Loeliger Burk W, Hanu Christine, Panyutin Irina V, Maass-Moreno Roberto, Wakim Paul, Pritchard William F, Neumann Ronald D, Panyutin Igor G
Department of Radiology and Imaging Sciences.
Department of Biostatistics and Clinical Epidemiology Service, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892.
Radiat Res. 2020 May;193(5):460-470. doi: 10.1667/RR15535.1. Epub 2020 Mar 27.
Human embryonic brain development is highly sensitive to ionizing radiation. However, detailed information on the mechanisms of this sensitivity is not available due to limited experimental data. In this study, differentiation of human embryonic stem cells (hESCs) to neural lineages was used as a model for early embryonic brain development to assess the effect of exposure to low (17 mGy) and high (572 mGy) doses of radiation on gene expression. Transcriptomes were assessed using RNA sequencing during neural differentiation at three time points in control and irradiated samples. The first time point was when the cells were still pluripotent (day 0), the second time point was during the stage of embryoid body formation (day 6), and the third and final time point was during the stage of neural rosette formation (day 10). Analysis of the transcriptomes revealed neurodifferentiation in both the control and irradiated cells. Low-dose irradiation did not result in changes in gene expression at any of the time points, whereas high-dose irradiation resulted in downregulation of some major neurodifferentiation markers on days 6 and 10. Gene ontology analysis showed that pathways related to nervous system development, neurogenesis and generation of neurons were among the most affected. Expression of such key regulators of neuronal development as NEUROG1, ARX, ASCL1, RFX4 and INSM1 was reduced more than twofold. In conclusion, exposure to a 17 mGy low dose of radiation was well tolerated by hESCs while exposure to 572 mGy significantly affected their genetic reprogramming into neuronal lineages.
人类胚胎大脑发育对电离辐射高度敏感。然而，由于实验数据有限，关于这种敏感性机制的详细信息尚不可得。在本研究中，人类胚胎干细胞（hESCs）向神经谱系的分化被用作早期胚胎大脑发育的模型，以评估低剂量（17 mGy）和高剂量（572 mGy）辐射暴露对基因表达的影响。在对照和辐照样本的神经分化过程中的三个时间点，使用RNA测序评估转录组。第一个时间点是细胞仍处于多能状态时（第0天），第二个时间点是在胚状体形成阶段（第6天），第三个也是最后一个时间点是在神经玫瑰花结形成阶段（第10天）。转录组分析揭示了对照细胞和辐照细胞中的神经分化。低剂量辐照在任何时间点均未导致基因表达的变化，而高剂量辐照导致在第6天和第10天一些主要神经分化标志物的下调。基因本体分析表明，与神经系统发育、神经发生和神经元生成相关的途径是受影响最大的途径之一。神经元发育的关键调节因子如NEUROG1、ARX、ASCL1、RFX4和INSM1的表达降低了两倍以上。总之，hESCs对17 mGy的低剂量辐射暴露耐受性良好，而572 mGy的辐射暴露显著影响了它们向神经元谱系的基因重编程。
