Thereby, MSC reveal a potential to control exacerbated inflammation, not only in affected lung as the prime site of injury, but also in the heart, kidneys, or intestinal microenvironment [134,135]

Thereby, MSC reveal a potential to control exacerbated inflammation, not only in affected lung as the prime site of injury, but also in the heart, kidneys, or intestinal microenvironment [134,135]. Furthermore, protection and regeneration of alveolar epithelial cells may be promoted by the MSC-released paracrine molecules, particularly those with proangiogenic and antiapoptotic efficacy such as angiopoietin 1 (ANGPT1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), and hepatocyte growth factor (HGF) [136]. However, licensed COVID-19 vaccines remain the most effective weapon in combating the pandemic. While there is an enormous effort to enhance the vaccination rate to increase the entire population immunity, the production and delivery of vaccines is becoming limited in several countries. In this regard, there are new challenges needing to be resolved by combining non-pharmacological intervention with effective therapies until vaccination is accessible to all. (TGF-), TNF- em /em -stimulated gene/protein 6 (TSG-6), superoxide dismutase (SOD), cyclooxygenase-2 (COX-2), prostaglandin-E2 (PGE2), and indoleamine 2,3 dioxygenase (IDO), which, by acting via different pathways, redirect immune cells toward an anti-inflammatory phenotype [131]. In addition, MSC regulates phagocytosis and tissue regeneration by macrophage polarization from an inflammatory M1 phenotype into an anti-inflammatory M2 phenotype [132]. All those bioactive molecules together frame an anti-inflammatory environment with a predominance of Treg cells and reduced cytokine storm profile [129,133]. Thereby, MSC reveal a potential to control exacerbated inflammation, not only in affected lung as the primary site of injury, but also in the heart, kidneys, or intestinal microenvironment [134,135]. Furthermore, protection and regeneration of alveolar epithelial cells may be promoted by the MSC-released paracrine molecules, particularly those with proangiogenic and antiapoptotic efficacy such as angiopoietin 1 (ANGPT1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), and hepatocyte growth factor (HGF) [136]. Other MSC-derived paracrine mediators are contributing to extracellular matrix (ECM) remodeling and to tissue healing with decreased scarring processes [137]. To date, an increasing quantity of studies suggest that many of these paracrine effects are also mediated via small Gap 27 extracellular vesicles (EVs) recognized as exosomes and microvesicles included in the MSC secretome [138]. MSC-derived EVs (MSC-EVs) are plasma membrane structures that carry lipids, proteins/peptides, DNA, mRNA, and non-coding microRNAs [139]. In particular, miRNAs such as Let-7, miR-34a, miR-2b/c, and miR-146 are implicated in downregulation of IL-6, reduction of match induced cytolysis, and regulation of NF-kB, and thus are taken as a whole, exerting Gap 27 anti-inflammatory and cytoprotective properties [139,140,141]. Interestingly, mitochondrial transfer from MSC to immune cells and respiratory epithelial cells has also been described. This unique intercellular transmission mechanism led to downregulation of inflammation and recovery of aerobic respiration in lungs Court et al., 2020, Han et al., 2020. MSC may affect secondary bacterial infection manifested during or after viral contamination through the secretion of antimicrobial factors, such as peptide LL-37 and lipocalin-2. Both promote migration and phagocytosis of macrophages, leading to pulmonary bacterial clearance [142]. Some studies point to possible antiviral mechanisms of MSC. Especially, undifferentiated progeny of MSC express constitutively elevated levels of specific interferon (IFN)-stimulated genes (ISG) including interferon-induced transmembrane family (IFITM) proteins (IFI6, ISG15, SAT1, PMAIP1, p21/CDKN1A). These proteins are capable of preventing viruses from crossing the lipid bilayer of the host cell and accessing the cytoplasm as well as blocking mRNA transcription, nuclear transport, amplification, and computer virus assembly and release [143,144]. In addition, pro-inflammatory cytokines, including IFN-, may further enhance level of antiviral proteins and induce innate defense that could lead to therapeutic benefits in COVID-19 patients. Thus, MSC interferon regulatory mechanisms may include both intrinsic (constitutive antiviral proteins) and inducible (secondary response to IFN) antiviral defense. On the other hand, it is necessary to mention that there are also studies showing that bone marrow-derived (BM) MSC can support replication of both avian H1N1 and H9N5 influenza strains; therefore, precious antiviral effects still remain to be decided [145]. In summary, due to the known and confirmed immunomodulatory effect of MSC, the therapy of COVID-19 patients should aim for very severe cases in which an uncontrolled immune response accompanied by cytokine storm, crucial ARDS, and systemic organ pathology is developed [143,146]. Thus, it should be contraindicated at the beginning of infection when physiological inflammation is fighting against the virus [147]. Furthermore, with regards to MSC-based therapy, several important challenges need to be addressed, principally, the selection of high quality MSC, the effective route of MSC delivery, appropriate dosing and timing, and the following of ethical and moral guidelines applicable for cell-based clinical trials [148,149]. Therefore, to achieve successful MSC-cell based therapies with effective and significant results for COVID-19 patients, one must prepare well-designed, randomized, placebo-controlled, large patient cohorts and controlled clinical trials [150]. 4. Prevention Vaccine Development As vaccines are considered the most promising way to eradicate the SARS-CoV-2 virus, several teams are intensively working on vaccine development [151]. Vaccines are being developed with different technologies, some well-known and others.In addition, for innovative approaches including peptides, ACE-2 inhibitors, and cell therapy, large and randomized clinical trials are still necessary. review, we summarize the progressive development of various treatments and vaccines as they have emerged, a year after the outbreak of the pandemic. Initially for COVID-19, patients were recommended drugs with presumed antiviral, anti-inflammatory, and antimicrobial effects that were previously used to treat other diseases. Thereafter, therapeutic interventions were supplemented with promising approaches based on antibodies, peptides, and stem cells. However, licensed COVID-19 vaccines remain the most effective weapon in combating the pandemic. While there is an enormous effort to enhance the vaccination rate to increase the entire population immunity, the production and delivery of vaccines is becoming limited in several countries. In this regard, there are new challenges needing to be addressed by combining non-pharmacological intervention with effective therapies until vaccination is accessible to all. (TGF-), TNF- em /em -stimulated gene/protein 6 (TSG-6), superoxide dismutase (SOD), cyclooxygenase-2 (COX-2), prostaglandin-E2 (PGE2), and indoleamine 2,3 dioxygenase (IDO), which, by acting via different pathways, redirect immune cells toward an anti-inflammatory phenotype [131]. In addition, MSC regulates phagocytosis and tissue regeneration by macrophage polarization from an inflammatory M1 phenotype into an anti-inflammatory M2 phenotype [132]. All those bioactive molecules together frame an anti-inflammatory environment with a predominance of Treg cells and reduced cytokine storm profile [129,133]. Thereby, MSC reveal a potential to control exacerbated inflammation, not only in affected lung as the prime site of injury, but also in the heart, kidneys, or intestinal microenvironment [134,135]. Furthermore, protection and regeneration of alveolar epithelial cells may be promoted by the MSC-released paracrine molecules, particularly those with proangiogenic and antiapoptotic efficacy such as angiopoietin 1 (ANGPT1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), keratinocyte growth factor (KGF), and hepatocyte growth factor (HGF) [136]. Other MSC-derived paracrine mediators are contributing to extracellular matrix (ECM) remodeling and to tissue healing with decreased scarring processes [137]. To date, an increasing number of studies suggest that many of these paracrine effects are also mediated via small extracellular vesicles (EVs) recognized as exosomes and microvesicles included in the MSC secretome [138]. MSC-derived EVs (MSC-EVs) are plasma membrane structures that carry lipids, proteins/peptides, DNA, mRNA, and non-coding microRNAs [139]. In particular, miRNAs such as Let-7, miR-34a, miR-2b/c, and miR-146 are implicated in downregulation of IL-6, reduction of complement induced cytolysis, and regulation of NF-kB, and thus are taken as a whole, exerting anti-inflammatory and cytoprotective properties [139,140,141]. Interestingly, mitochondrial transfer from MSC to immune cells and respiratory epithelial cells has also been described. This unique intercellular transmission mechanism led to downregulation of inflammation and recovery of aerobic respiration in lungs Court et al., 2020, Han et al., 2020. MSC may affect secondary bacterial infection manifested during or after viral infection through the secretion of antimicrobial factors, such as peptide LL-37 and lipocalin-2. Both promote migration and phagocytosis of macrophages, leading to pulmonary bacterial clearance [142]. Some studies point to possible antiviral mechanisms of MSC. Especially, undifferentiated progeny of MSC express constitutively elevated levels of specific interferon (IFN)-stimulated genes (ISG) including interferon-induced transmembrane family (IFITM) proteins (IFI6, ISG15, SAT1, PMAIP1, p21/CDKN1A). These proteins are capable of preventing viruses from crossing the Gap 27 lipid bilayer of the host cell and accessing the cytoplasm as well as blocking mRNA transcription, nuclear transport, amplification, and virus assembly and release [143,144]. In addition, pro-inflammatory cytokines, including IFN-, may further enhance level of antiviral proteins and induce innate defense that could lead to therapeutic benefits in COVID-19 patients. Thus, MSC interferon regulatory mechanisms may include both intrinsic (constitutive antiviral proteins) and inducible (secondary response to IFN) antiviral defense. On the other hand, TIMP2 it is necessary to mention that there are also studies showing that bone marrow-derived (BM) MSC can support replication of both avian H1N1 and H9N5 influenza strains; therefore, precious antiviral effects still remain to be determined [145]. In summary, due to the known and proven immunomodulatory effect of MSC, the therapy of COVID-19 patients should aim for very severe cases in which an uncontrolled immune response accompanied by cytokine storm, critical ARDS, and systemic organ pathology is developed [143,146]. Thus, it should be contraindicated at the beginning of infection when physiological inflammation is fighting against the virus [147]. Furthermore, with regards to MSC-based therapy, several important challenges need to be addressed, principally, the selection of high quality MSC, the effective route of MSC delivery, appropriate dosing and timing, and the following of ethical and moral guidelines applicable for cell-based clinical trials [148,149]. Therefore, to achieve successful MSC-cell based therapies with effective and significant results for COVID-19 patients, one must prepare well-designed, randomized, placebo-controlled, large patient cohorts and controlled clinical trials [150]. 4. Prevention Vaccine Development As vaccines are considered the most promising way to eradicate the SARS-CoV-2 virus, several teams are intensively working on vaccine development [151]. Vaccines are becoming developed with.