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

Huize Pan; Di Guan; Xiaomeng Liu; Jingyi Li; Lixia Wang; Jun Wu; Junzhi Zhou; Weizhou Zhang; Ruotong Ren; Weiqi Zhang; Ying Li; Jiping Yang; Ying Hao; Tingting Yuan; Guohong Yuan; Hu Wang; Zhenyu Ju; Zhiyong Mao; Jian Li; Jing Qu; Fuchou Tang; Guang-Hui Liu

doi:10.1038/cr.2016.4

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

Journal article

Open access

Peer reviewed

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

Huize Pan, Di Guan, Xiaomeng Liu, Jingyi Li, Lixia Wang, Jun Wu, Junzhi Zhou, Weizhou Zhang, Ruotong Ren, Weiqi Zhang, …

Cell research, Vol.26(2), pp.190-205

02/2016

DOI: 10.1038/cr.2016.4

PMCID: PMC4746611

PMID: 26768768

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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.

Heme Oxygenase-1 - metabolism

Antioxidants - metabolism

Humans

Oxidative Stress - physiology

Cells, Cultured

Cellular Senescence - physiology

Mesenchymal Stromal Cells - metabolism

Male

RNA Polymerase II - metabolism

Mice, SCID

Animals

Mice, Nude

Homeostasis - physiology

NF-E2-Related Factor 2 - metabolism

Mice, Inbred NOD

Mice

Sirtuins - metabolism

Details

Title: Subtitle: SIRT6 safeguards human mesenchymal stem cells from oxidative stress by coactivating NRF2
Creators: Huize Pan - University of Chinese Academy of Sciences, Beijing 100049, China
Di Guan - National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
Xiaomeng Liu - Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China
Jingyi Li - Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China
Lixia Wang - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
Jun Wu - Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
Junzhi Zhou - National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
Weizhou Zhang - Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
Ruotong Ren - FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China
Weiqi Zhang - FSU-CAS Innovation Institute, Foshan University, Foshan, Guangdong 528000, China
Ying Li - Chinese Academy of Sciences
Jiping Yang - National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
Ying Hao - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
Tingting Yuan - National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
Guohong Yuan - National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
Hu Wang - Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 310036, China
Zhenyu Ju - Institute of Aging Research, Leibniz Link Partner Group on Stem Cell Aging, Hangzhou Normal University School of Medicine, Hangzhou, Zhejiang 310036, China
Zhiyong Mao - School of life sciences and technology, Tongji University, Shanghai 200092, China
Jian Li - The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing 100730, China
Jing Qu - State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
Fuchou Tang - Center for Molecular and Translational Medicine, CMTM, Beijing 100101, China
Guang-Hui Liu - Beijing Institute for Brain Disorders, Beijing 100069, China
Resource Type: Journal article
Publication Details: Cell research, Vol.26(2), pp.190-205
DOI: 10.1038/cr.2016.4
PMID: 26768768
PMCID: PMC4746611
NLM abbreviation: Cell Res
ISSN: 1001-0602
eISSN: 1748-7838
Grant note: R00 CA158055 / NCI NIH HHS P30 CA086862 / NCI NIH HHS
Language: English
Date published: 02/2016
Academic Unit: Radiation Oncology
Record Identifier: 9984083265302771

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