mfat‐1 transgene protects cultured adult neural stem cells against cobalt chloride‐mediated hypoxic injury by activating Nrf2/ARE pathways
Omega‐3 polyunsaturated fatty acids (n‐3 PUFAs) have sparked clinical interest in their therapeutic application for promoting the survival, migration, proliferation, and differentiation of adult NSCs during replacement therapy in ischemic stroke. n‐3 PUFAs are essential for human beings, helping to maintain cellular membrane structural and functional integrity (Antonny, Vanni, Shindou, & Ferreira, 2015). Moreover, PUFAs are highly enriched in the brain and play a key role in brain development and repair under many conditions (Chang et al., 2012). Decades of research have provided insight into the elevation of the n‐3/n‐6 PUFA ratio, demonstrating that a higher ratio rather than n‐3 PUFAs exerts beneficial effects in a variety of neurological disorders, including ischemic stroke (Belayev, Khoutorova, Atkins, & Bazan, 2009; Belayev et al., 2011; Hong, Belayev, Khoutorova, Obenaus, & Bazan, 2014; Hu et al., 2013; Liu et al., 2016; Zhang et al., 2010).
In this study, NSCs were cultured from an mfat‐1 transgene mouse model that converts n‐6 PUFAs to n‐3 PUFAs in vivo, resulting in abundant endogenous n‐3 PUFA, without changing total PUFA in their organs and tissue, through overexpressing the C. elegans n‐3 fatty acid desaturase gene, mfat‐1 (Wei et al., 2010). This mfat‐1 transgene mouse model was firstly used to investigate whether overproduction of n‐3 PUFAs could protect adult NSCs against hypoxic damage induced by cobalt chloride (CoCl2), which is a well‐known hypoxia‐mimetic agent. There are numerous reports that CoCl2 is widely used to mimic the hypoxic‐ischemic microenvironment in various cultured cells (Chen, Zhao, & Huang, 2009; Lan et al., 2012; Sandner et al., 1997; Tan et al., 2009; Zou et al., 2001). Therefore, we used CoCl2‐treated adult NSCs as an in vitro model to study the adult NSCs' response to hypoxic‐ischemic injury. And we demonstrated that elevation of the n‐3/n‐6 PUFAs ratio significantly enhanced the survival of adult NSCs in a CoCl2‐mediated hypoxic injury model, but the underlying molecular protective mechanisms are still not fully understood. It has been reported that oxidative stress–induced neuronal apoptosis plays an important role in the pathogenesis of ischemic stroke (Chehaibi, Trabelsi, Mahdouani, & Slimane, 2016; Yamauchi et al., 2016).