title: RB maintains quiescence and prevents premature senescence through upregulation of DNMT1 in mesenchymal stromal cells.
abstract: Many cell therapies currently being tested are based on mesenchymal stromal cells (MSCs). However, MSCs start to enter the senescent state upon long-term expansion. The role of retinoblastoma (RB) protein in regulating MSC properties is not well studied. Here, we show that RB levels are higher in early-passage MSCs compared with late-passage MSCs. RB knockdown induces premature senescence and reduced differentiation potentials in early-passage MSCs. RB overexpression inhibits senescence and increases differentiation potentials in late-passage MSCs. Expression of DNMT1, but not DNMT3A or DNMT3B, is also higher in early-passage MSCs than in late-passage MSCs. Furthermore, DNMT1 knockdown in early-passage MSCs induces senescence and reduces differentiation potentials, whereas DNMT1 overexpression in late-passage MSCs has the opposite effect. These results demonstrate that RB expressed in early-passage MSCs upregulates DNMT1 expression and inhibits senescence in MSCs. Therefore, genetic modification of RB could be a way to improve the efficiency of MSCs in clinical use.
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan, ROC.
authors.forename: Shih-Pei
authors.initials: SP
authors.lastname: Lin
authors.affiliation: Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC.
authors.forename: Fang-Yao
authors.initials: FY
authors.lastname: Chiu
authors.affiliation: Department of Dentistry Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC; Department of Stomatology, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Departments of Primary Care Medicine and Obstetrics/Gynecology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei 100, Taiwan, ROC.
authors.forename: Men-Luh
authors.initials: ML
authors.lastname: Yen
authors.affiliation: Department of Dentistry Sciences, National Yang-Ming University, Taipei 112, Taiwan, ROC; Department of Stomatology, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC. Electronic address: sykao@vghtpe.gov.tw.
authors.forename: Shou-Yen
authors.initials: SY
authors.lastname: Kao
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 112, Taiwan, ROC; Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan, ROC; Institute of Traditional Medicine, Faculty of Medicine, National Yang-Ming University, Taipei 112, Taiwan, ROC; Department of Orthopaedics and Traumatology, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC; Stem Cell Laboratory, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei 112, Taiwan, ROC; Institute of Biomedical Sciences, Academia Sinica, Taipei 105, Taiwan, ROC. Electronic address: hungsc@vghtpe.gov.tw.
authors.forename: Shih-Chieh
authors.initials: SC
authors.lastname: Hung
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006801:Humans; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D016192:Resting Phase, Cell Cycle / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016755:Proto-Oncogene Proteins c-jun; D016160:Retinoblastoma Protein; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse