Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (5): 1416-1430.doi: 10.4103/NRR.NRR-D-23-01495

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Induced neural stem cells regulate microglial activation through Akt-mediated upregulation of CXCR4 and Crry in a mouse model of closed head injury.

Mou Gao1, 2, *, Qin Dong3 , Dan Zou1 , Zhijun Yang1 , Lili Guo1 , Ruxiang Xu1, *
  

  1. 1 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, China; 
    2 Department of Neurosurgery, Chinese PLA General Hospital, Beijing, China;  3 Department of Neurology, Fu Xing Hospital, Capital Medical University, Beijing, China
  • Online:2025-05-15 Published:2024-10-31
  • Contact: Ruxiang Xu, MD, jzprofxu@126.com; Mou Gao, MD, gaomou218@126.com.
  • Supported by:
    This work was supported by the National Natural Science Foundation of China, Nos. 82271397 (to MG), 82001293 (to MG), 82171355 (to RX), 81971295 (to RX), and 81671189 (to RX).

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Abstract: Microglial activation that occurs rapidly after closed head injury may play important and complex roles in neuroinflammation-associated neuronal damage and repair. We previously reported that induced neural stem cells can modulate the behavior of activated microglia via CXCL12/CXCR4 signaling, influencing their activation such that they can promote neurological recovery. However, the mechanism of CXCR4 upregulation in induced neural stem cells remains unclear. In this study, we found that nuclear factor-κB activation induced by closed head injury mouse serum in microglia promoted CXCL12 and tumor necrosis factor-α expression but suppressed insulin-like growth factor-1 expression. However, recombinant complement receptor 2-conjugated Crry (CR2-Crry) reduced the effects of closed head injury mouse serum-induced nuclear factor-κB activation in microglia and the levels of activated microglia, CXCL12, and tumor necrosis factor-α. Additionally, we observed that, in response to stimulation (including stimulation by CXCL12 secreted by activated microglia), CXCR4 and Crry levels can be upregulated in induced neural stem cells via the interplay among CXCL12/CXCR4, Crry, and Akt signaling to modulate microglial activation. In agreement with these in vitro experimental results, we found that Akt activation enhanced the immunoregulatory effects of induced neural stem cell grafts on microglial activation, leading to the promotion of neurological recovery via insulin-like growth factor-1 secretion and the neuroprotective effects of induced neural stem cell grafts through CXCR4 and Crry upregulation in the injured cortices of closed head injury mice. Notably, these beneficial effects of Akt activation in induced neural stem cells were positively correlated with the therapeutic effects of induced neural stem cells on neuronal injury, cerebral edema, and neurological disorders post–closed head injury. In conclusion, our findings reveal that Akt activation may enhance the immunoregulatory effects of induced neural stem cells on microglial activation via upregulation of CXCR4 and Crry, thereby promoting induced neural stem cell–mediated improvement of neuronal injury, cerebral edema, and neurological disorders following closed head injury.

Key words:

Akt signaling, cerebral edema, closed head injury, Crry, CXCR4, induced neural stem cell, microglia, neuroinflammation