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

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

  • Stem Cell Res Ther. 2025 Jul 21;16(1):392. doi: 10.1186/s13287-025-04489-x.
Wenjia Wang # 1 2,  Wenqiao Qiu # 3,  Pengyu Chen # 4,  Zhijun Yang # 1 5,  Mingming Zou # 1,  Yuhui Zhou 3 6,  Lili Guo 3,  Dan Zou 3,  Ruxiang Xu 7,  Mou Gao 8
Affiliations

Affiliations

  • 1 Senior Department of Neurosurgery, The First Medical Center of PLA General Hospital, Beijing, 100853, China.
  • 2 Department of ENT-HN, Hainan Hospital of PLA General Hospital, Sanya, 572013, China.
  • 3 Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, 610072, China.
  • 4 College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, 350122, China.
  • 5 Hebei Leren Biotechnology Co., LTD, Shijiazhuang, Hebei Province, 050000, China.
  • 6 Chuanxing Middle School, Xichang, Sichuan Province, 615000, China.
  • 7 Department of Neurosurgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan Province, 610072, China. jzprofxu@126.com.
  • 8 Senior Department of Neurosurgery, The First Medical Center of PLA General Hospital, Beijing, 100853, China. gaomou218@126.com.
  • # Contributed equally.
PMID: 40691843 DOI: 10.1186/s13287-025-04489-x
Abstract

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.

Conclusions: In short, our study shows that Akt signaling may regulate BDNF expression in iNSCs. Activation of Akt can up-regulate BDNF expression through inactivating EZH2 as well as reducing EZH2 and H3K27me3 levels at Bdnf promoter IV, meanwhile activating CREB as well as increasing CREB levels at Bdnf promoters I and IV.

Keywords

AKT; BDNF; CREB; Closed head injury; EZH2; H3K27me3; Induced neural stem cell; Microglia.

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