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首页> 美国卫生研究院文献>Cells >A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells
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A Matter of Choice: Inhibition of c-Rel Shifts Neuronal to Oligodendroglial Fate in Human Stem Cells

机译：选择事项：抑制c-Rel将神经元转变为人类干细胞的少突胶质命运。

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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.
机译：在神经元发育和神经退行性疾病期间，人类神经干细胞（hNSC）在神经发生和神经胶质发生之间命运决定的分子机制至关重要。尽管其在鼠神经系统中起关键作用，但人们对转录因子NF-κB在hNSCs神经元发育中的潜在作用知之甚少。在这里，我们分析了源自神经c衍生干细胞的hNSCs在谷氨酸能分化期间的NF-κB亚基分布。我们观察到了特定NF-κB亚基的几个峰。在分化开始后的2–5天内，c-REL亚基显示了最突出的核峰。此外，己酮可可碱（PTXF）对c-REL的抑制作用导致了向少突神经胶质命运的完全转变，这由OLIG2 / O4-少突胶质细胞的存在和转录水平所证实。此外，c-REL损伤进一步导致神经元存活率显着下降。将PTXF处理的预分化hNSCs移植到小鼠器官型小脑切片的离体氧化应激介导的脱髓鞘模型中，进一步导致白质整合并分化成MBP少突胶质细胞，从而验证了它们的功能性和治疗潜力。总之，我们提出了一种神经元分化的人类细胞模型，该模型在神经发生和少突胶质形成之间的命运选择中展现出NF-κB-c-REL的新型基本功能，这可能与多发性硬化症和精神分裂症有关。

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