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 QuFuchou Tang, Guang Hui Liu

Research output: Contribution to journalArticlepeer-review

135 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)190-205
Number of pages16
JournalCell Research
Volume26
Issue number2
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Keywords

  • NRF2
  • SIRT6
  • aging
  • oxidative stress
  • stem cell

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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