Inhibition of HSP90 Promotes Neural Stem Cell Survival from Oxidative Stress through Attenuating NF‐κB/p65 Activation

Abstract

Stem cell survival after transplantation determines the efficiency of stem cell treatment, which develops as a novel potential therapy for several central nervous system (CNS) diseases in recent decades. The engrafted stem cells face the damage of oxidative stress, inflammation, and immune response at the lesion point in host. Among the damaging pathologies, oxidative stress directs stem cells to apoptosis and even death through several signalling pathways and DNA damage. However, the in-detail mechanism of stem cell survival from oxidative stress has not been revealed clearly. Here, in this study, we used hydrogen peroxide (H2O2) to induce the oxidative damage on neural stem cells (NSCs). The damage was in consequence demonstrated involving the activation of heat shock protein 90 (HSP90) and NF-κB/p65 signalling pathways. Further application of the pharmacological inhibitors, respectively, targeting at each signalling indicated an upper-stream role of HSP90 upon NF-κB/p65 on NSCs survival. Preinhibition of HSP90 with the specific inhibitor displayed a significant protection on NSCs against oxidative stress. In conclusion, inhibition of HSP90 would attenuate NF-κB/p65 activation by oxidative induction and promote NSCs survival from oxidative damage. The HSP90/NF-κB mechanism provides a new evidence on rescuing NSCs from oxidative stress and also promotes the stem cell application on CNS pathologies.

Granulocyte Colony‐Stimulating Factor Alleviates Bacterial‐Induced Neuronal Apoptotic Damage in the Neonatal Rat Brain through Epigenetic Histone Modification

“…To activate the NF- κ B pathway, it depended on I κ B kinase phosphorylation of the inhibitory molecules and phosphorylation of the P65 protein. Then, the phosphorylation of the P65 protein was translocated into the nucleus [ 35 , 36 ]. This phosphorylated P65 protein has the ability to recruit histone acetyltransferases and lead to the production of proinflammatory factors, such as TNF- α .…”

Oxidative Stress in Stem Cell Aging

“… 53 IGF-1, mTOR, SIRT1, and p53 are reported to be the upstream signaling regulator of the NF-κB pathway during aging. 66 Attenuation of NF-κB activity (primarily p65) by heat shock protein 90 (HSP90) inhibitor, 67 NAC, 37 myoblast determination protein (MyoD), 68 and NF-κB small molecule inhibitor 69 was reported to reduce cellular oxidative stress, alleviate cell death, and enhance stemness in various stem cell types.…”

GRP78 Promotes Neural Stem Cell Antiapoptosis and Survival in Response to Oxygen‐Glucose Deprivation (OGD)/Reoxygenation through PI3K/Akt, ERK1/2, and NF‐κB/p65 Pathways

“…The NSCs were harvested from embryonic C57BL/6 mouse brain (E14), briefly as we described in our previous reports [ 15 ]. The neurosphere culture was kept in DMEM/F12 medium containing B27, EGF, and bFGF, at 37°C, 5% CO 2 .…”

“…Cell viability was detected with MTT assay and Hoechst 33342/PI double staining as previously described [ 15 , 17 ]. Cellular ROS production was detected with the DCF-DA probe kit, according to the manufacturer's instruction.…”

“…The whole cell or nuclear lysate of the treated NSCs was collected for Western blotting. The samples were subjected onto 4–12% SDS-PAGE gel for electrophoresis as previously described [ 15 ]. The protein bands were transblotted onto the PVDF membrane, followed by blocking in 5% BSA-TBST buffer and incubation with the primary and HRP-conjugated secondary antibodies in sequence.…”