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.

SIRT6, oxidative stress, and aging

“…Interestingly, these cells showed premature and progressively accelerated cellular senescence as demonstrated by several senescent markers and also exhibited elevation of reactive oxygen species (ROS), dysregulated redox metabolism, and increased sensitivity to oxidative stress. Contrary to a prior work performed in mouse embryonic fibroblasts (MEFs) [7], SIRT6 −/− hMSCs did not exhibit enhanced genomic instability [9], suggesting that cell type differences may underlie the divergent phenotypes. Indeed, Pan et al [9] found that transcriptional changes upon SIRT6 depletion in hMSCs were not recapitulated in human vascular endothelial cells.…”

“…Until now, however, SIRT6 has not been associated with oxidative stress. A new study from Pan et al [9] links the deacetylase activity of SIRT6 to redox homeostasis in human mesenchymal stem cells (hMSCs) and suggests that this activity may regulate the longevity and progeria phenotypes ( Figure 1). …”

“…Pan et al [9] generated SIRT6-deficient human embryonic stem cells (hESCs), differentiated them into hMSCs (SIRT6 −/− hMSCs) and characterized their properties. Interestingly, these cells showed premature and progressively accelerated cellular senescence as demonstrated by several senescent markers and also exhibited elevation of reactive oxygen species (ROS), dysregulated redox metabolism, and increased sensitivity to oxidative stress.…”

Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7

“…Knocking down GPX7 in wild‐type HMSCs resulted in accelerated cellular aging (Figure 5f–h). To investigate whether the metformin‐Nrf2‐GPx7 pathway could protect HMSCs in an in vivo context, HMSCs were implanted into the tibialis anterior muscle of immune‐deficient mice, and their in vivo retention was measured by an in vivo imaging system (IVIS) (Kubben et al., 2016; Pan et al., 2016; Wang et al., 2018; Yang et al., 2017). Metformin‐treated HMSCs displayed delayed cellular attrition compared to vehicle‐treated cells (Figure 5i), whereas GPX7 ‐deficient HMSCs exhibited accelerated cell exhaustion in the in vivo microenvironment (Figure 5j).…”

“…A total volume of 100 μl PBS of 1 × 10 6 HMSCs labeled with luciferase were injected into the midportion of the tibialis anterior muscle of immune‐deficient BALB/c nude mice (Pan et al., 2016); 5 or 6 days after implantation, mice were anesthetized and treated with D‐luciferin. Then, photon emission was measured by the IVIS Lumina System (PerkinElmer).…”