Uncovering of Immunoregulatory microRNAs in Cardiac Tissue of Septic Mice treated with Mesenchymal Stem Cells
CCCF ePoster library. Ektesabi A. Nov 9, 2018; 233439
Amin Ektesabi
Amin Ektesabi
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Abstract
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Various studies have shown that systemic administration of mesenchymal stromal/stem cell (MSC) alleviates sepsis-induced myocardial dysfunction and organ damage, and increases survival rates in murine models of polymicrobial sepsis, however, the mechanism behind this phenomenon is vastly unknown. In this study, we hypothesize that MSC administration regulates the differential expression of host-derived miRNAs that in turn determine the transcriptional response profile in the heart, one of the major sepsis-target organs. We used cecum ligation and puncture (CLP) to model polymicrobial sepsis; miRNA expression levels were compared between sham, CLP, and MSC-treated mice. Bioinformatics analysis identified a total of five miRNAs as significantly changed in MSC- vs. placebo-treated septic hearts (false discovery rate <0.05).To create the biological relevance of our in silico findings, we measured differential expression of target mRNAs for all five miRNAs using the Illumina microarray expression array. Presumed mRNA-miRNA interactions were clarified. The five miRNAs and 318 putative targets were identified as significantly regulated following MSC administration in septic hearts. Functional amelioration highlighted roles in suppression of inflammation and apoptosis and upregulation of cardiac-specific structural proteins. Hub-gene analysis identified a central role for miR-187 and its target genes Itpkc, Lrrc59, Tbl1xr1, which are known to play fundamental roles in cardiac inflammation and cardiomyocyte apoptosis. In murine septic hearts treated with placebo or MSCs, quantitative real-time PCR validated differential expression of these in silico targets in vivo, as well as markers of apoptosis. MSC administration results in the upregulation of host-derived miRNAs involved in protecting cardiomyocytes from sepsis-induced inflammation and apoptosis.



 


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