AKT signaling upregulates BDNF expression in induced neural stem cells that interact with microglia

作者：Wenjia Wang, Wenqiao Qiu, Pengyu Chen, Zhijun Yang, Mingming Zou, Yuhui Zhou, Lili Guo, Dan Zou, Ruxiang Xu, Mou Gao · 发表于：Stem Cell Research & Therapy · 年份：2025 · DOI：10.1186/s13287-025-04489-x · 被引用次数：4 · 研究领域：Nerve injury and regeneration、Neurogenesis and neuroplasticity mechanisms、Neuroinflammation and Neurodegeneration Mechanisms

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has the capacity to promote neuronal survival that is crucial to neurological recovery after closed head injury (CHI). We previously reported that intracerebral-transplanted induced neural stem cells (iNSCs) can up-regulate BDNF levels to exert neurotrophic effects in CHI-damaged brains. Here we aim to elucidate the mechanism of BDNF up-regulation in iNSCs. METHODS: We performed iNSC and lipopolysaccharide (LPS)-activated microglia co-culture experiments, iNSC transplantation, loss-of-function study, morphological and molecular biological analyses to uncover the mechanism underlying the overexpression of BDNF in iNSCs. RESULTS: Our results indicated that co-culture with LPS-activated microglia up-regulated the expression levels of BDNF, as well as Bdnf exons I and IV in iNSCs. Notably, AKT inhibition could counteract the effects of co-culture with LPS-activated microglia that decreased enhancer of zeste homolog 2 (EZH2) and H3K27 trimethylation (H3K27me3) levels at Bdnf promoter IV but increased EZH2 phosphorylation and BDNF expression in iNSCs. Additionally, blockage of AKT could counteract the effects of co-culture with LPS-activated microglia that increased cAMP response element binding protein (CREB) levels at Bdnf promoters I and IV, as well as CREB phosphorylation and BDNF expression in iNSCs. Furthermore, blocking AKT activity in grafted iNSCs could reduce BDNF expression in the injured cortices of CHI mice. CONCLUSI...