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Potential role of heat shock protein 90 in regulation of hyperthermia-driven differentiation of neural stem cells

By Lei Wang, Yi Zhuo, Zhengwen He, Ying Xia, Ming Lu

Posted 03 Apr 2019
bioRxiv DOI: 10.1101/598441

Objective: Our previous studies indicated that hyperthermia may play a role in differentiation of neural stem cells and that hypoxia inducible factor-1(HIF-1) was critical in this process. Heat shock protein 90 (Hsp90) is one of the most common heat-related proteins and involved in HIF-1 expression by regulating its activity and stabilization. Here, we hypothesized that HSP90 may be involved in regulation of hyperthermia-driven differentiation of neural stem cells(NSCs). We also investigated whether the HSP90 activity exert its regulatory action via HIF-1 pathway and the transcriptional level of the target genes of HIF-1. Method: The cultured NSCs were divided into three groups: an hyperthermic treatment group(40NSC) which NSCs was induced under 40°C temperature; a control group(37NSC) which NSCs was induced under 37°C temperature; an hyperthermic treatment and HSP90-inhibited group(40NSC+GA) which NSCs was induced with 0.5μM HSP90 inhibitor Geldanamycin(GA) under 40°C temperature. We examined cells HSP? and HIF-1? expression during a time window of 5 days(12h, 1d, 3d, 5d) post-differentiation. The expression HSPα, HIF-1α, VEGF (vascular endothelial growth factor) and erythmpoietin(EPO) of during a time window was evaluated by RT-qPCR. The proportion of Tuj-1 positive differentiated cells were observed by flow cytometry. Result: Hyperthermia promoted neuronal differentiation of NSC, and this effect could be blocked by HSP90 inhibitor GA. We observed the up-regulation of HSP90 during hyperthermia treatment, and that the protein levels of HIF-1α changed depending of the GA treatment. GA could not inhibited HSP90α expression but suppressed HSP activity and decreased the expression HIF-1α protein. Inhibition of HIF-1α expression by GA could consequently affect expression of its targeted genes such as VEGF and EPO. Conclusion: Hyperthermia promote differentiation of NSCs into neurons. HSP90 involved in the regulation of hyperthermia-driven differentiation of NSC, and the mechanism is related to HIF-1α and its downstream gene activation.

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