期刊
STEM CELLS
卷 40, 期 5, 页码 468-478出版社
OXFORD UNIV PRESS
DOI: 10.1093/stmcls/sxac018
关键词
oxygen-glucose deprivation; human dental pulp stem cell; human mesenchymal stem cell; autophagy; O-2 (-); H2O2; Ambra1; Beclin1
资金
- Science Engineering Research Board, Department of Science and Technology, Government of India [YSS/2015/001731]
This study investigated the impact of oxidative stress on dental pulp stem cells and mesenchymal stem cells. It was found that oxidative stress enhanced autophagy, which could be repressed by ROS scavengers. The involvement of the ROS-p38-Erk1/2 pathway and the depletion of SIRT3 were also discovered. Furthermore, inhibition of autophagy improved stem cell viability.
Stem cell therapies have emerged as a promising treatment strategy for various diseases characterized by ischemic injury such as ischemic stroke. Cell survival after transplantation remains a critical issue. We investigated the impact of oxidative stress, being typically present in ischemically challenged tissue, on human dental pulp stem cells (hDPSC) and human mesenchymal stem cells (hMSC). We used oxygen-glucose deprivation (OGD) to induce oxidative stress in hDPSC and hMSC. OGD-induced generation of O-2(center dot-) or H2O2 enhanced autophagy by inducing the expression of activating molecule in BECN1-regulated autophagy protein 1 (Ambra1) and Beclin1 in both cell types. However, hDPSC and hMSC pre-conditioning using reactive oxygen species (ROS) scavengers significantly repressed the expression of Ambra1 and Beclin1 and inactivated autophagy. O-2(center dot-) or H2O2 acted upstream of autophagy, and the mechanism was unidirectional. Furthermore, our findings revealed ROS-p38-Erk1/2 involvement. Pre-treatment with selective inhibitors of p38 and Erk1/2 pathways (SB202190 and PD98059) reversed OGD effects on the expression of Ambra1 and Beclin1, suggesting that these pathways induced oxidative stress-mediated autophagy. SIRT3 depletion was found to be associated with increased oxidative stress and activation of p38 and Erk1/2 MAPKs pathways. Global ROS inhibition by NAC or a combination of polyethylene glycol-superoxide dismutase (PEG-SOD) and polyethylene glycol-catalase (PEG-catalase) further confirmed that O-2(center dot-) or H2O2 or a combination of both impacts stems cell viability by inducing autophagy. Furthermore, autophagy inhibition by 3-methyladenine (3-MA) significantly improved hDPSC viability. These findings contribute to a better understanding of post-transplantation hDPSC and hMSC death and may deduce strategies to minimize therapeutic cell loss under oxidative stress.
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