Molecular Neurobiology, University of Bielefeld, 33615 Bielefeld, Germany.
Department of Cell Biology, University of Bielefeld, 33615 Bielefeld, Germany.
Cells. 2020 Apr 22;9(4):1037. doi: 10.3390/cells9041037.
The molecular mechanisms underlying fate decisions of human neural stem cells (hNSCs) between neurogenesis and gliogenesis are critical during neuronal development and neurodegenerative diseases. Despite its crucial role in the murine nervous system, the potential role of the transcription factor NF-κB in the neuronal development of hNSCs is poorly understood. Here, we analyzed NF-κB subunit distribution during glutamatergic differentiation of hNSCs originating from neural crest-derived stem cells. We observed several peaks of specific NF-κB subunits. The most prominent nuclear peak was shown by c-REL subunit during a period of 2-5 days after differentiation onset. Furthermore, c-REL inhibition with pentoxifylline (PTXF) resulted in a complete shift towards oligodendroglial fate, as demonstrated by the presence of OLIG2/O4-oligodendrocytes, which showed , and at the transcript level. In addition c-REL impairment further produced a significant decrease in neuronal survival. Transplantation of PTXF-treated predifferentiated hNSCs into an ex vivo oxidative-stress-mediated demyelination model of mouse organotypic cerebellar slices further led to integration in the white matter and differentiation into MBP oligodendrocytes, validating their functionality and therapeutic potential. In summary, we present a human cellular model of neuronal differentiation exhibiting a novel essential function of NF-κB-c-REL in fate choice between neurogenesis and oligodendrogenesis which will potentially be relevant for multiple sclerosis and schizophrenia.
人类神经干细胞 (hNSC) 在神经发生和神经胶质发生之间的命运决定的分子机制在神经元发育和神经退行性疾病中至关重要。尽管转录因子 NF-κB 在小鼠神经系统中具有重要作用，但它在 hNSC 神经元发育中的潜在作用仍知之甚少。在这里，我们分析了源自神经嵴衍生干细胞的 hNSC 谷氨酸能分化过程中 NF-κB 亚基的分布。我们观察到几个特定 NF-κB 亚基的峰。在分化开始后 2-5 天，c-REL 亚基表现出最明显的核峰。此外，用己酮可可碱 (PTXF) 抑制 c-REL 导致完全向少突胶质细胞命运转变，这表现为 OLIG2/O4-少突胶质细胞的存在，其在转录水平上显示 、 和 。此外，c-REL 损伤进一步导致神经元存活率显著降低。将经 PTXF 处理的预分化 hNSC 移植到体外氧化应激介导的小鼠器官型小脑切片脱髓鞘模型中，进一步导致其在白质中的整合和分化为 MBP 少突胶质细胞，验证了它们的功能和治疗潜力。总之，我们提出了一个人类神经分化细胞模型，该模型显示 NF-κB-c-REL 在神经发生和少突胶质发生之间的命运选择中具有新的重要功能，这可能与多发性硬化症和精神分裂症有关。
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