SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2

• Published in: Cell research Vol. 26; no. 2; pp. 190 - 205
• Main Authors: Pan, Huize, Guan, Di, Liu, Xiaomeng, Li, Jingyi, Wang, Lixia, Wu, Jun, Zhou, Junzhi, Zhang, Weizhou, Ren, Ruotong, Zhang, Weiqi, Li, Ying, Yang, Jiping, Hao, Ying, Yuan, Tingting, Yuan, Guohong, Wang, Hu, Ju, Zhenyu, Mao, Zhiyong, Li, Jian, Qu, Jing, Tang, Fuchou, Liu, Guang-Hui
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2016; Nature Publishing Group
• Subjects: 631/45/607/1172; 631/532/2074; 631/532/7; 631/80/86/2366; Animals; Antioxidants - metabolism; Biomedical and Life Sciences; Cell Biology; Cells, Cultured; Cellular Senescence - physiology; Decay; Heme Oxygenase-1 - metabolism; Homeostasis - physiology; Humans; Life Sciences; Male; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred NOD; Mice, Nude; Mice, SCID; NF-E2-Related Factor 2 - metabolism; Original; original-article; Oxidative stress; Oxidative Stress - physiology; RNA Polymerase II - metabolism; RNA聚合酶; Sirtuins - metabolism; Stem cells; 保护; 基因缺陷; 氧化应激; 激活; 蛋白复合物; 血红素氧合酶; 骨髓间充质干细胞; SIRT6; aging; stem cell; NRF2; oxidative stress
• ISSN: 1001-0602; 1748-7838; 1748-7838
• DOI: 10.1038/cr.2016.4

SIRT6 belongs to the mammalian homologs of Sir2 histone NAD＋-dependent deacylase family. In rodents, SIRT6 deficiency leads to aging-associated degeneration of mesodermal tissues. It remains unknown whether human SIRT6 has a direct role in maintaining the homeostasis of mesodermal tissues. To this end, we generated SIRT6 knockout hu- man mesenchymal stem cells （hMSCs） by targeted gene editing. SIRT6-deficient hMSCs exhibited accelerated func- tional decay, a feature distinct from typical premature cellular senescence. Rather than compromised chromosomal stability, SIRT6-null hMSCs were predominately characterized by dysregulated redox metabolism and increased sen- sitivity to the oxidative stress. In addition, we found SIRT6 in a protein complex with both nuclear factor erythroid 2-related factor 2 （NRF2） and RNA polymerase II, which was required for the transactivation of NRF2-regulated an- tioxidant genes, including heme oxygenase 1 （HO-1）. Overexpression of HO-1 in SIRT6-null hMSCs rescued prema- ture cellular attrition. Our study uncovers a novel function of SIRT6 in maintaining hMSC homeostasis by serving as a NRF2 coactivator, which represents a new layer of regulation of oxidative stress-associated stem cell decay.