key: cord-0919820-lqkii4c6 authors: Çetin, Zafer title: Targeting the PANoptosome with miRNA Loaded Mesenchymal Stem Cell Derived Extracellular Vesicles; a New Path to Fight Against the Covid-19? date: 2021-04-13 journal: Stem Cell Rev Rep DOI: 10.1007/s12015-021-10166-2 sha: b674fb328b84dd0da6fef5350f83870ebebe7150 doc_id: 919820 cord_uid: lqkii4c6 nan apoptosis and necroptosis is executed through Gasermin D (GSDMD), Caspases 3/6/7 and Mixed Lineage Kinase Domain-Like Protein (MLKL) proteins, respectively [8] . Although Lee et al. stated that SARS-CoV-2 infection does not activate necroptosis arm of the PANoptosis there are also publications suggesting the opposite [9] . The study conducted by Zheng et al., and observed that PANoptosis is induced by NLRP3 in bone marrow-derived macrophages infected with Murine Hepatitis Virus, which is murine corona virus, shows that corona viruses can induce PANoptosis [10] . Also in another report it was stated that cytokines TNF-α and IFN-γ, which are related to SARS-CoV-2 infection, stimulated the pyroptosis, apoptosis, and necroptosis pathways with a synergistic effect in mouse bone marrow derived macrophages while blokage of Signal Transducer And Activator Of Transcription 1 (STAT1) / Interferon Regulatory Factor 1n (IRF1) pathway suppressed PANoptosis [11] . In some studies on Covid-19 patients, it was determined that cell death pathways are activated in different types of cells. It is known that apoptosis is increased in B and T-cells in the peripheral blood of Covid-19 patients and it is associated with the disease severity [12, 13] . Li et al., reported that, in the lung biopsy materials obtained from two patients apoptosis and pyroptosis increased in type 1 and 2 pneumocyte and endothelial cells [14] . It has also been shown that inflammation-mediated pyroptosis is activated in monocytes infected with SARS-CoV-2 and in monocytes of Covid-19 patients [15] . Also in some reports it was reported that, PANoptosome components were overexpressed or activated in cells of Covid-19 patients. In a report it was suggested that the level of RIPK3 in the peripheral blood of patients with a severe course of Covid-19 was higher compared to patients with a mild course [16] . One of the components of the PANoptosome complex is NLRP3. Analysis of SARS-Cov-2 infected Calu-3 lung epithelial cells and lung tissue of patients who died due to Covid-19 showed that apoptotic and necroptotic pathways were activated by NLRP3 and Caspase 8 [17] . Studies conducted in peripheral blood mononuclear cells of Covid-19 patients and in tissue samples taken from patients who died due to Covid-19 have shown that NLRP3 inflammasomes are activated [18, 19] . Beyond that, there are publications stating that one of the mechanisms of action of chloroquine and hydroxychloroquine drugs might be to suppress the NLRP3 inflammasome [20] . However, it should be kept in mind that the clinical studies conducted show that the use of hydroxychloroquine in patients hospitalized due to Covid-19-induced lung distress has no superiority over placebo [21] . In addition, it is another important issue that the use of chloroquine and hydroxychloroquine has been shown to cause cardiac toxicity in Covid-19 patients [22] . Proteomic analysis performed on the plasma of Covid-19 patients showed that Caspase 8, which is a component of the PANoptosome, is upregulated compared to normal individuals [23] . One of the important components of the PANoptosome complex is RIPK1. It was determined that Covid-19 patients had active and phosphorylated RIPK1 in their respiratory tract epithelium biopsies [24] . Also, bioinformatics analyzes have determined that RIPK1 is an important hub gene that plays a pivotal role in SARS-CoV-2 viral pathogenesis in many tissues [25] . Today, we know that there are clinical studies on the usability of mesenchymal stem cell-derived extracellular vesicles in the treatment of Covid-19 [26] . miRNAs are 20-22 nucleotide long single stranded RNA molecules that play important roles in regulating gene expression. The publication of Schultz et al., (2021) which was as one of the pioneering works on this subject. In this publication, the researchers stated that some miRNAs found in extracellular vesicles (EVs) originating from mesenchymal stem cells have the ability to bind to mRNAs from which proteins in the PANoptosome complex are synthesized, thereby suppressing protein synthesis. In this study, the researchers examined miRNAs common in at least two data sets in a total of five EV gene expression datasets isolated from umbilical cord (1), bone marrow (3), and adipose-derived mesenchymal stem cells (1). They determined a total of 266 common miRNAs in these EVs. When they examined the interaction of these miRNAs with the mRNAs of these PANoptosis genes by bioinformatics analysis, they determined that some of these miRNAs have the capacity to bind to the 3'UTR regions of the mRNAs of PANoptosis genes. However, when these miRNAs are examined in detail, it is seen that there is no miRNA that collectively blocks the pathways of piroptosis, apoptosis and necroptosis. [27] . These reports provide hints that PANoptosis may be one of the factors that play a role in Covid-19 pathogenesis. More studies are needed within the scope of PANoptosis to confirm its accuracy. In a recent review, the preclinical applications of miRNA loaded bone marrow derived mesenchymal stem cell derived EVs in different disease models were discussed [28] . If PANoptosis is an important process in Covid-19 pathogenesis, it may be possible to suppress this process with different miRNA molecules that reduce the expression of components of this pathway. These miRNAs can be transferred to target cells using mesenchymal stem cell-derived vesicles as nanocarriers. In this system, since multiple miRNAs can be loaded into the same EVs, suppression of all three PANoptosis related pathways can be accomplished. The miRNA molecules loaded on these EVs can bind to the mRNAs of the proteins involved in the PANoptosis complex in target cells, thereby reducing their expression. With this approach, the efficiency of mesenchymal stem cell derived extracellular vesicles can be improved. In summary, these and similar studies on PANoptosis, which is a very current issue, are important for innovative new treatment approaches to be developed for fight against Covid-19 disease. Acknowledgements All of the persons contributed to the manuscript was placed as an Author in the manuscript. Author Contributions Prof. Dr. Zafer Cetin conducted literature surveys and prepared the main text. Data Availability In this 'Letter to Editor' no publicly available datasets were used. All of the articles discussed were cited. Consent for Publication All authors of the manuscript; have read and agreed the Journal BioMed Central 'Copyright and License Policy', have read and agreed to its content and are accountable for all aspects of the accuracy and integrity of the manuscript in accordance with ICMJE criteria and decleare that 'The Article' is original, has not already been published in a journal, and is not currently under consideration by another journal. This manusript is only prepared for scientific purposes and 'There is no conflict of interests'. SARS-CoV-2 and the pandemic of COVID-19 Predictors of COVID-19 severity: A literature review The cytokine storm and COVID-19. (2021) PANoptosis in microbial infection The PANoptosome: a deadly protein complex driving PANoptosis ZBP1 and TAK1: master regulators of NLRP3 inflammasome/ pyroptosis, apoptosis, and necroptosis (PAN-optosis) Newly Identified Function of Caspase-6 in ZBP1-mediated Innate Immune Responses, NLRP3 Inflammasome Activation, PANoptosis, and Host Defense Identification of the PANoptosome: a molecular platform triggering pyroptosis, apoptosis, and necroptosis (PANoptosis) Coronaviruses: innate immunity, inflammasome activation, inflammatory cell death, and cytokines Impaired NLRP3 inflammasome activation/pyroptosis leads to robust inflammatory cell death via caspase-8/RIPK3 during coronavirus infection Synergism of TNF-alpha and IFNgamma triggers inflammatory cell death, tissue damage, and mortality in SARS-CoV-2 infection and cytokine shock syndromes Apoptosis-induced T-cell lymphopenia is related to COVID-19 severity Apoptosis and immunophenotyping of peripheral blood lymphocytes in Iranian COVID-19 patients: Clinical and laboratory characteristics Clinical and pathological investigation of patients with severe COVID-19 SARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes Serum levels of receptor-interacting protein kinase-3 in patients with COVID-19 SARS-CoV-2 triggers inflammatory responses and cell death through caspase-8 activation Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients Inflammasome formation in the lungs of patients with fatal COVID-19 0 2 1 ) . C h l o r o q u i n e / hydroxychloroquine: an inflammasome inhibitor in severe COVID-19? Cardiac toxicity of chloroquine or hydroxychloroquine in patients with COVID-19: a systematic review and meta-regression analysis Longitudinal proteomic profiling reveals increased early inflammation and sustained apoptosis proteins in severe COVID-19 Proteome-wide data analysis reveals tissuespecific network associated with SARS-CoV-2 infection Exosomes derived from bone marrow mesenchymal stem cells as treatment for severe COVID-19 Mesenchymal Stem Cell-Derived Extracellular Vesicles Carrying miRNA as a Potential Multi Target Therapy to COVID-19: an In Silico Analysis Preclinical experimental applications of miRNA loaded BMSC extracellular vesicles Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations