key: cord-0684328-dwmoh3jo
authors: Paris, Gustavo C.; de A. Azevedo, Aline; Ferreira, Adriana L.; de A. Azevedo, Yanca M.; Rainho, Mateus A.; de Oliveira, Genilza P.; Silv, Karina R.; Cortez, Erika A.C.; Stumbo, Ana C.; Carvalho, Simone N.; de Carvalho, Lais; Thole, Alessandra A.
title: Therapeutic potential of mesenchymal stem cells in multiple organs affected by COVID-19
date: 2021-04-15
journal: Life Sci
DOI: 10.1016/j.lfs.2021.119510
sha: 01536fd55248e273f028a25a236efcf231db7aa1
doc_id: 684328
cord_uid: dwmoh3jo

Currently, the world has been devastated by an unprecedented pandemic in this century. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the agent of coronavirus disease 2019 (COVID-19), has been causing disorders, dysfunction and morphophysiological alterations in multiple organs as the disease evolves. There is a great scientific community effort to obtain a therapy capable of reaching the multiple affected organs in order to contribute for tissue repair and regeneration. In this regard, mesenchymal stem cells (MSCs) have emerged as potential candidates concerning the promotion of beneficial actions at different stages of COVID-19. MSCs are promising due to the observed therapeutic effects in respiratory preclinical models, as well as in cardiac, vascular, renal and nervous system models. Their immunomodulatory properties and secretion of paracrine mediators, such as cytokines, chemokines, growth factors and extracellular vesicles allow for long range tissue modulation and, particularly, blood-brain barrier crossing. This review focuses on SARS-CoV-2 impact to lungs, kidneys, heart, vasculature and central nervous system while discussing promising MSC's therapeutic mechanisms in each tissue. In addition, MSC's therapeutic effects in high-risk groups for COVID-19, such as obese, diabetic and hypertensive patients are also explored.

The outbreak of a new coronavirus has changed the global routine. In late December 2019, most of the staff at Huanan Seafood Wholesale Market, Wuhan, China, presented clinical symptoms resembling viral pneumonia WHO, n.d.; F. Wu et al., 2020) .

The disease rapidly spread among other Chinese provinces and then to other countries. The pathogen causing the novel infectious disease was identified as a coronavirus, initially called 2019 novel Coronavirus (2019-nCoV) and then renamed Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) by the International Committee on Taxonomy of Viruses (Gorbalenya et al., 2020) . The new disease was designated as coronavirus disease 2019 and classified as a pandemic on March 11, 2020, by the World Health Organization (WHO, 2020b).

Since treatment is still lacking, researchers around the world have been seeking drugs, vaccines, and other novel therapies. Stem cell therapy has emerged as a potential treatment for the dysfunctions in multiple organs affected by COVID-19. Mesenchymal stem cells (MSCs) are the most suitable stem cell type due to their immunomodulatory properties, as well as general safety regarding MSC interventions (Ullah et al., 2015) . Their major therapeutic factor is the secretion of paracrine mediators such as cytokines, chemokines, growth factors, and extracellular vesicles, which promote tissue regeneration and repair (Bochon et al., 2019; Crigna et al., 2018; Tsuji et al., 2018) .

This article discusses how MSCs therapy could help in the treatment of multiple organs affected by COVID-19.

SARS-CoV-2 belongs to the Coronaviridae family and is classified as a β-CoV (Betacoronavirus genus) (Gorbalenya et al., 2020) . It is the seventh coronavirus capable of infecting humans. However, unlike most of the other coronaviruses, it can cause severe respiratory syndrome, similar to SARS-CoV and MERS-CoV, which caused epidemics in the last two decades (Y.-C. .

The new coronavirus has a tropism for cells that present human angiotensin-converting enzyme 2 (ACE2), a protein involved in the renin-angiotensin system (RAS) regulation. This cells, CD8 + T cells, type II pneumocyte hyperplasia, and interstitial fibrosis, besides inclusions of SARS-CoV-2 in type II pneumocytes (Bao et al., 2020; Pernazza et al., 2020; Schaefer et al., 2020; Tian et al., 2020; . Moreover, thrombotic microvascular lesions were observed, apparently mediated by an intense activation and deposition of complement system proteins within the pulmonary septum microvasculature, such as C5b-9, C4d, and MASP2 (Magro et al., 2020; Schaefer et al., 2020) . Some severe cases of infected patients showed lymphocytopenia, depletion of CD4 + and CD8 + T cells, and neutrophilia, besides massive macrophage and neutrophil infiltrates into the lung tissue (S. Tian et al., 2020) . Patients with severe disease also presented a panel of increased proinflammatory cytokines and chemokines such as IL-6, IL-8, TNF-α, MCP1, and RANTES, as compared to patients with non-severe disease. Inflammatory cell infiltration exacerbates inflammation and exudation, which promotes alveoli dysfunction and a vicious cycle of continuous cytokine release, leading to cytokine storm. These findings demonstrate that pyroptosis and apoptosis contribute to lung injury, with pyroptosis predominating (S. . Therefore, the therapeutic alternative of MSC use might assist in the improvement of severe lung injury caused by direct infection and immunopathological lesions.

MSC's therapeutic potential has received considerable attention in preclinical settings, with marked therapeutic effects in multiple respiratory diseases, including ARDS, as observed in patients with COVID-19 (Laffey & Matthay, 2017) . MSCs have demonstrated many possible mechanisms for improving ARDS resolution through their anti-inflammatory and antiapoptotic effects on host cells, reducing lung alveolar epithelium permeability, increasing alveolar fluid clearance, and enhancing host mononuclear cell phagocytic activity (Walter et al., 2014) . Therefore, MSCs are currently under investigation as a potential therapy for COVID-19.

One of the critical mechanisms implicated in COVID-19 pathology is alveolar edema and infiltration, mainly due to loss of epithelial selective permeability. Therefore, it is crucial to recover alveolar epithelial integrity with concomitant edema resolution (Laffey & Matthay, 2017) . The ability of MSCs to restore alveolar fluid clearance has been noted in ex vivo perfused human lungs. Intrabronchial administration of either MSCs or MSC-conditioned media (MSC-CM) in lipopolysaccharide (LPS)-induced ARDS has been shown to reduce lung edema and normalize alveolar fluid clearance (J. W. Lee et al., 2013) . Mouse models also demonstrated diminished apoptosis in airway epithelial cells (Monsel et al., 2015; Shen et al., 2015) . Moreover, in vitro, MSCs or MSC-CM prevented epithelial barrier dysfunction, J o u r n a l P r e -p r o o f selective permeability loss, and consequent disruption of fluid transport by restoring epithelial sodium transporters and tight junctions (Fang et al., 2010; Goolaerts et al., 2014) .

Another mechanism MSCs can improve epithelial integrity and regulation is by transferring healthy mitochondria to epithelial cells, reducing oxidative damage and apoptosis, thus increasing survival in mice (Ahmad et al., 2014; Islam et al., 2012) . Immunomodulation can also be regulated by direct mitochondrial transfer, either to T cells, stimulating T reg phenotype that restricts inflammatory responses, or to macrophages, promoting enhanced phagocytosis (Court et al., 2020; Jackson et al., 2016) .

The therapeutic potential of MSCs was assessed in other respiratory viruses. Immediate MSC therapy significantly attenuated H9N2 avian influenza virus-induced acute lung injury and inflammation in mice. They were capable of increasing the survival rate, decreasing lung edema and histological injury, improving gas exchange, and reducing alveolar proinflammatory chemokines and cytokines, such as granulocyte macrophage colonystimulating factor (GM-CSF), monokine induced by gamma interferon (MIG), IL-1α, IFN-γ, IL-6, and TNF-α (Y. Li et al., 2016) . In an in vivo pig model of swine H1N1 influenza, MSC-EVs reduced virus shedding and virus-induced production of proinflammatory cytokines, alleviating histopathological lesions in the lungs. When analyzed in vitro, MSC vesicles inhibited H1N1 influenza virus replication and virus-induced apoptosis in lung epithelial cells, mainly through RNA transfer (Khatri et al., 2018) . Similar results were found in an H5N1-infected mouse model treated with MSCs (Chan et al., 2016) . MSCs have been hypothesized to neutralize free virus particles through the production of antibiotic proteins such as Cathelicidin antimicrobial peptide LL-37 (LL-37), which binds to virus and lung cell binding sites while also stimulating immunosuppression (Gordon et al., 2005; Oliveira-Bravo et al., 2016) .

However, MSC effects in virus-induced lung injury appear to be viral strain-specific. H1N1infected mice administered MSCs, although showing modestly reduced viral load and lower influenza-induced thrombocytosis, did not display any improvements in survival, histopathology, inflammatory profile resolution or prevention (Darwish et al., 2013; Gotts et al., 2014; Laffey & Matthay, 2017) . As the virus induced ARDS model is not yet fully established, with variable viral concentrations in inoculation dose, frequency and timing, MSC's therapeutic effect is still under question in viral scenarios.

Many cytokines and chemokines are involved in MSC's therapeutic capacity in respiratory diseases. Prostaglandin E2 (PGE2) produced by MSCs can drive macrophages from M1 to M2, an anti-inflammatory phenotype, increasing their production of anti-inflammatory J o u r n a l P r e -p r o o f cytokine IL-10 [20]. Another key potent anti-inflammatory protein secreted by MSCs is TNF stimulated gene-6 (TSG-6), which can contribute to decreasing inflammatory cytokine and cell counts in bronchoalveolar lavage fluid, while also contributing to fibrosis resolution (R.

H. . Knockdown of TSG-6 expression in MSCs nullified most of these antiinflammatory effects (Danchuk et al., 2011) . TSG-6 is involved in a well-described mechanism by acting on resident macrophages, decreasing TLR2/NFk-B signaling, and thereby decreasing the secretion of proinflammatory mediators (Magaña-Guerrero et al., 2017; Prockop, 2013) . Herpesvirus entry mediator (HVEM) and B-and T-lymphocyte attenuator (BTLA) signaling also seems to be involved in MSC response to ARDS, particularly its immunomodulatory effects. Transplanted lung MSCs expressing HVEM showed improved regulation of inflammatory responses in innate and adaptive immune cells in LPS-induced ARDS model (T. .

Moreover, MSC therapy can be beneficial even in indirect COVID-19 injuries. Preclinical studies using ventilator-induced lung injury models in rats showed that treatment with MSCs or MSC-CM decreased bronchoalveolar liquid concentrations of cytokines and inflammatory cells (Curley et al., 2012 (Curley et al., , 2013 . MSCs can also prevent secondary bacterial infections in patients with COVID-19 through their anti-microbial capacity, showing reduced bacterial levels in the alveoli, blood, and spleen in mice as well as in ex vivo human lungs (Krasnodembskaya et al., 2012 ; J. W. Lee et al., 2013) .

Although few studies have investigated MSC therapy in viral-induced ARDS, the collective literature suggests a moderate beneficial effect of MSCs in general ARDS. Therefore, as COVID-19 patients receive mainly support therapy, MSCs are promising therapeutic candidates. Further investigations are necessary, especially regarding MSC timing and frequency of administration, hopefully in the strongest evidence scenario: randomized double-blind clinical trials.

Many clinical conditions, including general pneumonia, increase the risk of venous thromboembolism (VTE); hence, anticoagulants are routinely used as prophylaxis. (Julien et al., 2020; Konstantinides et al., 2020; Schünemann et al., 2018) . However, COVID-19 seems to cause more frequent thrombotic disorders or endothelial damage than infections by other respiratory viruses such as SARS-CoV, MERS, and influenza .

Preliminary reports suggest that disseminated thrombotic events such as disseminated intravascular coagulation (DIC) occur in patients affected by COVID-19 Tang et al., 2020; Xie et al., 2020) . Two studies from Netherlands and China with severely ill J o u r n a l P r e -p r o o f COVID-19 patients demonstrated that, respectively, 31% of 184 had thrombosis with most events being VTE, and that 25% of 81 developed VTE Klok et al., 2020) .

Out of the 1,026 patients hospitalized with COVID-19, 40% were considered to be at a high risk of VTE, based on the Padua Prediction Score (T. .

A retrospective multicenter study investigating 183 patients found higher levels of D-dimer and fibrin degradation products (~3.5-and ~1.9-fold, respectively) as well as increased prothrombin time (~14%) in COVID-related deaths. Approximately 71.4% of non-survivors vs 0.6% of survivors met the criteria for DIC . Elevations in prothrombin time, D-dimer, and IL-6 levels are associated with a procoagulant profile and poor prognosis in patients with COVID-19 . Furthermore, based on a meta-analysis of 400 severely ill patients, platelet count was inversely correlated with COVID-19 severity .

One aspect that still raises questions in COVID-19 is the dissociation between relatively wellpreserved lung mechanics and the severity of hypoxemia. Patients with COVID-19 maintain high respiratory system compliance, indicating a well-preserved elastic lung tissue, but display a high shunt fraction, indicating poor gas exchange (i.e., low oxygenated blood leaving the lungs). In physiological settings, endothelial self-regulation due to low oxygen levels takes place to activate vasoconstriction in the alveoli-endothelium which is not properly exchanging gas. However, COVID-19 may dysregulate this mechanism, leading to hyperperfusion of inefficient alveoli causing lower pO 2 , even though the ventilation capacity is only moderately reduced (Gattinoni et al., 2020; Santamarina et al., 2020) .

As SARS-CoV-2 is capable of infecting ACE2-expressing cells, direct endothelial cell infection was detected in multiple organs in post-mortem patients with COVID-19, revealing viral endothelial inclusions and a high frequency of congested small lung vessels (Varga et al., 2020) . Therefore, the direct endothelial lesion pathway may have a central role in the onset of COVID-19 coagulopathy and thrombotic disorders. As risk factors for COVID-19

and thrombotic diseases, such as age (Cushman, 2007) , obesity (Stein et al., 2005) , diabetes (Stein et al., 2005) , and hypertension (L. Huang et al., 2016; Lip, 2000) overlap, vascular damage may be a critical enhancer of disease progression. The World Health Organization (WHO) has already recognized COVID-19-related thrombosis, recommending daily prophylactic low molecular weight heparin or twice daily subcutaneous unfractionated heparin use in severe cases even after hospital discharge (Spyropoulos et al., 2020; WHO, 2020a) .

Increased research efforts are being made to investigate possible therapeutic strategies aimed J o u r n a l P r e -p r o o f to reduce blood clot formation, vascular damage and reverse the inflammatory and procoagulant systemic state caused by COVID-19 (Connors & Levy, 2020; Whyte et al., 2020) . MSC's proangiogenic signaling, enhancing endothelial cell survival, and its supportive role in vascular remodeling, make them great therapeutic candidates in endothelial disorders (Au et al., 2008; Melero-Martin et al., 2008; Németh et al., 2009) .

MSCs are potent stabilizers of the vascular endothelium, decreasing endothelial permeability and protecting against inflammatory disruption of barrier function. In ex vivo perfused human lungs, MSCs reduced extravascular lung water, improved lung endothelial barrier permeability and restored alveolar fluid clearance in LPS models (J. W. ).

Keratinocyte growth factor (KGF) was essential for the beneficial effect of MSCs on alveolar epithelial fluid transport, in part by restoring amiloride-dependent sodium transport (J.-W. . MSCs could protect the endothelial barrier function and regulate inflammation as they secrete VEGF and HGF, contributing to endothelial barrier stabilization in pulmonary capillaries, endothelial cell apoptosis inhibition, endothelial VE-cadherin recovery, and proinflammatory factors reduction (Németh et al., 2009; Walter et al., 2014) .

Epithelium-derived microparticles from pulmonary damage are a potential source of procoagulant mediators in the alveolar space in patients with ARDS (Bastarache et al., 2008) .

There is also a positive feedback between coagulation and inflammation, optimizing the response to injury and resulting in a wide range of diseases related to excessive inflammation and/or thrombosis (Coppin et al., 2019) . Regarding the uncontrolled coagulation and thrombotic events due to COVID-19, reports on transfused MSC indicate that they express tissue-factor, a procoagulant, potentially leading to thrombosis and complement activation.

There is considerable concern regarding the use of MSCs in clinical trials investigating thrombotic pathologies, as most protocols include transfusion of MSCs to the blood circulation (Coppin et al., 2019) . Since the injection of cells and appropriated solution might elicit coagulatory responses, to the best of our knowledge no clinical trials have been conducted using MSC in thrombogenic settings. However, this behavior is still in question, as MSC could decrease thrombi size in acute pulmonary thromboembolism mice (Peng et al., 2015; B. Wang et al., 2017) .

Thus, we can speculate that MSC therapy could modulate inflammation in the endothelial cell microenvironment and regulate endothelial permeability during COVID-19, preventing dysfunction. Synergistically, continuing the WHO-recommended treatment with anticoagulants, MSCs could directly inhibit endothelium apoptosis, acting as a potent regulator of vascular remodeling and recuperating blood flow control. In fact, the J o u r n a l P r e -p r o o f simultaneous use of both strategies seems to inhibit procoagulant events related to MSC transfusion. (Liao et al., 2017) Heart Several studies have shown that CVD predisposes patients to severe COVID-19 conditions, increasing the probability of mortality Guan et al., 2020; Klok et al., 2020; Xie et al., 2020) . However, the effects of SARS-CoV-2 specifically in the heart are not well known. COVID-19 patients without previous history of CVD displayed cardiovascular manifestations, such as increased protein levels of cardiac troponin, myoglobin, creatine kinase and NT-proBNP, in addition to clinical symptoms, in particular chest pressure, suggesting myocarditis involvement Gattinoni et al., 2020; Tang et al., 2020; . Even small increases in troponin I levels (0.03-0.09ng/mL) were significantly associated with death (Lala et al., 2020) . Myocardial injury occurs in ~25% of hospitalized patients and is associated with a greater need for mechanical ventilator support and higher hospital mortality (Giustino et al., 2020).

One proposed cardiac pathophysiological mechanism is through direct myocardial injury, as SARS-CoV-2 seems to have the capacity to infect cardiomyocytes, pericytes and fibroblasts via the ACE2 pathway (Hendren et al., 2020) . Furthermore, systemic cytokine-mediated injury, inflammatory cells infiltration, cardiac hypoxemia, coronary plaque rupture with acute myocardial infarction and adrenergic stress are other mechanisms implicated in COVID-19 cardiac pathology (Giustino et al., 2020) . Post-mortem endomyocardial biopsy from COVID-19 positive patients found hypertrophied cardiomyocytes along with inflammatory infiltrates, focal edema, interstitial hyperplasia, fibrosis, degeneration, necrosis and signs of lymphocytic myocarditis (Deshmukh et al., 2020) .

Evidence suggesting that SARS-CoV-2 can cause myocardial lesions are corroborated by the structural similarity of the virus to SARS-CoV-1 (virus responsible for the 2002-2004 SARS epidemic) (Gattinoni et al., 2020; Matthay et al., 2019) . Both were found to be dependent on ACE-2 receptors for targeting and infecting human cells, and also to cause excessive cytokine responses, hypoxia and impaired left ventricular performance Cushman, 2007; Magro et al., 2020; Tang et al., 2020; Varga et al., 2020) .

Previous studies indicated that SARS-CoV-1 infection, promotes ACE-2 dysregulation, arresting the cardioprotective effects of angiotensin 1-7 and leading to the synthesis of TNF-α (Barnes et al., 2020; Vabret et al., 2020) . Moreover, the activation of Smad signaling pathway triggers TGF-β signaling, which develops myocardium interstitial fibrosis (Barnes et al., J o u r n a l P r e -p r o o f Journal Pre-proof 2020; Risitano et al., 2020) .

To the best of our knowledge, no published study described the action of MSCs specifically in the heart of patients with COVID-19. Therefore, our review discusses the role and effectiveness of MSCs and MSC-EVs therapy based on similar cardiovascular manifestations.

Multiple studies reported the use of MSCs as beneficial for myocardial restoration (Abraham & Krasnodembskaya, 2020; Melero-Martin et al., 2008; Németh et al., 2009; Rossi et al., 2017; Smadja et al., 2012) . In a model of Coxsackievirus B3-induced myocarditis in mice, MSCs exhibited a cardioprotective role by inhibiting the expression of NOD2, ASC, caspase-1, IL-1β, IL-18 and NLRP3 inflamassome in the left ventricle, which recovered myocardial contractility and fibrosis. They also reduced apoptosis, oxidative stress, intracellular viral particles production and TNF-α mRNA expression, while activated cardiac mononuclear cells and the IFN-γ protective pathway (Au et al., 2008; Miteva et al., 2018) .

MSCs have also demonstrated beneficial effects in models of acute myocardial infarction.

MSCs were able to reduce infarct size, preserve systolic and diastolic cardiac performance and activate resident cardiac stem cells, promoting its proliferation, migration and angiogenic capacity, which ultimately led to reduced fibrosis (J. W. Lee et al., 2009b; Walter et al., 2014) . These results validate the cardioprotective, proangiogenic, and prosurvival effects of MSCs in the heart via immune system and tissue repair modulation (J.-W. Li, 2015; J. W. Lee et al., 2009b; Pati, Khakoo, et al., 2011) .

Clinical trials involving the therapeutic use of MSCs in cardiac pathologies are still in very early phases. General safety has been demonstrated using mixed methodologies and MSCs source . The main challenges encompass MSC's low tissue retention and survival after transplantation. However, initial results suggest that MSCs improved left ventricular function, questionnaire-assessed symptoms and quality of life, although more robust investigation is necessary .

Taken together, these data demonstrate the promising therapeutic potential of MSCs for various cardiovascular complications. Based on SARS-CoV-2 pathophysiology in the heart and the similarity observed in CVD, mainly in myocarditis, MSC therapy could constitute a potential treatment for COVID-19 related heart alterations. Puelles et al., 2020; Qi et al., 2020) . Therefore, this set of proteins forms a key point that allows viral entry, replication, and immune response establishment, thereby promoting acute kidney injury (Menon et al., 2020; Pan et al., 2020; Puelles et al., 2020) Studies have shown viral particles in the peritubular space, renal tubular epithelial cytoplasm, podocytes, glomerular capillaries, and a lower proportion in distal tubule epithelium, where ACE2 is known to be expressed (Su et al., 2020; Varga et al., 2020) . These findings show that SARS-CoV-2 can directly infect renal epithelia, promoting acute renal injury in patients with COVID-19 (Farkash et al., 2020; Su et al., 2020) . Recent research described major renal morphological changes in COVID-19 postmortem individuals, such as acute proximal tubular injury with loss of brush border, vacuolar degeneration, tubular lumen dilation, necrotic regions, and epithelium detachment with a bare tubular basement membrane (Larsen et al., 2020; Su et al., 2020) Tubular atrophy, mild interstitial fibrosis, Bowman's capsule rupture with global collapse of glomerular capillaries, podocytes vacuolization, and glomerular basement membrane retraction were also observed (Larsen et al., 2020; Peleg et al., 2020; Su et al., 2020) . In addition, patients with COVID-19 showed renal dysfunction leading to increased levels of creatinine, urea, uric acid, proteinuria, hematuria, and inflammatory markers (Y. Larsen et al., 2020; Peleg et al., 2020; Su et al., 2020) Although SARS-CoV-2 viral particles can promote renal injury by direct infection, some studies reported that the virus was not present in podocytes and tubules. It is suggested that the host inflammatory response to coronavirus is exacerbated, causing cytokines such as interferons to damage cells (Larsen et al., 2020; Peleg et al., 2020) . A study showed lymphocyte infiltration, high levels of complement system proteins, and macrophage infiltration in tubulointerstitial regions, in which proinflammatory cytokines derived from macrophages led to tubular injury, enhancing SARS-COV-2 cytotoxic effect (Diao et al., 2020) . Virus-induced inflammatory mediators cause indirect effects such as hypoxia, shock and rhabdomyolysis, damaging kidney tissues (Y. . Besides, high levels of these inflammatory substances are responsible for rapid multiorgan failure and death (Z. .

MSCs are being extensively studied for their therapeutic potential to treat renal injury (Lira et al., 2017) . MSCs were able to reduce tubular cell apoptosis, inflammatory infiltrate, and interstitial fibrosis in rats with unilateral ureteral obstruction (UUO). MSC also have the ability to promote anti-inflammatory outcomes at long distances through their direct and indirect paracrine effects. In mice with ischemic or reperfusion acute kidney injury (AKI), intravenously infused MSCs are incorporated into the lungs and secrete soluble factors into bloodstream that improve kidney injury and ischemic renal repair by suppressing inflammatory reactions (Jie Hu et al., 2013) . Recent evidence has shown that a combination of exosomes with soluble factors secreted by MSCs contribute to anti-inflammatory response, repair, and regeneration of renal tissues. The miRNAs transported by MSC exosomes are involved in tubular epithelium protection and regeneration (Nagaishi et al., 2016) . In a mice model of aristolochic acid-induced nephropathy, MSC EVs reduced creatinine and urea levels, tubular necrosis, and interstitial fibrosis, while also reduced profibrotic genes expression (e.g., αSMA, Col 1a1, and TGF-β) and cellular activity of fibroblasts, pericytes, and myofibroblasts. In addition, they reduced inflammatory cells, promoted renal cell proliferation, and reduced apoptosis (Kholia et al., 2020) . MSC-EV's miRNAs were transferred to host cells, altering their genetic expression, inhibiting inflammatory and profibrotic pathways (Kholia et al., 2020) . miRNAs are also involved in tubular epithelium protection and regeneration (Nagaishi et al., 2016) . These data show that MSC EVs have antifibrotic and anti-inflammatory properties, attenuating the innate immune response and favoring renal regeneration.

The renoprotective feature of MSCs is attributed to their unique ability to modulate the inflammatory immune response. MSCs promoted accelerated M2-polarized macrophage J o u r n a l P r e -p r o o f infiltration, trophic factors secretion, tubular epithelium proliferation, renal function improvement and IL-6 and TNFα reduction in mice with rhabdomyolysis-induced AKI (Geng et al., 2014) . Other studies also reported that MSCs promoted an increased expression of IL-10 and IL-4 mRNA, decreased expression of IL-1β and TNF-α mRNA, and decreased inflammatory cells infiltration, reduced a proinflammatory (Th1) environment, and increased anti-inflammatory effects (Th2) (Lira et al., 2017; Oliveira-Sales et al., 2013; Ornellas et al., 2019) .

MSC transplantation into the renal subcapsular region of rats with podocyte injury induced by puromycin promoted blood pressure reduction and decreased proteinuria, albuminuria, and serum creatinine. Renal regenerative and reparative effects of MSCs are also related to restoration of Wilms' tumor suppressor 1 (WT1) and VEGF expression and improvement of podocytes' functional and structural integrity, including proteins such as nephrin and podocin (slit diaphragm), synaptopodin, and podocalyxin (cytoskeletal proteins) (Ornellas et al., 2019) . Marrow mononuclear cell fraction, that includes MSC and other progenitor cells, can also promote renal tissue restoration (M. Oliveira et al., 2019) .

Clinical trials with MSC administration in patients with AKI or sepsis-associated AKI, chronic kidney disease or diabetic nephropathy has been limited to a small number of early phase clinical trials. Overall, MSC demonstrated good safety and tolerability, however only modest alterations in plasma cytokine profiles were observed, without a clear signal of improved outcome for MSC-treated patients (Fazekas & Griffin, 2020; Packham et al., 2016; Zilberman-Itskovich & Efrati, 2020) .

Beyond MSC's paracrine effect, mitochondrial transfer also plays a role in kidney injury regeneration and repair. Bone marrow-derived MSCs transferred mitochondria to proximal tubular epithelial cells of mice with diabetic nephropathy in vivo (Nagaishi et al., 2016) .

These embedded mitochondria suppressed apoptosis, regulated mitochondrial factors such as Bcl-2, Bax, and PGC-1α, inhibited reactive oxygen species (ROS) production, recovered transporter expression such as megalin and SGLT2, and repaired tubular structures (Konari et al., 2019) . Therefore, it was shown that MSCs have several mechanisms that promote renal regeneration and repair, thus unraveling the very promising therapeutic potential for patients affected by COVID-19.

Several patients with COVID-19 have reported neurological events such as headache, dizziness, hypogeusia, and hyposmia (S. Mao et al., 2020) . In a systematic review of 554 patients who tested positive for COVID-19, the average prevalence of J o u r n a l P r e -p r o o f headaches was approximately 8% and dizziness was 7%-9.4% (Rodriguez-Morales et al., 2020; . There are also many reports of cases that manifested more severe neurological symptoms, such as acute cerebrovascular diseases (acute ischemic stroke, cerebral venous sinus thrombosis, cerebral hemorrhage and subarachnoid hemorrhage), meningitis or encephalitis, acute hemorrhagic necrotizing encephalopathy, acute Guillain-Barré syndrome, hypopsia, and neuralgia (Giacomelli et al., 2020; Mao et al., 2020; Moriguchi et al., 2020) . In a large retrospective cohort study comparing 1,916 COVID-19 patients and 1,486 influenza patients adjusted for age, sex, and race, the likelihood of stroke was almost 8-fold higher for COVID-19 (odds ratio 7.6) (Merkler et al., 2020) .

The mechanisms underlying neural manifestations in COVID-19 are probably multifactorial: viral, immune, hypoxia, and hypercoagulability. Direct damage to the brain caused by SARS-CoV-2 is still under debate. Some authors have suggested direct brain infection as endothelial cells, arterial smooth muscle cells, glial cells, and neurons express ACE2 receptors in the brain (Baig et al., 2020; Zou et al., 2020) . In a preprint, SARS-CoV-2 was capable of infecting human brain organoids and the brain of mice overexpressing human ACE2 in vivo . In another preprint, all 6 patients autopsies displaying affected brain tissues exhibited foci of SARS-CoV-2 infection and replication, particularly in astrocytes. In vitro, astrocyte infection changed energy metabolism, altered key proteins and metabolites ultimately reducing neuronal viability (Crunfli et al., 2020) . On the other hand, although autopsies showed SARS-CoV-2 could be detected in the brains of 21 (53%) of 40 examined patients, they were not associated with the severity of neuropathological changes, which were mainly attributed to mild neuroinflammatory or hypoxic changes (Matschke et al., 2020; Solomon et al., 2020) . To the best of our knowledge, no conclusive proof of direct neural infection has been demonstrated in live humans, as most studies did not find SARS-CoV-2 RNA in cerebrospinal fluid (CSF) or brain samples (Bellon et al., 2020; Espíndola et al., 2020; Filatov et al., 2020; Neumann et al., 2020; Oxley et al., 2020; Saiegh, 2020; Yin et al., 2020) .

Cerebrovascular alterations such as large-vessel ischemic strokes and cerebral venous thrombosis are consequences of the procoagulant vascular state induced by COVID-19 (Román et al., 2020) . Meanwhile, inflammatory cytokine storm provoked by SARS-CoV-2 infection may damage the blood-brain or blood-CSF barriers, oligodendrocytes and neurons (Y. . The most common histopathologic findings in autopsies were astrogliosis, ischaemic lesions, neuronal degeneration and activated microglia in the J o u r n a l P r e -p r o o f brainstem (Deshmukh et al., 2020; Solomon et al., 2020) .

Several studies have demonstrated positive results of MSC therapy in other neurological diseases, as they have high regenerative capacity and immunoregulatory function. In neurological complications (neurodegenerative diseases or neural inflammation), the main obstacle to treatment is the blood-brain barrier, which many drugs cannot cross to reach the target organ (Biol et al., 2020; Gorabi et al., 2019) . However, MSC EVs can overcome this barrier and solve the problem. Thus, from work already published, and where it is possible to parallel neurological manifestations to those caused by SARS-CoV-2, the performance and effectiveness of MSC and MSC-EVs are discussed.

Inflammatory conditions in the central nervous system (CNS) are involved in the pathogenesis of acute and chronic neurodegenerative diseases, such as brain and spinal cord trauma, and stroke (Wyss-Coray & Mucke, 2002) . In inflammatory responses, microglia are activated, leading to neurotoxic and proinflammatory factors release, including cytokines, ROS, NO, and eicosanoids that can damage neurons and glial cells (G. Wyss-Coray & Mucke, 2002) . There is also the activation and recruitment of neutrophils and monocyte-derived macrophages into the bloodstream, further inducing neurodegeneration (Lima et al., 2007) . Sun et al. demonstrated that therapy with umbilical cord-derived MSC-EVs helped to recover spinal cord injury by reducing levels of IFN-γ, IL-6, TNF-α, and MIP-1α in mice (G. . Another study using MPTP-induced mouse model, which kills dopamine-producing neurons, reported that bone marrow-derived MSCs decreased proinflammatory cytokines, suppressed microglia activation, recovered blood-brain barrier integrity and prevented neuronal death by releasing TGF-β1. As a result, MSCs promote neuroprotective effect against cytotoxicity (Chao et al., 2009 ).

MSC and MSC-EVs also release neurotrophic factors, rescuing neuromotor activity in spinal cord injury (Nosrat et al., 2001; Sakai et al., 2012) . A study that evaluated MSC-EV therapy following stroke in mice found that the treatment helped to improve peripheral immune responses, alleviating the quality and quantity of immunosuppression (Xin et al., 2013) .

MSCs were observed to promote neurovascular recovery and plasticity in other studies that performed the same analysis in rats (Xin et al., 2013; Y. Zhang et al., 2015) . Recently, using a stroke model Xin et al. reported that MSC-EVs carry miR-133b, which is suggested to be the main component involved in improving cerebral recovery in stroke. MSCs could increase miR-133b levels in ischemic brain tissues, promoting an increase in neuron growth (Xin et al., 2013; Y. Zhang et al., 2015) . Thus, MSCs have important neuromodulatory capacity that can be used therapeutically.

In clinical trials utilizing MSC for spinal cord injury, stroke or traumatic brain injury side effects related to the procedure noted, although none of them were followed with sequelae.

Transplantation of MSCs resulted in neurologic improvement in the majority of clinical trials, with superior performance in motor function, sensory level and daily living activities (Badyra et al., 2020) . MSCs have great potential to improve patient symptoms and quality of life, whereas traditional medicine offers no efficient treatment.

The research presented here demonstrates the promising therapeutic potential of MSC and MSC-EVs in the treatment of various neurological complications. Although far from ideal, those models illustrate the potential benefits MSC may have on the neurological pathology of COVID-19, in different time points of the disease progression.

The main groups at risk of developing severe COVID-19 are elderly and obese individuals, who often have related comorbidities such as hypertension and type 2 diabetes (T2D) (Stefan et al., 2020; Watanabe et al., 2020; Williamson et al., 2020) . The Centers for Disease Control and Prevention (CDC) reported that the majority of patients hospitalized with COVID-19 in march 2020 were elderly (≥ 65 years) and among them, most of those who were obese experienced complications (Garg et al., 2020; Muniyappa & Gubbi, 2020; Petrilli et al., 2020) . Simonnet and colleagues (2020) showed a high prevalence of mechanical ventilation support as Body Mass Index (BMI) increased, being greatest in patients with obesity (BMI > 35), independent of age, diabetes, and hypertension (Simonnet et al., 2020) .

Overweight or severely obese patients with COVID-19 had elevated metabolic damage linked to pneumonia aggravation, with higher prevalence of mechanical ventilation, and death (Muniyappa & Gubbi, 2020; Stefan et al., 2020) .

The enhanced pathophysiology observed in individuals with obesity and COVID-19 is not clear, but probably is multi-factorial, ranging from complement system hyperactivation, chronic inflammation and comorbidities progression (Butler & Barrientos, 2020; . There is a consensus that obesity negatively affects the immune response. In particular, inflammatory responses are triggered and develop to a constant low-grade systemic inflammation directly impacting the whole body (Butler & Barrientos, 2020) . This complex cellular event involves hyperplasia and hypertrophy of white adipose tissue cells and a macrophage profile switch to a proinflammatory state, that triggers the release of proinflammatory cytokines, such as TNF-α and IL-6. IL-6 is positively correlated to COVID-19 aggressiveness and is one of the main markers of lung injury (Chiappetta et al., 2020; Dal Moro et al., 2020) . Furthermore, weight excess is largely known to be positively associated J o u r n a l P r e -p r o o f with multiple respiratory diseases, such as asthma, obstructive sleep apnea syndrome, acute lung injury, and ARDS, even after adjusting for other risk factors .

Over time, this low-grade inflammation contributes to the development of insulin resistance and progression to T2D (Chiappetta et al., 2020; Mraz & Haluzik, 2014; Oliver et al., 2010; Thole et al., 2012) . Individuals with T2D also have impaired immune system responses with altered activities of macrophages, NK cells, and neutrophils. In this scenario, lymphocytes induce production of proinflammatory cytokines due to impaired T reg function (Erener, 2020) .

In a cohort study, patients with COVID-19 that had well-controlled levels of glycemia showed controlled COVID-19 symptoms, while T2D patients showed higher levels of neutrophils and IL-6 cytokines (L. Zhu et al., 2020) . Higher levels of proinflammatory cytokines, D-dimmers, and a lower rate of survival were also associated with patients that had T2D and COVID-19 in another study (Sardu et al., 2020) . Hyperglycaemia, regardless of diabetes status, was independently correlated to increased disease severity and mortality in 11,312 hospital patients with COVID (Carrasco-Sánchez et al., 2021) .

The proinflammatory state seen in obesity can also contribute to the development of hypertension (Drummond et al., 2019; Vinciguerra et al., 2020) . In multiple studies, hypertension was associated with poor COVID-19 outcome, including ARDS, need for intensive care unit, disease progression and mortality (Guan et al., 2020; Iaccarino et al., 2020; Pranata et al., 2020; Rodilla et al., 2020) These data highlight the urgent need to develop therapies designed for potential high-risk COVID-19 patients (Dietz & Santos-Burgoa, 2020) . The chronic pro-inflammatory state and impaired immunity typically found in patients with obesity, T2D and hypertension make it even more complex to design strategies aiming to treat COVID-19 based on controlling inflammation and preventing cytokine storm. In this regard MSC therapy may be a strategy to counteract COVID-19 especially in high-risk patients.

MSC therapy has positive metabolic and trophic effects in obesity models. In a preclinical systematic review, MSCs demonstrated strong positive effect in obese mice, improving glucose metabolism homeostasis, lipid profiles, non-alcoholic fatty liver disease and systemic inflammation (Saleh et al., 2018) . Obese mice that received MSCs showed reduced liver fat deposition, IL-6 expression, blood glucose levels and increased glucose tolerance (Cao et al., 2015) . MSCs and MSC-CM have also presented a recovery effect on obesity-related cardiac alterations, reducing fibrosis, improving arrhythmias and exercise capacity (Daltro et al., 2017) .

In the T2D context, MSC transplantation has shown improvement in reversing peripheral J o u r n a l P r e -p r o o f Journal Pre-proof insulin resistance and relieving β-cell destruction through paracrine activity (Hao et al., 2013; Si et al., 2012; Solis et al., 2019; . Moreover, in hypertension disease, MSC's effects can reduce arterial pressure and induce a decrease in cardiac hypertrophy while also stimulating vascular recovery through secretion of VEGF, IGF, and HGF (L. F. De Oliveira et al., 2015; Z. Zhu et al., 2015) . MSC could also improve systolic blood pressure in renovascular and salt-sensitive hypertension in mice (Abumoawad et al., 2020; Junping Hu et al., 2014) . Therefore, although safety must still be thoroughly validated, MSC-based therapy might be appropriate to patients with COVID-19 who have obesity and co-morbidities, as MSC has broad potential therapeutic benefits. Ischaemic lesions ↓ neurocytotoxicity Neuron degeneration ↑ miR-133b ↑ neurovascular recovery and plasticity PGE2 -Prostaglandin E 2 ; TSG-6 -TNF-stimulated gene-6; HVEM -Herpesvirus entry mediator; BTLA -B-and T-lymphocyte attenuator; LL-37 -Cathelicidin antimicrobial peptides LL-37; TGF-β -Transforming Growth Factor-beta; IFN-γ -Interferon-gamma; IL-6 -Interleukin 6; TNF-α -Tumor Necrosis Factor-alpha; MIP-1α -Macrophage Inflammatory Protein; KGF -Keratinocyte Growth Factor; VEGF -Vascular Endothelial Growth Factor; HGF -Hepatocyte Growth Factor

Currently, there are 308 clinical trials registered to assess the therapeutic potential of MSCs for clinical use in patients affected with COVID-19 (Trials, 2020) . Most of these clinical trials use bone marrow or umbilical cord as sources of MSCs, which are intravenously administered. These studies are in phases I and II, evaluating safety and efficacy, mainly in patients with exacerbated inflammatory responses. As the therapy is innovative, there is a need for caution when administering cells into patients. In preclinical trials, MSCs are quite efficient, but advanced clinical trials have fallen short of expectations. Clinical trials involving the use of MSC in patients with COVID-19 although presented partial improvement of outcome, have received critics regarding loose definitions and limited data availability Meng et al., 2020) . Some aspects such as dose standardization, frequency of MSC doses and treatment timing, as defining the optimal stage

Mesenchymal stem cell-derived extracellular vesicles for the treatment of acute respiratory distress syndrome

In a Phase 1a escalating clinical trial, autologous mesenchymal stem cell infusion for renovascular disease increases blood flow and the glomerular filtration rate while reducing inflammatory biomarkers and blood pressure

Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy

SARS-CoV-2 infection of kidney organoids prevented with soluble human ACE2

Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature

Immune response to SARS-CoV-2 and mechanisms of immunopathological changes in COVID-19

Mesenchymal stem cells as a multimodal treatment for nervous system diseases

Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms

Can mesenchymal stem cell therapy be the interim management of COVID-19?

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice

Targeting potential drivers of COVID-19: Neutrophil extracellular traps

Intra-alveolar tissue factor pathway inhibitor is not sufficient to block tissue factor procoagulant activity

Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America

COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-ofthe-Art Review

Turkish Journal of Biology Mesenchymal stem cell derived extracellular vesicles: promising immunomodulators against autoimmune, autoinflammatory disorders and SARS-CoV-2 infection

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

Mesenchymal Stem Cells-Potential Applications in Kidney Diseases

The impact of nutrition on COVID-19 susceptibility and long-term consequences

Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat dietinduced obese mice

Admission hyperglycaemia as a predictor of mortality in patients hospitalized with COVID-19 regardless of diabetes status: data from the Spanish SEMI-COVID-19 Registry

Human mesenchymal stromal cells reduce influenza A H5N1-associated acute lung injury in vitro and in vivo

Clinical characteristics and diagnostic challenges of pediatric COVID-19: A systematic review and meta-analysis

Mesenchymal stem cell transplantation attenuates blood brain barrier damage and neuroinflammation and protects dopaminergic neurons against MPTP toxicity in the substantia nigra in a model of Parkinson's disease

MiR-34 Cooperates with p53 in Suppression of Prostate Cancer by Joint Regulation of Stem Cell Compartment

Lung-resident mesenchymal stem cells regulated the inflammatory responses in innate and adaptive immune cells through HVEM-BTLA pathway during ARDS

Kidney disease is associated with in-hospital death of patients with COVID-19

COVID-19 and the role of chronic inflammation in patients with obesity

Comparative Replication and Immune Activation Profiles of SARS-CoV-2 and SARS-CoV in Human Lungs: An Ex Vivo

Clinical Infectious Diseases : An Official Publication of the Infectious Diseases Society of America

COVID-19 and its implications for thrombosis and anticoagulation

Thrombogenic Risk Induced by Intravascular Mesenchymal Stem Cell Therapy: Current Status and Future Perspectives

Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response

Stem/stromal cells for treatment of kidney injuries with focus on preclinical models

A Perivascular Origin for Mesenchymal Stem Cells in Multiple Human Organs

SARS-CoV-2 is found in the human brain, where it infects astrocytes and, to a lesser extent

Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia

Effects of Intratracheal Mesenchymal Stromal Cell Therapy during Recovery and Resolution after Ventilator-induced Lung Injury

Mesenchymal stem cells enhance recovery and repair following ventilator-induced lung injury in the rat

Epidemiology and risk factors for venous thrombosis

Mesenchymal stem cells reside in virtually all post-natal organs and tissues

The war against the SARS-CoV2 infection: Is it better to fight or mitigate it?

Therapy with mesenchymal stromal cells or conditioned medium reverse cardiac alterations in a high-fat diet-induced obesity model

Human multipotent stromal cells attenuate lipopolysaccharide-induced acute lung injury in mice via secretion of tumor necrosis factor-α-induced protein 6

Mesenchymal Stromal (Stem) Cell Therapy Fails to Improve Outcomes in Experimental Severe Influenza

Priming Mesenchymal Stem Cells with Endothelial Growth Medium Boosts Stem Cell Therapy for Systemic Arterial Hypertension

Histopathological observations in COVID-19: a systematic review

Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. MedRxiv

Obesity and its Implications for COVID-19 Mortality

Mesenchymal stem cells

Eleven faces of coronavirus disease

Immune mechanisms of hypertension

Diabetes, infection risk and COVID-19

Patients with COVID-19 and neurological manifestations show undetectable SARS-CoV-2 RNA levels in the cerebrospinal fluid

Hematologic parameters in patients with COVID-19 infection

Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1

Ultrastructural Evidence for Direct Renal Infection with SARS-CoV-2

Mesenchymal stromal cell-based therapies for acute kidney injury: progress in the last decade

Neurological Complications of Coronavirus Disease (COVID-19): Encephalopathy. In Cureus

Human Coronavirus: Host-Pathogen Interaction

Hospitalization Rates and Characteristics of Patients Hospitalized with Laboratory-Confirmed Coronavirus Disease 2019 -COVID-NET, 14 States

COVID-19 does not lead to a "typical" acute respiratory distress syndrome

The therapeutic potential of mesenchymal stem cells for cardiovascular diseases

Extrapulmonary manifestations of COVID-19

Multiple intravenous infusions of bone marrow mesenchymal stem cells reverse hyperglycemia in experimental type 2 diabetes rats

On the Alert for Cytokine Storm: Immunopathology in COVID-19

Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome

Mesenchymal stem cells attenuate ischemic acute kidney injury by inducing regulatory T cells through splenocyte interactions

Transplantation of mesenchymal stem cells into the renal medulla attenuated salt-sensitive hypertension in Dahl S rat

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet

Association between hypertension and deep vein thrombosis after orthopedic surgery: a meta-analysis

Age and multimorbidity predict death among COVID-19 Patients: Results of the SARS-RAS study of the Italian society of hypertension

Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis

Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury

Mesenchymal stem cells ameliorate LPS-induced acute lung injury through KGF promoting alveolar fluid clearance of alveolar type II cells

Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS

Immune modulation by mesenchymal stem cells

Pulmonary Embolism in Patients With COVID-19

Comparison of Platelet-Rich Plasma and VEGF-Transfected Mesenchymal Stem Cells on Vascularization and Bone Formation in a Critical-Size Bone Defect

Mesenchymal stem cell-derived extracellular vesicles: novel frontiers in regenerative medicine

Mesenchymal stem cell-derived extracellular vesicles attenuate influenza virus-induced acute lung injury in a pig model

Mesenchymal Stem Cell Derived Extracellular Vesicles Ameliorate Kidney Injury in Aristolochic Acid Nephropathy

Cell-based therapies for coronavirus disease 2019: proper clinical investigations are essential

Incidence of thrombotic complications in critically ill ICU patients with COVID-19

Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo

2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the

Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes

Angiotensin-converting enzyme 2 in lung diseases

Cell-based therapy for acute respiratory distress syndrome: Biology and potential therapeutic value

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): The epidemic and the challenges

Prevalence and Impact of Myocardial Injury in Patients Hospitalized With COVID-19 Infection

Collapsing Glomerulopathy in a Patient With COVID-19

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung

Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria

Intravenous hMSCs Improve Myocardial Infarction in Mice because Cells Embolized in Lung Are Activated to Secrete the Antiinflammatory Protein TSG-6

Prevalence and Duration of Acute Loss of Smell or Taste in COVID-19 Patients

Coronavirus infections and immune responses

Mouse Umbilical Cord Mesenchymal Stem Cell Paracrine Alleviates Renal Fibrosis in Diabetic Nephropathy by Reducing Myofibroblast Transdifferentiation and

Cell Proliferation and Upregulating MMPs in Mesangial Cells

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues

Clinical and pathological investigation of patients with severe COVID-19

Mesenchymal stromal cell treatment prevents H9N2 avian influenza virus-induced acute lung injury in mice

Caution on Kidney Dysfunctions of COVID-19 Patients

Heparin improves BMSC cell therapy: Anticoagulant treatment by heparin improves the safety and therapeutic effect of bone marrow-derived mesenchymal stem cell cytotherapy

Inflamação em doenças neurodegenerativas

Extracellular Vesicles Released from Mesenchymal Stromal Cells Modulate miRNA in Renal Tubular Cells and Inhibit ATP Depletion Injury

Hypertension and the prothrombotic state

Laboratory abnormalities in patients with COVID-2019 infection

Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: A meta-analysis

Transplantation of bone marrow-derived MSCs improves renal function and Na++K+-ATPase activity in rats with renovascular hypertension

Human Amniotic Membrane Mesenchymal Stem Cells inhibit Neutrophil Extracellular Traps through TSG-6

Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: A report of five cases

Neurologic Manifestations of Hospitalized Patients with Coronavirus Disease

Neuropathology of patients with COVID-19 in Germany: a post-mortem case series

Acute respiratory distress syndrome

Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells

Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial

SARS-CoV-2 receptor networks in diabetic and COVID-19 associated kidney disease. MedRxiv : The Preprint Server for Health Sciences

Risk of Ischemic Stroke in Patients With Coronavirus Disease 2019 (COVID-19) vs Patients With Influenza

Droplets and Aerosols in the Transmission of SARS-CoV-2

Improved outcomes after mesenchymal stem cells injections for knee osteoarthritis: results at 12-months follow-up: a systematic review of the literature

Mesenchymal stromal cells inhibit NLRP3 inflammasome activation in a model of Coxsackievirus B3-induced inflammatory cardiomyopathy

Therapeutic effects of human mesenchymal stem cellderived microvesicles in severe pneumonia in mice

Inhibition of SARS-CoV-2 Infections in Engineered Human Tissues Using Clinical-Grade Soluble Human ACE2

A first case of meningitis/encephalitis associated with SARS-Coronavirus-2

The role of adipose tissue immune cells in obesity and lowgrade inflammation

COVID-19 pandemic, coronaviruses, and diabetes mellitus

Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine

Mesenchymal stem cell therapy ameliorates diabetic nephropathy via the paracrine effect of renal trophic factors including exosomes

Bone marrow stromal cells attenuate sepsis via prostaglandin E2-dependent reprogramming of host macrophages to increase their interleukin-10 production

& groups, P. and the I. study. (2020). Cerebrospinal fluid findings in COVID-19 patients with neurological symptoms

Dental Pulp Cells Produce Neurotrophic Factors, Interact with Trigeminal Neurons in Vitro, and Rescue Motoneurons after Spinal Cord Injury

LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells

Mesenchymal Stem Cells (MSC) Prevented the Progression of Renovascular Hypertension, Improved Renal Function and Architecture

Bone marrow mononuclear cell transplantation rescues the glomerular filtration barrier and epithelial cellular junctions in a renovascular hypertension model

Postgraduate Symposium: The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chain n-3 PUFA

Mesenchymal Stromal Cells Induce Podocyte Protection in the

Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young

Allogeneic Mesenchymal Precursor Cells (MPC) in Diabetic Nephropathy: A Randomized, Placebo-controlled

Identification of a potential mechanism of acute kidney injury during the COVID-19 outbreak: a study based on single-cell transcriptome analysis

Bone Marrow Derived Mesenchymal Stem Cells Inhibit Inflammation and Preserve Vascular Endothelial Integrity in the Lungs after Hemorrhagic Shock

Human mesenchymal stem cells inhibit vascular permeability by modulating vascular endothelial cadherin/β-catenin signaling

Acute Kidney Injury Due to Collapsing Glomerulopathy Following COVID-19 Infection

Therapeutic effectiveness of bone marrow-derived mesenchymal stem cell administration against acute pulmonary thromboembolism in a mouse model

Early histologic findings of pulmonary SARS-CoV-2 infection detected in a surgical specimen

Factors associated with hospitalization and critical illness among 4,103 patients with COVID-19 disease in New York City

Mesenchymal stem cell perspective: cell biology to clinical progress

Hypertension is associated with increased mortality and severity of disease in COVID-19 pneumonia: A systematic review, meta-analysis and meta-regression

Concise review: Two negative feedback loops place mesenchymal stem/stromal cells at the center of early regulators of inflammation

Multiorgan and Renal Tropism of SARS-CoV-2

Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses

the wake of the pandemic Preparing for Long COVID

Complement as a target in COVID-19?

Multiple organ dysfunction in SARS-CoV-2: MODS-CoV-2

Association of Hypertension with All-Cause Mortality among Hospitalized Patients with COVID-19

Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis

The neurology of COVID-19 revisited: A proposal from the Environmental Neurology Specialty Group of the World Federation of Neurology to implement international neurological registries

Coinjection of mesenchymal stem cells with endothelial progenitor cells accelerates muscle recovery in hind limb ischemia through an endoglin-dependent mechanism

Status of SARS-CoV-2 in cerebrospinal fluid of patients with COVID-19 and stroke Cerebrovascular disease

Human dental pulp-derived stem cells promote locomotor recovery after complete transection of the rat spinal cord by multiple neuro-regenerative mechanisms

Adipose-derived Mesenchymal Stem Cells in the Treatment of Obesity: A Systematic Review of Longitudinal Studies on Preclinical Evidence

COVID-19: a hypothesis regarding the ventilation-perfusion mismatch

Aerosol and surface contamination of SARS-CoV-2 observed in quarantine and isolation care

Outcomes in Patients with Hyperglycemia Affected by COVID-19: Can We Do More on Glycemic Control? Diabetes Care

In situ detection of SARS-CoV-2 in lungs and airways of patients with COVID-19

American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients

Molecular Detection of SARS-CoV-2 Infection in FFPE Samples and Histopathologic Findings in Fatal SARS-CoV-2 Cases

Paracrine factors from mesenchymal stem cells attenuate epithelial injury and lung fibrosis

Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases

Infusion of mesenchymal stem cells ameliorates hyperglycemia in type 2 diabetic rats: Identification of a novel role in improving insulin sensitivity

High Prevalence of Obesity in Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Requiring Invasive Mechanical Ventilation

Angiogenic potential of BM MSCs derived from patients with critical leg ischemia

Stem cells as a potential therapy for diabetes mellitus: A call-to-action in Latin America

Neuropathological Features of Covid-19

Neuroinvasion of SARS-CoV-2 in human and mouse brain

Modified IMPROVE VTE Risk Score and Elevated D-Dimer Identify a High Venous Thromboembolism Risk in Acutely Ill Medical Population for Extended Thromboprophylaxis

Obesity and impaired metabolic health in patients with COVID-19

Obesity as a risk factor in venous thromboembolism

Renal histopathological analysis of 26 postmortem findings of patients with COVID-19 in China

hucMSC derived exosomes promote functional recovery in spinal cord injury mice via attenuating inflammation

Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving β-cell destruction

Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia

Myocardial localization of coronavirus in COVID-19 cardiogenic shock

The trinity of COVID-19: immunity, inflammation and intervention

Progenitor cells and TNF-alpha involvement during morphological changes in pancreatic islets of obese mice

Pulmonary Pathology of Early-Phase 2019 Novel Coronavirus (COVID-19) Pneumonia in Two Patients With Lung Cancer

VEGF is a mediator of the renoprotective effects of multipotent marrow stromal cells in acute kidney injury

Search of: MSC | COVID19 -List Results -ClinicalTrials.gov

Therapeutic potential of mesenchymal stem cells and their exosomes in severe novel coronavirus disease 2019 (COVID-19) cases. Inflammation and Regeneration

Secretomes from Mesenchymal Stem Cells against Acute Kidney Injury: Possible Heterogeneity

Human mesenchymal stem cells -current trends and future prospective

Immunology of COVID-19: Current State of the Science

Endothelial cell infection and endotheliitis in COVID-19

A review of the main histopathological findings in coronavirus disease

Atherosclerosis as pathogenetic substrate for Sars-Cov2 "'cytokine storm

Mesenchymal stem cells: Mechanisms of potential therapeutic benefit in ARDS and sepsis

Bone Marrow-Derived Mesenchymal Stem Cells-Mediated Protection Against Organ Dysfunction in Disseminated Intravascular Coagulation Is Associated With Peripheral Immune Responses

Clinical Characteristics of

Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan

Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2

Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19

Unique epidemiological and clinical features of the emerging 2019 novel coronavirus pneumonia (COVID-19) implicate special control measures

Clinical Features of 69 Cases With Coronavirus Disease

Obesity and <scp>SARS-CoV</scp> -2: A population to safeguard

Clinical management of severe acute respiratory infection when novel coronavirus (2019-nCoV) infection is suspected Interim guidance 28

Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19

OpenSAFELY: factors associated with COVID-19-related hospital death in the linked electronic health records of 17 million adult NHS patients

Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease

A new coronavirus associated with human respiratory disease in China

The outbreak of COVID-19 -overview

Nervous system involvement after infection with COVID-19 and other coronaviruses

Inflammation in Neurodegenerative Disease-A Double-Edged Sword

Evidence for Gastrointestinal Infection of SARS-CoV-2

COVID-19 Complicated by Acute Pulmonary Embolism

Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats

Prevalence of comorbidities and its effects in patients infected with SARS-CoV-2: a systematic review and meta-analysis

Pathological evidence for residual SARS-CoV-2 in pulmonary tissues of a ready-for-discharge patient

Concomitant neurological symptoms observed in a patient diagnosed with coronavirus disease 2019

COVID-19 and Multiorgan Response

Histopathologic Changes and SARS-CoV-2 Immunostaining in the Lung of a Patient With COVID-19

Clinical characteristics of 140 patients infected with SARS-CoV-2 in Wuhan

Effect of exosomes derived from multipluripotent mesenchymal stromal cells on functional recovery and neurovascular plasticity in rats after traumatic brain injury

Association of Blood Glucose Control and Outcomes in Patients with COVID-19 and Pre-existing Type 2 Diabetes

MicroRNAs e células-tronco mesenquimais: Esperança para a hipertensão pulmonar

Mesenchymal Stromal Cell Uses for Acute Kidney Injury-Current Available Data and Future Perspectives: A Mini-Review

Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection

Cardiovascular diseases DIC -Disseminated intravascular coagulation EV -Extracellular vesicles FGF -Fibroblast growth factor GM-CSF -Granulocyte macrophage colony-stimulating factor hACE2 mice -Transgenic mice expressing human ACE2 HGF -Hepatocyte growth factor IFN -Interferon IGF -Insulin growth factor-1 IL-2 -Interleukin-2 KGF -Keratinocyte growth factor

2 RAS -Renin-angiotensin system RBD -Receptor-binding domain ROS -reactive oxygen species SARS-CoV-2 -Severe acute respiratory syndrome-coronavirus 2 TGF-β -Transforming Growth Factor-beta TNF-α -Tumor necrosis factor-alpha TSG-6 -TNF-stimulated gene-6 UUO -Unilateral ureteral obstruction VEGF -Vascular endothelial growth factor VTE -Venous thromboembolism WT1 -Wilms' tumor suppressor 1 HVEM -Herpesvirus entry mediator BTLA -B-and T-lymphocyte attenuator LL-37 -Cathelicidin antimicrobial peptides LL-37 T2D -Type 2 Diabetes S protein

 COVID-19 pathophysiology affects primarily lungs but also a miryad of organs and tissues. Even recovered patients have lingering tissue dysfunction and scarring  Mesenchymal stem cells have shown immunomodulatory, angiogenic, antiinflammatory, and anti-apoptotic properties in related pre-clinical models  MSC generally improves inflamation resulotion, enhances cell survival and promotes tissue remodeling  MSC therapy may be benefetial even in high-risk patients with obesity, hypertension and diabetes