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

• Main Authors: Shih-Pei Lin, Fang-Yao Chiu, Yu Wang, Men-Luh Yen, Shou-Yen Kao, Shih-Chieh Hung
• Format: Article
• Language: English
• Published: Elsevier 2014-12-01
• Series: Stem Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2213671114003087

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.