RB Maintains Quiescence and Prevents Premature Senescence through Upregulation of DNMT1 in Mesenchymal Stromal Cells

• Published in: Stem cell reports 2014-12, Vol.3 (6), p.975-986
• Main Authors: Lin, Shih-Pei, Chiu, Fang-Yao, Wang, Yu, Yen, Men-Luh, Kao, Shou-Yen, Hung, Shih-Chieh
• Format: Article
• Language: English
• Subjects: Animals; Bone Marrow Transplantation; Cell Differentiation - genetics; Cell Proliferation; Cellular Senescence - genetics; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; Gene Expression; Gene Expression Regulation; Gene Knockdown Techniques; Humans; Mesenchymal Stem Cell Transplantation; Mesenchymal Stromal Cells - cytology; Mesenchymal Stromal Cells - metabolism; Mice; Protein Binding; Proto-Oncogene Proteins c-jun - metabolism; Resting Phase, Cell Cycle - genetics; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Up-Regulation
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2014.10.002

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. [Display omitted] •RB levels are higher in early-passage MSCs than in late-passage MSCs•RB knockdown induces a premature senescence and reduces differentiation potentials•RB overexpression reverses senescence and increases differentiation potentials•RB upregulates DNMT1 to inhibit senescence and promote differentiation potentials In this article, Hung, Kao, and colleagues show that retinoblastoma (RB) levels are higher in early-passage mesenchymal stromal cells (MSCs) than in late-passage MSCs, which serves to regulate senescence and differentiation potentials. Expression of DNMT1 is also higher in early-passage MSCs than in late-passage MSCs. This study demonstrates that RB expressed in early-passage MSCs upregulates DNMT1 expression and inhibits senescence in MSCs.