Mild hypothermia promotes neuronal differentiation of human neural stem cells via RBM3-SOX11 signaling pathway

Both therapeutic hypothermia and neural stem cells (NSCs) transplantation have shown promise in neuroprotection and neural repair after brain injury. However, the effects of therapeutic hypothermia on neuronal differentiation of NSCs are not elucidated. In this study, we aimed to investigate whether mild hypothermia promoted neuronal differentiation in cultured and transplanted human NSCs (hNSCs). A significant increase in neuronal differentiation rate of hNSCs was found when exposing to 35°C, from 33% to 45% in vitro and from 7% to 15% in vivo, respectively. Additionally, single-cell RNA sequencing identified upregulation of RNA-binding motif protein 3 (RBM3) in neuroblast at 35°C, which stabilized the SRY-box transcription factor 11 (SOX11) mRNA and increased its protein expression, leading to an increase in neuronal differentiation of hNSCs. In conclusion, our study highlights that mild hypothermia at 35°C enhances hNSCs-induced neurogenesis through the novel RBM3-SOX11 signaling pathway, and provides a potential treatment strategy in brain disorders.

治疗性低体温（therapeutic hypothermia）与神经干细胞（neural stem cells, NSCs）移植在脑损伤后的神经保护及神经修复领域均展现出潜在应用价值。然而，治疗性低体温对神经干细胞神经元分化的调控效应尚未阐明。本研究旨在探究轻度低体温是否可促进体外培养及移植的人源神经干细胞（human NSCs, hNSCs）的神经元分化。实验发现，将hNSCs置于35℃环境时，其神经元分化率显著提升：体外实验中分化率从33%升至45%，体内实验中则从7%提升至15%。此外，单细胞RNA测序（single-cell RNA sequencing）结果显示，35℃环境下神经母细胞中的RNA结合基序蛋白3（RNA-binding motif protein 3, RBM3）表达上调，该蛋白可稳定SRY盒转录因子11（SRY-box transcription factor 11, SOX11）的mRNA并提升其蛋白表达水平，进而促进hNSCs的神经元分化。综上，本研究证实35℃轻度低体温可通过全新的RBM3-SOX11信号通路增强hNSCs介导的神经发生，为脑部疾病的治疗提供了潜在策略。