mfat-1 transgene protects cultured adult neural stem cells against cobalt chloride-mediated hypoxic injury by activating Nrf2/ARE pathways

Abstract

Ischemic stroke is a devastating neurological disorder and one of the leading causes of death and serious disability in adults. Adult neural stem cell (NSC) replacement therapy is a promising treatment for both structural and functional neurological recovery. However, for the treatment to work, adult NSCs must be protected against hypoxic-ischemic damage in the ischemic penumbra. In the present study, we aimed to investigate the neuroprotective effects of the mfat-1 transgene on cobalt chloride (CoCl₂ )-induced hypoxic-ischemic injury in cultured adult NSCs as well as its underlying mechanisms. The results show that in the CoCl₂ -induced hypoxic-ischemic injury model, the mfat-1 transgene enhanced the viability of adult NSCs and suppressed CoCl₂ -mediated apoptosis of adult NSCs. Additionally, the mfat-1 transgene promoted the proliferation of NSCs as shown by increased bromodeoxyuridine labeling of adult NSCs. This process was related to the reduction of reactive oxygen species. Quantitative real-time polymerase chain reaction and Western blot analysis revealed a much higher expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream genes (HO-1, NQO-1, GCLC). Taken together, our findings show that the mfat-1 transgene restored the CoCl₂ -inhibited viability and proliferation of NSCs by activating nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response elements (ARE) signal pathway to inhibit oxidative stress injury. Further investigation of the function of the mfat-1 transgene in adult protective mechanisms may accelerate the development of adult NSC replacement therapy for ischemic stroke.

Keywords: RRID: AB_11156457; RRID: AB_1645170; RRID: AB_2107436; RRID: AB_2107804; RRID: AB_2109645; RRID: AB_302944; RRID: AB_306966; RRID: AB_570918; RRID: AB_881738; RRID: AB_944418; RRID: AB_94872; RRID: IMSR_-JAX:000664; RRID: SCR_002865; RRID: SCR_003070; RRID: SCR_007369; adult neural stem cells (NSCs); cobalt chloride (CoCl2); ischemic stroke; mfat-1 gene; nuclear factor erythroid 2-related factor 2 (Nrf2); oxidative stress.