title: SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2.
abstract: 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 human mesenchymal stem cells (hMSCs) by targeted gene editing. SIRT6-deficient hMSCs exhibited accelerated functional 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 sensitivity 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 antioxidant genes, including heme oxygenase 1 (HO-1). Overexpression of HO-1 in SIRT6-null hMSCs rescued premature 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.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Huize
authors.initials: H
authors.lastname: Pan
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Di
authors.initials: D
authors.lastname: Guan
authors.affiliation: Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Li
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China.|State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Lixia
authors.initials: L
authors.lastname: Wang
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Junzhi
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
authors.forename: Weizhou
authors.initials: W
authors.lastname: Zhang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China.
authors.forename: Ruotong
authors.initials: R
authors.lastname: Ren
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Zhang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|University of Chinese Academy of Sciences, Beijing 100049, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jiping
authors.initials: J
authors.lastname: Yang
authors.affiliation: FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China.|State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hao
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yuan
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Yuan
authors.affiliation: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 310036, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 310036, China.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Ju
authors.affiliation: School of life sciences and technology, Tongji University, Shanghai 200092, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Mao
authors.affiliation: The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Qu
authors.affiliation: Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.|Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China.|Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.|Center for Molecular and Translational Medicine, CMTM, Beijing 100101, China.
authors.forename: Fuchou
authors.initials: F
authors.lastname: Tang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.|FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China.|Center for Molecular and Translational Medicine, CMTM, Beijing 100101, China.|Beijing Institute for Brain Disorders, Beijing 100069, China.
authors.forename: Guang-Hui
authors.initials: GH
authors.lastname: Liu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D012319:RNA Polymerase II / Q000378:metabolism; D037761:Sirtuins / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051547:Heme Oxygenase-1; D012319:RNA Polymerase II; C516592:SIRT6 protein, human; D037761:Sirtuins