicates an impairment of immune system and further supports the evidence of innate immunity as initiator of the cytokine storm. 20 Nonetheless, adaptive immune cells, namely T lymphocytes, may drive inflammation at later disease stages, 21 thus secondary hemophagocytic lymphohistiocytosis may be another pathophysiological feature of notable attention. 9, 21 However, while the general concept of an excessive or uncontrolled release of pro-inflammatory cytokines is well known, there remains lack of good understanding of the molecular events that unleash the cytokine storm as well as its respective prevention and therapeutic strategies. 6 It has been proposed that SARS-CoV-2 binds to the Toll-like receptors (TLRs) leading to the synthesis and release of proinflammatory IL-1, IL-6, and TNF-α as main mediators of the inflammation pathway. 22, 23 Indeed, after the binding to the TLR, myeloid differentiation primary response 88 (MyD88) or TIR domaincontaining adapter-inducing interferon-β (TRIF) activates tumor necrosis factor receptor associated factor 6 (TRAF6), which in turn stimulates caspase 1, inducing the cleavage of pro-IL-1 and the activation of the inflammasomes as well as tumor growth factorβ-activated kinase and I kappa B kinase (IKK). This cascade ultimately initiates the activation of nuclear factor-kappa B in the nucleus. Subsequently, pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β, initiate the inflammatory processes in the lung, giving rise to the classic COVID-19 symptoms. 22, 23 Moreover, in a proposed model based on SARS-CoV-1, viral protein encoded by ORF8b directly interacts with inflammasome NLRP3 (nucleotidebinding domain leucine-rich repeat and pyrin domain containing receptor 3), which activates the adaptor protein apoptosis-associated speck-like protein containing CARD (ASC) and caspases 4, 5, and 11. This leads to a disruption of the cell membrane and the release of the cell content to the extracellular space, causing local inflammation. 24 Furthermore, the binding of SARS-CoV-2 to the ACE2 on the cell surface impairs its enzymatic activity, thus resulting in increased levels of Angiotensin II (AngII) in the extracellular space which, in turns, leads to higher levels of TNF-α and IL-6 in the cell that upregulate NF-κβ, ultimately activating the inflammasome. 23 Finally, recruitment of macrophages to the site of injury and phagocytosis of dead cells results in the release of ATP, which binds to the P2X purinoceptor 7 (P2RX7) giving another important contribution to the activation of the inflammasome. 25 Also, the increased calcium levels caused by the viral proteins results in lysosomal damage, thereby releasing cathepsins that, again, activate the inflammasome. 22 Several strategies to suppress the degree of immune storm have been attempted to treat critically ill patients with COVID-19. In this respect, as serum IL-6 plays an important role in CRS which correlates with respiratory failure, ARDS, elevated serum C-reactive protein (CRP), and poor clinical outcomes, [26] [27] [28] tocilizumab, a IL-6 receptor blocker, has been tested and shown to improve respiratory function in 21 patients with severe COVID-19. 5 These encouraging results suggest that neutralizing monoclonal antibodies against IL-6 or other proinflammatory cytokines such as IL-1 and their receptors may provide a novel strategy for counteracting the cytokine storm in COVID-19 patients. A great deal of effort has been devoted to targeting the host response with a variety of anti-inflammatory drugs and adjunct approaches, including corticosteroids, nonsteroidal anti-inflammatory drugs, 29 neutralizing monoclonal antibodies such as Lenzilumab and Tocilizumab, 30,31 statins, 32 chloroquine and hydroxychloroquine, complement inhibitors, 33 and others. 34 However, these therapeutic approaches possess safety concerns due to their low specificity to lung immunopathology. 35 Despite multiple therapeutic strategies have been attempted, the mortality of severely ill COVID-19 patients remains high and warrants an urgent need of identifying a better therapeutic strategy against the cytokine storm. The use of living cells as effectors offers intrinsic advantages from a pharmacokinetic and pharmacodynamic point of view, compared to the administration of conventional drugs. Cell therapies render the effect localized at the site where the cell resides, reducing the possibility of side effects at a distant site. Moreover, cells have the possibility to persist in the tissue, allowing a longer-lasting effect. Furthermore, their mechanism of action is often multifaceted and involves different pathways simultaneously. 36, 37 Related to this, cell-based therapies can offer additional mechanisms to dampen lung inflammation by regulating the activation of specific cell types. For example, CD200R expression on alveolar macrophages helps in resolving lung inflammation during influenza virus infection by restraining macrophage activity. 38 Moreover, the production of antiinflammatory cytokines, mainly IL-10 by macrophages and certain types of T (Th2 and regulatory T cells) and B cells, represents another mechanism involved in regulating pro-inflammatory responses. 7 In this respect, mesenchymal stem cells (MSCs) demonstrate a remarkable immune-modulatory capacity in different settings and represent an attractive option for the treatment of COVID-19 related cytokine storm.

In the last decade, cell-based therapies have emerged as promising therapeutic options for many incurable diseases. Among different cell platforms, MSCs raised a particular interest due to easy sourcing and attractive features of plasticity, tropism for inflamed tissues, and a high immunomodulatory potential. 39 MSCs are characterized phenotypically by the expression of certain cell surface markers, including CD73, CD90, and CD105, and lack of expression of CD11b, CD14, CD34, CD45, CD79, or HLA-DR, and functionally by the ability to differentiate into mesenchymal lineages. 40 Preclinical studies and clinical trials have provided compelling evidence supporting their immunomodulatory functions in the context of various conditions, including graft-vs-host disease, autoimmune diseases, inflammatory illnesses, myocardial infarction, lung injuries, liver cirrhosis, diabetes, and cancer. 41 43, 44 On the other side, MSCs exert paracrine action by releasing biologically active molecules, and shedding extracellular vesicles, or exosomes, that contain a broad spectrum of cytokines, chemokines, and growth factors. 43 In a preclinical setup, MSCderived exosomes have demonstrated aptitude as an acellular alternative to cell-based therapy, against ARDS. 45 Among these, the main immunomodulatory players are prostaglandin E2 (PGE-2), indoleamine 2,3-dioxygenase (IDO), TNF, nitric oxide (NO), IL-1Rα, HLA-G, and IL-10. 43, 46, 47 Finally, MSCs can be manipulated ex vivo to integrate and empower their features. In particular, it has been demonstrated experimentally that MSCs preconditioned by hypoxia, oxidative stress, heat shock, nutrient starvation, or genetic manipulation with immunomodulatory molecules have the ability to increase their survival and potency, and thereby enhancing the therapeutic efficacy. 48, 49 Although MSCs possess a marked immune-regulatory effect against inflammatory and autoimmune disorders, it is widely acknowledged that they are not immunosuppressive in nature. Instead, MSCs may have different immunoregulatory effects depending on the immune milieu and disease setting. For example, while MSCs are able to suppress compromising antiviral responses needed for disease

through cell-to-cell contacts and paracrine activity (mainly by secretome). Figure drawn with BioRender (https://biorender.com/). ICAM-1, intercellular adhesion molecule-1; IDO, indoleamine-pyrrole 2,3-dioxygenase; IFN, interferon; IL, interleukin; NK, natural killer; PD-L1, programmed death ligand 1; PD-L2, programmed death ligand 2; PGE2, prostaglandin E2; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VEGF, vascular endothelial growth factor control, 50,51 they can also exert differential effects on alloantigen and virus specific T cells that retain the ability to proliferate and kill the virus-infected cells. 52 Moreover, an increased risk to (opportunistic) infections has never been reported, as described in a recent metaanalysis on almost 2700 patients treated by MSC for different indications. 53 A number of studies have demonstrated the preliminary safety and efficacy of both MSCs and exosomes in alleviating comorbidities associated with COVID-19. 54-56 MSC-shed exosomes, owing to their ability to endogenously repair and decrease the inflammatory reactions involved in the morbidity and mortality of COVID-19, present a promising potential to be used following clinical evaluation. Thus, MSCs represent a valuable and versatile cell platform which is able to modulate the immune response at different levels. However, the interplay between MSC and various elements of the immune system is not fully understood and may result in controversial outcomes depending on MSC sources, target cells, and the microenvironment. 43, 44 A further advantage of applying MSCs is the possibility to use an allogeneic source, thus circumventing the time lag needed to produce a clinical grade product. Most importantly, the low levels of expression of HLA class I molecules and lack of HLA class II and costimulatory molecules 57 enable their administration across HLA barriers without preventive immune-ablative treatment. 58 However, when sought, measurable humoral alloimmunization in human subjects receiving mismatched MSCs has been detected, 59 although it does not seem to affect their therapeutic efficacy. In this regard, it should be pointed out that MSCs are now considered immune-evasive and not immune-privileged as previously thought. 60 Notwithstanding, after more than a decade of clinical application of MSCs, an overwhelming safety profile has been repeatedly documented, 53 including the absence of malignant transformation since they do not engraft host tissues. Indeed, their mechanism of action does not depend on their differentiation into specific end-organ cells, but rather on the creation of an appropriate microenvironment, called "quasi niche" 61 where both resident and immune cells are aided in re-establishing tissue homeostasis. 62 Finally, it was recently found that human MSCs are SARS-CoV-2 infection resistant, likely due to the low ACE2 and TMPRSS2 expression on their surface, and that they keep their IDO-1 production capacity in the presence of SARS-CoV-2. 63 This represents a unique strength when evaluating new treatment strategies in the specific clinical setting of COVID-19. All these properties, together with the absence of ethical controversies, make MSCs very attractive for cell-based therapy.

One of the most harmful consequences of SARS-CoV-2 infection is the excessive and aberrant host immune response, accompanied by a cytokine storm and the subsequent ARDS, resulting in multiple organ failure and death. By virtue of their powerful immunomodulatory ability, MSCs offer a promising innovative strategy for attenuating the cytokine storm and ultimately improving patients' outcome ( Figure 3 ). 10 After intravenous infusion, MSCs get trapped in the inflamed lung and exert immunomodulatory function via direct interaction with respiratory epithelial cells and immune cells, or release of a wide variety of soluble mediators, ultimately reducing the inflammation and protecting the alveolar epithelial cells. [64] [65] [66] As discussed, it is likely that the local immunological events in the deep tissues of the lungs are crucial for the initiation of the cytokine storm and thus a localized treatment might be, in theory more effective to stop the cascade. 18, 19 In this regard, it should be emphasized that MSC administration may be performed by using different routes: intravenously with access from a peripheral or central vein, intra-arterial depending on the target organ, but also directly in the damaged tissue as in fistulizing Crohn's disease where local injections have proved successful in inducing closure of fistula tracks refractory to standard treatment. 67 Additionally, delivery routes such as intrathecal, intra-articular, and intradermal have been shown feasible in patients suffering from amyotrophic lateral sclerosis, osteoarthritis, and scleroderma, respectively. [68] [69] [70] It is conceivable therefore, that also in the case of COVID-19 patients, intratracheal administration might work better.

Nonetheless, all the clinical trials so far use intravenous route of MSC administration (Table 1) (Table 2) . 45 The encouraging preclinical data indicating the suitability of MSCs in controlling inflammatory responses in the lungs as well as in other organs have led to their application in early stage clinical trials. These trials have confirmed the ability of MSC to improve diseaseassociated parameters in ARDS subjects 78 with anti-inflammatory and antiapoptotic effects. 78 Furthermore, MSC administration protects and reduces morphological and multiple organ dysfunction. 78,79 A phase IIa study including 60 patients with moderate to severe ARDS showed intravenous infusion of MSC was safe but did not improve the rate of 28-day mortality (30% vs 15%), suggesting that studies with larger patient cohorts are necessary. 80 A recently published paper reported a clinical study for transplantation of allogeneic menstrual-blood-derived MSCs for treating influenza H7N9-induced ARDS in 17 patients. 28 Results showed that MSC transplantation significantly lowered the mortality compared to control group (17.6% vs 54.5%) without harmful effects. 5, 28 Given that H7N9 and COVID-19

share similar complications (including ARDS, lung failure, and multiorgan dysfunction), MSCs offer an innovative therapy for treating 28 While no firm conclusions may be drawn on the effi- infusion. 87 Moreover, freeze-thawed MSCs trigger a strong instant blood-mediated inflammatory reaction when washed with buffer containing human blood type AB plasma instead of human serum albumin. 88 It is strongly recommended to use regular low-dose anticoagulants and, possibly, to perform standardized hemocompatibility testing in those MSC products that are intended for intravascular delivery. Nevertheless, the largest meta-analysis on MSC in clinical settings did not report increased thromboembolic risk. 53 On the contrary, data demonstrated that MSCs have the ability to reduce platelet adhesion and aggregation in a rat model of a vascular graft, which depended on cell-surface heparan sulfate proteoglycans. 89 In addition, MSC can inhibit platelet activation and aggregation through CD73 ectonucleotidase activity, 90 ing Remestemcel-L administration (Table 3) . 96 In the United Kingdom, the REALIST trial is in phase II and is test- 

COVID-19 has emerged as a global health care crisis and several studies have demonstrated that hyperinflammation associated with high levels of circulating cytokines induced by SARS-CoV-2 is a major contributing factor of disease severity and death in patients. 9 113, 114 whereas the increase of TRAIL may induce lymphocyte apoptosis in SARS-CoV infection. 114 Furthermore, an alternative mechanism of action of TRAIL is the induction of autophagy, which contributes to viral clearance by transferring viral materials to cellular endosomes and subsequently activating adaptive immune system. 115 Therefore, engineering

MSCs to express TRAIL may present promise for future clinical applications in COVID-19 management, 116 as it has previously been reported in cancer therapy. 117, 118 Alternative options have been conceived using MSCs delivering leukemia inhibitory factor to antagonize COVID-19 cytokine storm. 16 Taken together, we discussed the nature of the inflammatory responses that have been detected in patients with COVID-19

and outlined the scientific rationale as well as several preliminary findings to corroborate that MSCs emerge as a promising therapeutic candidate to manage this condition. To ensure that MSC intervention reaches its full potential, research and development will need to focus on understanding the complexity of COVID-19

pathophysiology and precise therapeutic mechanisms of action to optimize the therapeutic procedures and stratify patient cohorts. 

We would like to thank all the members of CSTI for their support and hard work during the conception and writing of this review. 

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Khalid Shah https://orcid.org/0000-0002-5474-0974

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