Downregulation of Nrf2 promotes autophagy-dependent osteoblastic differentiation of adipose-derived mesenchymal stem cells.
Adipose derived stem cells (ADSCs) are an important source of stem cells for tissue repair and regeneration; therefore, understanding the mechanisms that regulate stem cell differentiation into a specific lineage is critical. The NF-E2-related factor 2 (Nrf2) pathway and autophagy promote cell survival in response to oxidative stress. However, the roles of Nrf2 and autophagy in bone metabolism under oxidative stress are controversial. Here, we explored the involvement of Nrf2 signaling and autophagy on the differentiation of ADSCs under conditions of oxidative stress. Exposure of ADSCs to H2O2promoted reactive oxygen species (ROS) accumulation concomitant with the reduction of cell viability, upregulation of Nrf2, the induction of apoptosis and autophagy, and the promotion of osteogenesis. Suppression of autophagic activity at particular stages resulted in the activation of the Nrf2 pathway, whereas osteoblastic differentiation of ADSCs was inhibited upon ROS stimulation. Silencing of Nrf2 promoted autophagy and osteoblastic differentiation upon ROS stimulation in vitro, and this effect was confirmed in vivo in a mouse model, in which bone formation was enhanced in mice receiving Nrf2-knockdown ADSCs. Taken together, these findings indicate that a negative interaction between the Nrf2 pathway and autophagy may modulate oxidative stress-induced ADSC osteogenesis, and suggest that Nrf2 is a potential target to regulate the differentiation of ADSCs into a specific lineage.
Department of General Dentistry, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.
Jiang
J
Tao
Department of General Dentistry, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.
Haining
H
Wang
Department of General Dentistry, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.
Yue
Y
Zhai
Department of General Dentistry, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.
Hyun
H
Park
Department of General Dentistry, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.
Jian
J
Wang
Department of Orthodontics, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, No. 639 Zhi Zao Ju Road, Shanghai 200011, China. Electronic address: smilefang98@hotmail.com.
Fang
F
Ji
Department of Plastic and Reconstructive Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Tissue Engineering, Shanghai, China; National Tissue Engineering Center of China, Shanghai, China. Electronic address: mr.zhiyong@gmail.com.
Zhiyong
Z
Zhang
D000273:Adipose Tissue / Q000166:cytology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D015536:Down-Regulation; D006861:Hydrogen Peroxide / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects*; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide
Adipose derived stem cells; Differentiation; Nrf2; Oxidative stress