Hypoxic environment has been suggested in stem cell culturing as their physiologic niche requires oxygen tension to maintain sternness. The administration of cobalt chloride (CoCl2) was widely applied in mimicking hypoxia for its economic advantages and convenience. We confirmed that CoCl2 could maintain sternness and promote the osteogenesis capacity of MSCs. However, CoCl2 could induce the apoptosis and hinder the proliferation of MSCs. To find out a potential method maintaining their sternness without threatening their survival, we analyzed the database of Gene Expression Omnibus (GEO) and proposed that NRF2 (nuclear factor erythroid-derived 2-like 2) might be the potential target. We found that knocking down NRF2 expression in MSCs impaired the expression of stern cell markers and the osteogenesis process even under hypoxic environment, but with NRF2 overexpression, the proliferation of MSCs was increased with significantly reduced rate of apoptosis. Therefore, our findings suggested that overexpressing NRF2 could be a potential method for maintaining sternness and preventing apoptosis in MSCs under oxidative stress. (C) 2017 Elsevier Inc. All rights reserved.