Bidirectional Transcriptome Analysis of Rat Bone Marrow-Derived Mesenchymal Stem Cells and Activated Microglia in an In Vitro Coculture System.

Abstract

Microglia contribute to the regulation of neuroinflammation and play an important role in the pathogenesis of brain diseases. Thus, regulation of neuroinflammation triggered by activated microglia in brain diseases has become a promising curative strategy. Bone marrow-derived mesenchymal stem cells (BM-MSCs) have been shown to have therapeutic effects, resulting from the regulation of inflammatory conditions in the brain. In this study, we investigated differential gene expression in rat BM-MSCs (rBM-MSCs) that were cocultured with lipopolysaccharide- (LPS-) stimulated primary rat microglia using microarray analysis and evaluated the functional relationships through Ingenuity Pathway Analysis (IPA). We also evaluated the effects of rBM-MSC on LPS-stimulated microglia using a reverse coculture system and the same conditions of the transcriptomic analysis. In the transcriptome of rBM-MSCs, 67 genes were differentially expressed, which were highly related with migration of cells, compared to control. The prediction of the gene network using IPA and experimental validation showed that LPS-stimulated primary rat microglia increase the migration of rBM-MSCs. Reversely, expression patterns of the transcriptome in LPS-stimulated primary rat microglia were changed when cocultured with rBM-MSCs. Our results showed that 65 genes were changed, which were highly related with inflammatory response, compared to absence of rBM-MSCs. In the same way with the aforementioned, the prediction of the gene network and experimental validation showed that rBM-MSCs decrease the inflammatory response of LPS-stimulated primary rat microglia. Our data indicate that LPS-stimulated microglia increase the migration of rBM-MSCs and that rBM-MSCs reduce the inflammatory activity in LPS-stimulated microglia. The results of this study show complex mechanisms underlying the interaction between rBM-MSCs and activated microglia and may be helpful for the development of stem cell-based strategies for brain diseases.