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.

治疗性低温与神经干细胞（NSCs）移植在脑损伤后的神经保护和神经修复方面均展现出显著潜力。然而，治疗性低温对NSCs神经元分化的影响尚未得到充分阐明。在本研究中，我们旨在探究轻度低温是否能够促进培养和移植的人源神经干细胞（hNSCs）的神经元分化。体外实验发现，在35°C条件下，hNSCs的神经元分化率显著提高，从33%上升至45%；体内实验中，该比率从7%上升至15%。此外，单细胞RNA测序结果显示，在35°C时，神经母细胞中RNA结合基序蛋白3（RBM3）的表达上调，这稳定了SRY框转录因子11（SOX11）的mRNA，并增加了其蛋白质表达，进而导致hNSCs神经元分化的增加。综上所述，本研究突显了35°C的轻度低温能够通过新颖的RBM3-SOX11信号通路增强hNSCs诱导的神经发生，并为脑部疾病的治疗提供了潜在策略。