DNA methyltransferase inhibition accelerates the immunomodulation and migration of human mesenchymal stem cells

Abstract

DNA methyltransferase (DNMT) inhibitors regulate target gene expression through epigenetic modifications, and these compounds have primarily been studied for cancer therapy or reprogramming. However, the effect of DNMT inhibitors on the immunomodulatory capacity of human mesenchymal stem cells (hMSCs) has not been investigated. In the present study, we treated hMSCs with 5-azacytidine (5-aza), a DNMT inhibitor, and confirmed that the inhibitory effects on mononuclear cell proliferation and cell migration toward activated T cells were increased. To identify the immunomodulatory factors stimulated through 5-aza treatment, we investigated the changes in promoter methylation patterns using methylation arrays and observed that the promoters of immunomodulatory factors, COX2 and PTGES, and migration-related factors, CXCR2 and CXCR4, were hypomethylated after 5-aza treatment. In addition, we observed that the COX2-PGE2 pathway is one of the main pathways for the enhanced immunosuppressive activity of hMSCs through 5-aza treatment. We also determined that the migration of hMSCs toward ligands for CXCR2/CXCR4 was increased after 5-aza treatment. Moreover, using an experimental colitis model, we showed that 5-aza pre-treatment could enhance the therapeutic effect of MSCs against immune-related diseases.

The anti-tumor effects of Mfn2 in breast cancer are dependent on promoter DNA methylation, the P21Ras motif and PKA phosphorylation site

“…In the present study, the anti-proliferation, anti-migration and anti-invasion effects of Mfn2 were confirmed in breast cancer cells. The results are consistent with previous studies in VSMCs (3) and in various types of cancer, including breast cancer (18,37) gastric cancer (18), urinary bladder carcinoma (38) and hepatocellular carcinoma (20,21,23) and lung adenocarcinoma (5,8,24,(38)(39)(40)(41). However, tumor-promoting functions of Mfn2 in lung adenocarcinoma have also been reported (42,43).…”

“…DNA methylation is a reversible process, making it a promising target for cancer therapy. 5-aza-CdR is widely used as an inhibitor of DNMTs and can increase the expression of genes silenced by DNA methylation (18)(19)(20)(21). In order to confirm whether the expression of Mfn2 in human breast cancer cells is regulated by DNA methylation of its promoter, the MCF-7 breast cancer cells were treated with 5-aza-CdR for 1, 2 and 3 days at concentrations of 5.0 10 and 15 µM.…”

Direct modulation of the bone marrow mesenchymal stromal cell compartment by azacitidine enhances healthy hematopoiesis

“…31 In addition, induction of inflammatory and immune-response pathways by AZA may facilitate immune modulation by MSCs in the leukemic niche. 29,30,32 Accordingly, our FNEA analyses demonstrated upregulation of TGF-b and RIG-I in AZA-treated stromal cells. The second significantly regulated HSPC support network (ECM receptor interaction, brown module; Figure 6) is composed, in large part, of collagens, important components of the ECM.…”

“…Furthermore, colony genotyping performed on 5 selected MDS HSPC samples with high VAF (nos. 31,32,33,34,38) confirmed that all colonies contained MDS-defining mutations and thus belonged to the dominant MDS clone (supplemental Figure 2). In line with previous reports, MDS HSPCs were significantly less able to form colonies than healthy HSPCs after culture on healthy MSCs ( Figure 3B).…”

Sensitive electrochemical assaying of DNA methyltransferase activity based on mimic-hybridization chain reaction amplified strategy

“…In this case, 5-Aza and procaine were chosen as inhibitor models in subsequent tests because they were previously reported to be anticancer drugs by inhibiting DNA methylation in various cancer cells [46,47]. All the inhibition experiments were carried out in the same conditions as that for M.SssI MTase activity assay.…”