key: cord-0851126-q0chevs1
authors: Sanders, Jason; Schneider, E. Marion
title: How severe RNA virus infections such as SARS-CoV-2 disrupt tissue and organ barriers—Reconstitution by mesenchymal stem cell-derived exosomes
date: 2021-06-25
journal: Tissue Barriers in Disease, Injury and Regeneration
DOI: 10.1016/b978-0-12-818561-2.00004-7
sha: aa9d1f29eced0448880537a30f76d4b2e560afa6
doc_id: 851126
cord_uid: q0chevs1

The host tissue barriers arrange numerous lines of resistance to influx and cell-to-cell spread of pathogenic viruses. However, the highly virulent pathogens are equipped with diverse molecular mechanisms that can subvert the host countermeasures and/or exaggerate the host cell responses to toxic levels leading to severe illnesses. In his review, we discuss the immune-mediated pathogenesis of COVID-19 disease induced by the SARS-Cov-2 coronavirus. SARS-Cov-2 primarily infects type II alveolar epithelial cells. These cells are highly abundant with the ACE2 receptor protein, which occurs to be counterpart of the viral Spike protein and thus facilitates internalization of the virus. Following infection onset, the rapid clinical deterioration occurs about in a week suggesting that the respiratory failure in COVID-19 could result from a unique pattern of immune impairment characterized by severe Cytokine Release Syndrome (known as cytokine storm) leading to macrophage activation syndrome. In addition, the SARS-Cov-2 infection can induce a profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer cells, i.e., all major guardians cell components of the host immune barrier. However, while the numbers of that cells decline in the sequelae of the disease, the presence of persistent hyper-inflammation driving progressive tissue injury, suggests that the deteriorating impact of the systemic reactive responses can be more significant than the virus-induced cytopathic effects on the immunocompetent cells. In this respect, the authors discuss the emerging evidence of beneficial effects of administration of exosomes derived from mesenchymal stem cells—another sentinel-type cells—in management of the hyper-inflammatory response to SARS-CoV-2. Moreover, they also discuss the exosomes-originated mechanisms, which sustain regeneration of the damaged pulmonary lining cells and the vascular endothelial cells in various organs, including the brain.

SARS-Cov-2 is a coronavirus with a single-strand, positive-sense RNA genome with multiple open reading frames that codes for 10 proteins including the nucleocapsid and the Spike protein, which is important for infection [1] . SARS-Cov-2 primarily infects type II alveolar epithelial cells (AECs) because they have a high concentration of ACE2 receptors, which have a strong interaction with the viral Spike protein, facilitating internalization of the virus [2, 3] . COVID-19, the viral respiratory illness that results from SARS-Cov-2 infection, initially presents with mild symptoms for several days concurrent with the highest levels of viral shedding [4] . The inflammatory damage of COVID-19 follows as the natural immune response to the virus causes the release of high levels of inflammatory mediators, such as tumor necrosis factor-a (TNF-a) and interleukin-6 (IL-6), in a sustained pattern distinct from bacterial sepsis or influenza [5, 6] . The rapid clinical deterioration about 7 days after initial onset of symptoms suggests that the respiratory failure in COVID-19 results from a unique pattern of immune dysregulation characterized by macrophage activation syndrome (MAS) or profound depletion of CD4 lymphocytes, CD19 lymphocytes, and natural killer (NK) cells. The persistent immune response, despite falling viral titers in this inflammatory phase, leads to progressive organ and tissue injury, suggesting that the immune-mediated damage is more significant than the viral cytopathic damage [7, 8] .

SARS-Cov-2 induces immune dysregulation in a different pattern than influenza or SARS-CoV. Chemokines (CCL2 [MCP 1], CCL3 [MIP1a], CXCL1, CXCL5, and CXCL10) are significantly upregulated in COVID-19 and act to recruit macrophages, neutrophils, and effector T cells [9] . These inflammatory conditions are linked to defective antigen presentation. Individual viral antigens may be responsible for lymphocyte apoptosis which further drives monocytes to produce high levels of TNF-a and IL-6. TNF-a activates endothelial cells to recruit leukocytes, stimulates neutrophils, and increases the levels NF-kB, AP-1, IL-8, and caspases, which induce apoptosis of target tissues [10] . The ratio of lymphocytes to neutrophils appears to be an important predictor for outcome of COVID-19. Finally, advanced cases of COVID-19 respiratory failure are characterized by features of immune dysregulation or MAS.

Over-production of IL-6 promotes immune dysregulation with inhibition of HLA-DR expression on CD14 monocytes contributing to the impaired T cell response. IFN-g produced by CD4þ TH1, NK, and CD8þ T cells normally increases MHC class I and II to promote killing of infected cells by T cells, increased macrophage activity and production of IgG antibodies, but there are very low levels of IFN-g detected in COVID-19. Immune dysregulation caused by COVID-19 features lower counts of CD4þ T cells, CD8þ T cells, and NK cells than at the intermediate immune state. Recently, SARS-CoV2 specific genes have been identified which counter-regulate appropriate interferon responses in COVID-19. Infection by SARS-CoV-2 is characterized by fewer CD4þ T cells but more NK cells and B cells than H1N1 influenza. IL-17 production, indicating Th17 function, is downregulated in COVID-19 patients with immune dysregulation. There is also some evidence to suggest that SARS-Cov-2 infects and induces apoptosis of T lymphocytes, such as CD4þ TH1 cells that activate macrophages, CD4þ TH17 cells that activate neutrophils, and CD8þ cytotoxic T cells that kill infected cells. NK cells that kill infected or damaged cells are also reduced in SARS-CoV and SARS-CoV2 infection possibly resulting from the rapidly propagating virus [11] . In some cases of COVID-19, elevated levels of IL-1b promote a MAS with a pattern that may be similar to secondary hemophagocytic lymphohistiocytosis [12, 13] .

The massive release of inflammatory mediators termed cytokine storm can cause an acute lung injury (ALI) characterized by disruption of junctions between cells, damage to AECs, damage to pulmonary capillary endothelial cells, and loss of alveolar fluid clearance mechanism [14, 15] . Inflammatory mediators (cytokines and chemokines) released by type II AECs increase vasodilation, leukocyte adhesion, and capillary permeability [16, 17] . Proteolytic enzymes and reactive oxygen species released by neutrophils and macrophages within the alveoli damage alveolar cells and the extracellular matrix [18, 19] . Disruption of the junctions between the cells in the alveolar-capillary barrier promotes recruitment of nonspecific immune cells (e.g., neutrophils, macrophages) and allows exudative leak from the pulmonary capillaries [20] . In this context, the detrimental role of the kallikrein-bradykinin system is likely responsible for extensive fluid loss and inflammation for endothelial barriers. Neutrophils, macrophages, and other immune cells thus evade from the circulation, accumulate in the lungs, and increase their release of inflammatory mediators creating a positive feedback loop.

Viral inhibition of ACE2-mediated inactivation of des-Arg bradykinin and proinflammatory cytokine-mediated upregulation of bradykinin receptor type 1 (B1) on endothelial cells may cause pulmonary angioedema consistent with the radiographic findings of COVID-19 [21] , which is in part because of increased expression of bradykinin receptor 2 (B2). The diffuse alveolar damage and angioedema could progress to acute respiratory distress syndrome with accumulation of proteinaceous fluid in alveoli that interferes with arterial oxygenation. This proteinous fluid consists of gelatinous hyaluronic acid and explains the opaque signs of COVID-19 lung images ( Fig. 3.1 ). Diffuse thrombosis in the pulmonary vasculature and ventilator pressure support may also increase pulmonary artery pressure causing pulmonary hypertension, which could have secondary cardiovascular effects.

Endogenous repair systems that regulate the immune response and stimulate tissue regeneration exist to promote recovery from ALI but may How severe RNA virus infections be overwhelmed by the cytokine storm of COVID-19. The natural regulatory mechanisms of the immune system include production of antiinflammatory cytokines such as IL-10, TGF-b3, and IL-1ra, as well as immune cells with more regulatory phenotypes such as M2 macrophages and regulatory T cells [22] . Antiinflammatory cytokines (IL-10) promote phenotypes by polarizing M1 macrophages, which release high levels of inflammatory mediators, into tissue regenerative M2 macrophages, which release much lower levels of inflammatory mediators and also improve phagocytosis of cell debris, and danger ligands [23e25]. Antiinflammatory cytokines (TGF-b3) promote polarization of T lymphocytes from TH1, which produce high levels of inflammatory mediators to Treg cells, which regulate the cytotoxic activity of cytotoxic T lymphocytes (CTLs) and NK cells [26] . Regenerative cytokines including Ang-1, KGF, HGF, VEGF, EGF, Tsp1, S1P promote repair of the junctions between cells in the alveolar-capillary barrier, repair of the damaged alveoli and bronchioles by type II AECs and bronchoalveolar stem cells, and repair of pulmonary capillaries by epithelial cells [27e30]. 

In newborns and young children, mesenchymal stem cells (MSCs) are found in almost every organ and tissue. In adults, these large amounts of MSCs have been shown to be restricted to fat tissues including the bone marrow (BM). In addition to their potential to function as progenitors, MSCs have demonstrated the capacity to modulate the immune response and promote tissue regenerat ion. MSCs exert their paracrine effects through the release of soluble mediators including anti-inflammatory and regenerative cytokines and extracellular vesicles containing transcriptionally active RNA species, such as miRNA, lncRNA, and effector species. These soluble mediators and RNA species could potentially arrest the inflammatory response, repair the damage to the alveoli and pulmonary capillaries, and allow the immune system to clear the virus [20,30e36] . A Chinese study at Shanghai University on COVID-19 treatment using a master cell bank created from stromal progenitor cells harvested from lipoaspirate successfully treated seven patients who recovered, while three patients treated with placebo progressed to severe viral pneumonia or death [37] . An Israeli study of COVID-19 treatment using a clonal cell line of expanded, placental, MSCs treated six critically ill COVID-19 patients under a compassionate use program and demonstrated improvement in respiratory parameters and a 100% survival rate [38] . In the Israel study, four patients had other organ failures (cardiovascular, renal failure) and the placental MSCs therapy promoted recovery of the other organ failures as well as improvement in unrelated pre-existing conditions. Nearly 1000 clinical trials investigating administration of MSCs derived from sources such as BM, adipose tissue, cord blood, and others have also demonstrated a well-established safety profile of MSCs [39] .

MSCs exert the vast majority of their paracrine effects through the release of EVs, vesicles of roughly 50e1000 nm in diameter that are secreted by all cell types [40] . Small EVs (sEVs, 30e200 nm diameter, (Fig. 3.2) , harvested using different protocols from cell culture supernatants of MSCs grown under diverse culture conditions, have been reported to be therapeutically active in various preclinical models [41] . EVs further may be responsible for the tissue regenerative effects observed with atopically transplanted MSCs in various animal models. The origin of MSC-sEVs, a population of exosomes and small microvesicles produced by MSCs, suggests a similar safety profile to their parent cells that could expedite the development of clinical applications.

MSCs-EVs are internalized by target cells through endocytosis, and delivery of RNA species influences the behavior of these cells. Noncoding RNA such as miRNA, abundant in MSC-sEVs, target specific processes and pathways within target cells. The RNA content of MSC-sEVs confers their biological properties, which include being anti-inflammatory (e.g., miR1, miR100, miR181c), immunomodulatory (e.g., miR146a), proangiogenic (e.g., let-7, miR29), prosynthetic (e.g., miR92-3p, miR140-5p), antiapoptotic (e.g., miR21, miR199a), antifibrotic (e.g., miR21, miR23a, miR125b), and tumor suppressive (e.g., miR15a, miR145) ( Fig. 3.2) . It is important to note that the biological effects of MSC-sEVs are not the result of any single factor, but rather the combined activity of the abundant RNA moleculesaffecting multiple cellular pathways in the context of target cell behavior prior to internalization.

Internalization of MSC-sEVs by cells exhibiting pathologic behavior may influence cellular pathways to regulate the hyperinflammatory response to SARS-CoV-2 and promote regeneration of damaged pulmonary and other tissues. MSC-sEVs may positively regulate expression of proteins such as TGF-b3, IL-10, IL-4, TNFR, IL-1ra, and HGF that could modulate the excessive immune response that contributes to tissue damage in COVID- 19 [42e53] . MSC-sEVs could also promote alveolar tissue regeneration through Enhanced expression of angiopoietin-1 after endocytosis of MSC-sEVs could also promote alveolar tissue regeneration and decrease alveolar-capillary barrier permeability in ALI [28, 29] . MSC-sEV induced expression of KGF (FGF-7) may also contribute to repair of AECs and increased alveolar fluid clearance [27] . EGF and HGF expression induced by MSC-sEVs has been demonstrated to be mitogenic for type II AECs and promoted alveolar regeneration [54] . One small cohort study in humans demonstrated direct evidence of a therapeutic benefit of MSC-sEVs in the treatment of COVID-19 with significant improvements in absolute neutrophil count, lymphopenia and acute phase reactants including C-reactive protein, ferritin, and D-dimer. Another phase I study of exosomes bearing CD24 also demonstrated complete recovery in all 30 patients with moderate to severe COVID-19, and recovery within three to five days in 29 of these patients.() Transfer of MSC-sEV miRNA has also demonstrated beneficial effects on pathologic cellular processes that are believed to contribute to the pathogenesis of COVID-19. miR-455-3p inhibited the activation and cytokine production of macrophages challenged with lipopolysaccharide (LPS) both in vivo and in vitro and reduced levels of IL-6, G-CSF, IL-17, IL-10, IP-10 (CXCL10), MCP-1 (CCL2) [55] . miR-146a-5p targeted the expression of IRAK-1 and TRAF-6, significantly suppressed LPSmediated TNF-a, IL-6, and IL-1b induction in alveolar macrophages, and increased IL-10, M2 macrophage polarization, and phagocytosis [56e60]. miR-223 targeted the transcription factor Pknox1 decreasing IL-1b, TNF-a, IL-6, and NF-kB, suppressed the proinflammatory activation of macrophages and promoted the alternative antiinflammatory M2 phenotype [61, 62] . miR-511-3p targeted Rho-associated coiled-coil containing protein kinase 2 (Rock2), which is a serine threonine kinase that phosphorylates IRF4, and thus promoted the expression of M2-related genes [63] Fig. 3.2 , MiR-100, an mTOR inhibitor, positively regulated autophagy, attenuated bleomycin-induced cellular apoptosis in type II AECs and reduces the levels of proinflammatory cytokines IL-6, IL-8, and TNF-a [64] . miR-30b-3p and miRNA-21-5p reduced apoptosis of AECs ALI induced by LPS and ischemia-reperfusion injury, respectively [65, 66] . miR-615-5p is an antiangiogenic microRNA targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2) that interfered with eNOS (endothelial nitric oxide synthase) signaling which contributes to endothelial leakage [67] . Furthermore, nine miRNA molecules identified by bioinformatic analysis to be complementary to the SARS-Cov-2 viral genome could be candidates to interfere with viral RNA transcription or protein translation essential for viral replication [68, 69] . An example of miRNAs identified from EVs of placental derived mesenchymal stem cells is shown Fig. 3.3 .

Modulation of the hyperinflammatory immune response through reduction of inflammatory mediators, increased expression ofanti-inflammatory mediators, decreased influx of inflammatory cells (neutrophils, M1 macrophages), increased polarization into M2 macrophages providing high capacity to eliminate tissue debris (Fig. 3.3) , and differentiation of a regulatory T cell phenotype could arrest the progression of the lung damage in COVID-19. Consequently, intercellular junctions between alveolar cells and pulmonary capillary endothelial cells could be regenerated along with AEC repair. Degradation of hyaluronic acid accumulating in ARDS lungs and improved mucociliary activity are likely to improve clearance of alveolar fluid and debris. Also, if the nine human miRNA molecules found to be complementary to the SARS-Cov-2 RNA genome can demonstrate any direct or indirect activity to inhibit viral replication, as in the cases of other RNA viruses such as influenza and hepatitis C, MSC-sEVs could interfere with viral replication [71e78].

Investigation of MSC-sEVs in preclinical models of ALI and ARDS have demonstrated significant reduction in inflammatory mediators, inflammatory cell influx, AEC apoptosis, bacterial load, and viral replication, as well as significant improvement in anti-inflammatory mediators, alveolar-capillary barrier permeability, monocyte phagocytosis and alveolar-arterial oxygen gradient [25,28,29,79e81] . Preclinical studies of MSC exosomes as therapy for influenza virus-induced ALI (similar to COVID-19 pulmonary disease) in a clinically relevant swine model demonstrated inhibition of virusinduced apoptosis in AECs, inhibition of influenza virus replication through miRNA transfer, decreased virus shedding, decreased virus replication in the lungs, and decreased production of proinflammatory cytokines [82] .

Early clinical studies demonstrating 100% clinical recovery rate from COVID-19 with systemic administration of adipose-derived stromal progenitor cells and placental MSCs, whose mechanism of action is transfer of EVs, also suggest potential efficacy of MSC-sEVs produced by these types of cells. One small cohort study in humans demonstrated direct evidence of a therapeutic benefit of MSC-sEVs in the treatment of COVID-19 with significant improvements in absolute neutrophil count, lymphopenia and acute phase reactants including C-reactive protein, ferritin, and D-dimer. Another phase I study of exosomes bearing CD24 also demonstrated complete recovery in all 30 patients with moderate to severe COVID-19, and recovery within three to five days in 29 of these patients. (https:// www.jpost.com/health-science/tel-aviv-hospital-cures-29-of-30-covid-19patients-in-days-it-says-658024) . The vast majority of these studies have focused on bone marrow-derived MSC (BM-MSC) exosomes, perhaps because they were the first type to be isolated. The remainder of these studies have evaluated adipose tissue-(AT-MSC), umbilical cord-(UC-MSC) and placentaderived (P-MSC) exosomes to a lesser extent [90] . Comparative studies of these types of MSC exosomes have demonstrated that their cargo and bioactivity differ significantly [91] . It is important to note that the type and state of the producer cells significantly influences the bioactivity of the exosomes they release. Placental MSCs have demonstrated greater immunomodulatory effects and regenerative capacity than bone marrow, adipose and umbilical cord derived MSCs [92, 93] . Also, whereas placental MSCs are isolated from perinatal donor tissue usually discarded as medical waste, bone marrow-and adipose-derived MSCs are most commonly isolated from adult donor tissue. Perhaps as a result of changes associated with aging or environmental exposure, BM-MSC and AT-MSC exosomes have demonstrated some tumorigenic and pro-metastatic effects in preclinical studies [94, 95, 96, 97] . As suggested by preclinical studies in which RNAse treatment of MSC exosomes abrogates their bioactivity, this malignant behavior may correlate with the miRNA cargo of these types of MSC exosomes. The miRNA content of BM-MSC exosomes differs significantly from that of P-MSC exosomes [98] . In the case of BM-MSC exosomes, the most abundant microRNA species is miR-1246, which has demonstrated significant oncogenic and metastatic effects. This microRNA species is not present in biologically significant quantities in P-MSC exosomes. Instead, the abundant miRNAs identified in PMSC exosomes participate in important tissue reconstitution, anti-inflammatory pathways and tumor suppression [98] . MSC exosomes hold tremendous potential for the reconstitution of natural tissue barriers, such as the alveolarcapillary barrier that is disrupted in COVID-19, as well as those barriers disrupted in many other clinical conditions. Knowing that the producer cell type and environment strongly influence the character and bioactivity of the exosomes secreted, the development of exosome-based therapeutics for conditions such as COVID-19 and acute lung injury will require optimal producer cell selection, standardized biomanufacturing protocols and rigorous quality management standards. Orthogonal exosome characterization methods including mass spectrometry proteomics and lipidomics, RNA sequencing, nano-flow cytometry and electron microscopy will help to confirm optimal purity and consistency of these products and enable the development and eventual clinical use upon regulatory approval of this next generation of biopharmaceuticals.

The miRNAs of certain mesenchymal stem cell-derived exosomes participate in important tissue reconstitution and anti-inflammatory pathways (Fig. 3.3 ).

Isolated MSC-sEVs derived from cultures of P-MSCs of fetal origin can be primed with an optimal combination of IL-6, IFN-g, IL-1b, and Poly (I:C) or overexpressing specific miRNA could be an excellent drug candidate for clinical trials such as for COVID-19. The investigational study participant population could be inclusive of for patients suffering from post COVID-19 disease, because MSC exosomes may be able to arrest the progression of fibrosis in pulmonary disease, and may influence the detrimental progression of autoimmunity [99] .

The process of exosome enrichment for in-vitro, ex-vivo (whole blood assays), and the application in-vivo requires highly purified and well-defined material. Among different biochemical and molecular methods, electron microscopy performed under most stringent conditions of biological structure preservation is highly valid (Fig. 3.4) .

In vivo, exosomes may attenuate inflammation and eventually reconstitute endothelial barrier function in acute respiratory distress syndromes, primarily by reconstituting the balance of pro-(M1) and antiinflammatory macrophages (M2) as schematically demonstrated (Fig. 3.3) , In this illustration the preferential release of exosomes targeted by MSC-derived exosomes may constitute a highly relevant amplification mechanism occuring at the site of damage and inflammation. This local amplification mechanism would be followed by resolution of thrombotic elements in small vessels of other organs as well. 

The establishment of reference sequence for SARS-CoV-2 and variation analysis

SARS-CoV-2 receptor ACE2 and TMPRSS2 are primarily expressed in bronchial transient secretory cells

SARS-CoV replicates in primary human alveolar type II cell cultures but not in type I-like cells

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Lung epithelial cells: therapeutically inducible effectors of antimicrobial defense

COVID-19: immunopathology and its implications for therapy

A novel coronavirus associated with severe acute respiratory syndrome

Temporal dynamics in viral shedding and transmissibility of COVID-19

Comparative replication and immune activation profiles of SARS-CoV-2 and SARS-CoV in human lungs: an ex vivo study with implications for the pathogenesis of COVID-19. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, ciaa410. Advance online publication

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

The involvement of natural killer cells in the pathogenesis of severe acute respiratory syndrome

Level of IL-6 predicts respiratory failure in hospitalized symptomatic COVID-19 patients

Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies

Pathological study on severe acute respiratory syndrome

Administration of microparticles from blood of the lipopolysaccharide-treated rats serves to induce pathologic changes of acute respiratory distress syndrome

Innate immune response of human alveolar type II cells infected with severe acute respiratory syndrome-coronavirus

Cellular and molecular immunology

Severe acute respiratory syndrome (SARS) coronavirus-induced lung epithelial cytokines exacerbate SARS pathogenesis by modulating intrinsic functions of monocyte-derived macrophages and dendritic cells

Pathology and pathogenesis of severe acute respiratory syndrome

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

Kinins and cytokines in COVID-19: a comprehensive pathophysiological approach

Therapeutic potential of regulatory cytokines that target B cells

Regulation of the IL-10-driven macrophage phenotype under incoherent stimuli

Mesenchymal stem cell derived secretome and extracellular vesicles for acute lung injury and other inflammatory lung diseases

Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer

Reevaluation of pluripotent cytokine TGF-b3 in immunity

Conditioned media from mesenchymal stromal cells restore sodium transport and preserve epithelial permeability in an in vitro model of acute alveolar injury

Mesenchymal stem cell microvesicles restore protein permeability across primary cultures of injured human lung microvascular endothelial cells

Mesenchymal stem cell microvesicles attenuate acute lung injury in mice partly mediated by Ang-1 mRNA

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

Prevention of LPS-induced acute lung injury in mice by mesenchymal stem cells overexpressing angiopoietin 1

Mesenchymal stem cells reduce inflammation while enhancing bacterial clearance and improving survival in sepsis

Modulation of bone marrow stromal cell functions in infectious diseases by toll-like receptor ligands

Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37

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

Mesenchymal stem/stromal cells (MSCs): role as guardians of inflammation

Transplantation of ACE2-mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia

Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications

Applying extracellular vesicles based therapeutics in clinical trials e an ISEV position paper

Mesenchymal stem/stromal cell-derived extracellular vesicles and their potential as novel immunomodulatory therapeutic agents

Combination of adipose-derived mesenchymal stem cells (ADMSC) and ADMSC-derived exosomes for protecting kidney from acute ischemia-reperfusion injury

Hepatoprotective effect of exosomes from human-induced pluripotent stem cell-derived mesenchymal stromal cells against hepatic ischemia-reperfusion injury in rats

Microvesicles derived from human Wharton's Jelly mesenchymal stromal cells ameliorate renal ischemia-reperfusion injury in rats by suppressing CX3CL1

Exosomes derived from human menstrual bloodderived stem cells alleviate fulminant hepatic failure

The immunosuppressive effect of mesenchymal stromal cells on B lymphocytes is mediated by membrane vesicles

Immunomodulatory potential of human adipose mesenchymal stem cells derived exosomes on in vitro stimulated T cells

Microvesicles derived from mesenchymal stem cells: potent organelles for induction of tolerogenic signaling

Immunoregulatory effects of mesenchymal stem cell-derived extracellular vesicles on T lymphocytes

Human mesenchymal stem cell-derived microvesicles modulate T cell response to islet antigen glutamic acid decarboxylase in patients with type 1 diabetes

Microvescicles derived from mesenchymal stromal cells are not as effective as their cellular counterpart in the ability to modulate immune responses in vitro

Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization

LPS-preconditioned mesenchymal stromal cells modify macrophage polarization for resolution of chronic inflammation via exosome-shuttled let-7b

Comparison of biological characteristics of mesenchymal stem cells derived from the human umbilical cord and decidua parietalis

Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate IL-6-induced acute liver injury through miR-455-3p

Myeloid cell-targeted miR-146a mimic inhibits NF-kB-driven inflammation and leukemia progression in vivo

Upregulation of miR-146a contributes to the suppression of inflammatory responses in LPS-induced acute lung injury

Upregulation of miR-146a contributes to the suppression of inflammatory responses in LPS-induced acute lung injury

MicroRNAs miR-146a/b negatively modulate the senescence-associated inflammatory mediators IL-6 and IL-8

Exosomal miR-146a contributes to the enhanced therapeutic efficacy of interleukin-1b-primed mesenchymal stem cells against sepsis

A novel regulator of macrophage activation: miR-223 in obesityassociated adipose tissue inflammation

Impact of miR-223-3p and miR-2909 on inflammatory factors IL-6, IL-1ß, and TNF-a, and the TLR4/ TLR2/NF-kB/STAT3 signaling pathway induced by lipopolysaccharide in human adipose stem cells

miR-511-3p modulates genetic programs of tumor-associated macrophages

Microvesicles derived from human Wharton's jelly mesenchymal stem cells enhance autophagy and ameliorate acute lung injury via delivery of miR-100

Exosomes derived from microRNA-30b-3p-overexpressing mesenchymal stem cells protect against lipopolysaccharide-induced acute lung injury by inhibiting SAA3

Mesenchymal stromal cells-derived exosomes alleviate ischemia/reperfusion injury in mouse lung by transporting anti-apoptotic miR-21-5p

MicroRNA-615-5p regulates angiogenesis and tissue repair by targeting AKT/eNOS (protein kinase B/endothelial nitric oxide synthase) signaling in endothelial cells

Comparative analyses of SAR-CoV2 genomes from different geographical locations and other coronavirus family genomes reveals unique features potentially consequential to host-virus interaction and pathogenesis

Computational analysis of microRNA-mediated interactions in SARS-CoV-2 infection

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

Cellular microRNAs inhibit replication of the H1N1 influenza A virus in infected cells

The micro-RNA miR-485 targets host and influenza virus transcripts to regulate antiviral immunity and restrict viral replication

Human miR-3145 inhibits influenza A viruses replication by targeting and silencing viral PB1 gene

Cellular microRNA let-7c inhibits M1 protein expression of the H1N1 influenza A virus in infected human lung epithelial cells

Dissecting the role of COPI complexes in influenza virus infection

Human host factors required for influenza virus replication

Micro-RNA-Based attenuation of influenza virus across susceptible hosts

Exosomal MicroRNAs derived from umbilical mesenchymal stem cells inhibit hepatitis C virus infection

Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice

Microvesicles derived from human mesenchymal stem cells restore alveolar fluid clearance in human lungs rejected for transplantation

Therapeutic effects of human mesenchymal stem cell microvesicles in an ex vivo perfused human lung injured with severe E. coli pneumonia

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

Comparative analysis of human mesenchymal stem cells from bone marrow and adipose tissue under xenofree conditions for cell therapy

Exosomes derived from bone marrow mesenchymal stem cells promote osteosarcoma development by activating oncogenic autophagy

miR-221-3p delivered by BMMSC-derived microvesicles promotes the development of acute myelocytic leukemia

Platelets enhance the ability of bone-marrow mesenchymal stem cells to promote cancer metastasis

An efficient protocol to generate placental chorionic plate-derived mesenchymal stem cells with superior proliferative and immunomodulatory properties

Therapeutic effects of human mesenchymal stem cell-derived microvesicles in severe pneumonia in mice

Extracellular vesicles from interferon-g-primed human umbilical cord mesenchymal stromal cells reduce Escherichia coli-induced acute lung injury in rats

Stem cell research & therapy

Prothrombotic autoantibodies in serum from patients hospitalized with COVID-19