title: 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.
authors.affiliation: 1] Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea [2] Institute for Stem Cell and Regenerative Medicine in KangstemBiotech, Biotechnology Incubating Center, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Seunghee
authors.initials: S
authors.lastname: Lee
authors.affiliation: Institute for Stem Cell and Regenerative Medicine in KangstemBiotech, Biotechnology Incubating Center, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Hyung-Sik
authors.initials: HS
authors.lastname: Kim
authors.affiliation: 1] Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea [2] Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea [3] Institute for Stem Cell and Regenerative Medicine in KangstemBiotech, Biotechnology Incubating Center, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Kyoung-Hwan
authors.initials: KH
authors.lastname: Roh
authors.affiliation: 1] Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea [2] Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Byung-Chul
authors.initials: BC
authors.lastname: Lee
authors.affiliation: 1] Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea [2] Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Tae-Hoon
authors.initials: TH
authors.lastname: Shin
authors.affiliation: Institute for Stem Cell and Regenerative Medicine in KangstemBiotech, Biotechnology Incubating Center, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Ju-Mi
authors.initials: JM
authors.lastname: Yoo
authors.affiliation: Institute for Stem Cell and Regenerative Medicine in KangstemBiotech, Biotechnology Incubating Center, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Yu-Lee
authors.initials: YL
authors.lastname: Kim
authors.affiliation: 1] Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea [2] Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Kyung-Rok
authors.initials: KR
authors.lastname: Yu
authors.affiliation: Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Kyung-Sun
authors.initials: KS
authors.lastname: Kang
authors.affiliation: 1] Research Institute for Veterinary Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, South Korea [2] Institute for Stem Cell and Regenerative Medicine in KangstemBiotech, Biotechnology Incubating Center, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Kwang-Won
authors.initials: KW
authors.lastname: Seo
mesh_terms: D001374:Azacitidine / Q000008:administration & dosage; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D000071876:Prostaglandin-E Synthases; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019718:Receptors, CXCR4; D023063:Receptors, Interleukin-8B; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D001374:Azacitidine