Role of miRNAs in altering sepsis-induced cytokine production in mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) have great capacity for proliferation, self-renewal and differentiation into different, more specialized cell lines. This population of adult stem cells is easily obtained and, due to their immunomodulatory and antimicrobial characteristics, they have been strong candidates as a new therapeutic tool to treat sepsis. In this context, preliminary studies in our laboratory showed that in vivo environment of 8 hours of septicemia induced by cecal ligation and perforation (CLP) did not interfere in cells' morphology and proliferative and senescence characteristics. However, cells from septic animals produced less cytokines and chemokines when kept in culture for 48 hours. From 32 proteins, 28 had their expression reduced in septic cells. We know that both innate and adaptive immune responses are highly controlled, and recent studies have shed light on epigenetic regulation in this complex defense system. The relevant role of miRNAs in the differentiation of MCTs into different cell types has already been described by several groups. However, there are no studies showing the mechanisms involved in the decreased production of inflammatory mediators by mesenchymal stem cells from septic animals. For this reason, in this project we will study the role of miRNAs in this modulation. Therefore, mesenchymal stem cells from bone marrow of sham and CLP subjected animals will be kept in culture and we will analyze the expressed miRNAs using the PCRArray technique. Modulation of miRNA expression will be confirmed by real-time PCR and their involvement will be tested using inhibitors and mimetics of miRNA. (AU)