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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.

SUBMITTER: Pan H

PROVIDER: S-EPMC4746611 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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

Pan Huize H Guan Di D Liu Xiaomeng X Li Jingyi J Wang Lixia L Wu Jun J Zhou Junzhi J Zhang Weizhou W Ren Ruotong R Zhang Weiqi W Li Ying Y Yang Jiping J Hao Ying Y Yuan Tingting T Yuan Guohong G Wang Hu H Ju Zhenyu Z Mao Zhiyong Z Li Jian J Qu Jing J Tang Fuchou F Liu Guang-Hui GH

Cell research 20160115 2

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 ...[more]

PMID: 26768768

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Project description:BackgroundAn important feature of aging cells is the gradual loss of physiological integrity. As aging progresses, MSCs change preferring to differentiate toward adipocytes rather than osteoblasts. Oxidative stress accumulation is an important factor in age-related bone loss. Many experiments have demonstrated the good therapeutic effect of Ginsenoside (Rg1) on oxidative stress injury. In this study, we investigated the effect of Rg1 on the osteogenic-adipogenic differentiation balance of bone marrow mesenchymal stem cells (BMMSC).ObjectiveTo analyze the potential application value of Rg1 in the treatment of senile osteoporosis.MethodsBMMSCs were isolated from healthy donors of different ages and identified based on isotype and by multi-differentiation induction. Rg1 was used to treat BMMSCs, The differentiation propensity was analyzed by induction of differentiation assay. Antioxidant capacity of BMMSCs as measured by oxidative stress product assay Related mechanism studies were confirmed by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), immunofluorescence, western blotting, and inhibitor treatment. Moreover, Observation of the effects of Rg1 on aging BMMSCs under in vivo conditions by treatment of aged mice with Rg1 injections.ResultsRg1 treatment rescued age-induced switch of BMMSCs differentiation fate in vitro. In elderly people, Rg1 markedly increased osteogenic differentiation of BMMSCs by decreasing oxidative stress, while inhibiting adipogenic differentiation. However, this effect was abolished in BMMSCs by an Nrf2-inhibitor. Notably, aging mice showed a reduction in adipocyte distribution in the bone marrow and a decrease in oxidative stress products after a 3-month period of Rg1 treatment.ConclusionWe have uncovered a novel function for Rg1 that involves attenuating bone loss via Nrf2 antioxidant signaling, which in turn may potentially be utilized as a therapeutic agent for improving osteogenic differentiation in aging BMMSCs.

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

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

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