Background N6-methyladenosine (m6A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain. Results We show that m6A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m6A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m6A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m6A sites compared to mice. Differential m6A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m6A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m6A methylation in a mouse model of Alzheimer’s disease, which is correlated with reduced protein levels. Conclusions Our results suggest that m6A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m6A controls protein levels of key genes involved in Alzheimer’s disease-associated pathways, suggesting that m6A plays an important role in aging and neurodegenerative disease.

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Th type 17 (Th17) cells have been identified as a proinflammatory T-cell subset. Here, we investigated the regulation of human Th17 cells by fetal BM-derived mesenchymal stem cells (FBM-MSC). We cocultured FBM-MSC with human PBMC or CD4 1 T cells from healthy donors. FBM-MSC significantly suppressed the proliferation of CD4 1 T cells stimulated by PHA and recombinant IL-2. Significantly higher levels of IL-17 were observed in FBM-MSC cocultured with either PBMC or CD4 1 T cells than that in PBMC cultured alone or CD4 1 T cells cultured alone. Flow cytometry analysis showed that the percentage of Th17 cells in coculture of FBM-MSC and CD4 1 T cells was significantly higher than that in CD4 1 T-cell cultured alone. FBM-MSC did not express IL-17 protein. Consistent with the augmentation of Th17 cells, significantly higher levels of IL-6 and IL-1 were observed in coculture of FBM-MSC and CD4 1 T cells than that in CD4 1 T-cell culture, while the levels of IL-23 were similar between FBM-MSC 1 PBMC coculture and PBMC alone, or FBM-MSC 1 CD4 1 T-cell and CD4 1 T-cell alone. The presence of FBM-MSC decreased the percentage of Th1 cells, but minimally affected the expansion of CD4 1 CD25 1 T cells. In conclusion, our data demonstrate for the first time that FBM-MSC promote the expansion of Th17 cells and decrease IFN-c-producing Th1 cells. These data suggest that IL-6 and IL-1, instead of IL-23, may be partly involved in the expansion of Th17 cells.Key words: Fetal BM-derived mesenchymal stem cells . IL-1 . IL-6 . Th1 . Th17 IntroductionMesenchymal stem cells (MSC) are multipotent stem cells found in many tissues in the body, such as BM, muscle, adipose, synovial membrane, amniotic fluid [1][2][3][4], umbilical cord, cord blood [5] and fetal tissues [6]. Accumulating evidence has shown that MSC perform an immune regulatory function partly by suppressing the proliferation of T cells in vitro [7][8][9]. MSC-induced immunotolerance has been used therapeutically for reducing GVH disease and for modulation of autoimmune disorders [10,11].Classically, effector CD4 1 Th cells have been categorized into two subsets: Th1 and Th2. Th1 cells produce IFN-g, which is à These authors contributed equally to this work. 2840required for the clearance of certain intracellular pathogens; while Th2 cells produce IL-4, which is required for the clearance of parasites [12]. Recently, a new effector CD4 1 T-cell lineage, Th17, has been identified in an EAE model. Th17 cells are characterized by their production of a distinct profile of cytokines, including IL-17, IL-17F and IL-6, and are thought to be involved in inflammatory and autoimmune diseases [13,14]. There have been many investigations in mouse Th17 cells, but the knowledge of human Th17 cells remains limited.So far little is known about the interaction of fetal BM-derived MSC (FBM-MSC) with immune cells, especially human Th17 cells. Therefore, in this study, we cocultured FBM-MSC with human PBMC or CD4 1 T cells and demonstrated for the first time that FBM-MSC had the capability to p...