DataSheet3_Impaired Cell Cycle Progression and Self-Renewal of Fetal Neural Stem and Progenitor Cells in a Murine Model of Intrauterine Growth Restriction.PDF

Individuals with intrauterine growth restriction (IUGR) are at an increased risk for neurodevelopmental impairment. Fetal cortical neurogenesis is a time-sensitive process in which fetal neural stem cells (NSCs) follow a distinct pattern of layer-specific neuron generation to populate the cerebral cortex. Here, we used a murine maternal hypoxia-induced IUGR model to study the impact of IUGR on fetal NSC development. In this model, timed-pregnant mice were exposed to hypoxia during the active stage of neurogenesis, followed by fetal brain collection and analysis. In the IUGR fetal brains, we found a significant reduction in cerebral cortical thickness accompanied by decreases in layer-specific neurons. Using EdU labeling, we demonstrated that cell cycle progression of fetal NSCs was delayed, primarily observed in the G2/M phase during inward interkinetic nuclear migration. Following relief from maternal hypoxia exposure, the remaining fetal NSCs re-established their neurogenic ability and resumed production of layer-specific neurons. Surprisingly, the newly generated neurons matched their control counterparts in layer-specific marker expression, suggesting preservation of the fetal NSC temporal identity despite IUGR effects. As expected, the absolute number of neurons generated in the IUGR group remained lower compared to that in the control group due to a reduced fetal NSC pool size as a result of cell cycle defect. Transcriptome analysis identified genes related to energy expenditure and G2/M cell cycle progression being affected by maternal hypoxia-induced IUGR. Taken together, maternal hypoxia-induced IUGR is associated with a defect in cell cycle progression of fetal NSCs, and has a long-term impact on offspring cognitive development.

患有宫内生长受限（IUGR）的个体，其神经发育障碍的风险显著增加。胎儿皮质神经发生是一个时间敏感的过程，其中胎儿神经干细胞（NSCs）遵循特定的层特异性神经元生成模式，以充填大脑皮质。在本研究中，我们采用由母体缺氧诱导的宫内生长受限小鼠模型，以探讨IUGR对胎儿NSC发育的影响。在该模型中，妊娠小鼠在神经发生活跃阶段暴露于缺氧环境，随后收集胎儿脑组织并进行分析。在IUGR胎儿脑组织中，我们发现大脑皮质厚度显著降低，伴随层特异性神经元数量的减少。通过EdU标记，我们证实胎儿NSC的细胞周期进程延迟，主要在向内间期核迁移的G2/M期观察到。在解除母体缺氧暴露后，剩余的胎儿NSC恢复了其神经发生能力，并重新开始产生层特异性神经元。令人惊讶的是，新产生的神经元在层特异性标记物表达上与对照样本相匹配，表明即使在IUGR的影响下，胎儿NSC的时间特异性身份也得到了保留。正如预期，由于细胞周期缺陷导致胎儿NSC池大小的减少，IUGR组生成的神经元绝对数量仍低于对照组。转录组分析揭示了受母体缺氧诱导的IUGR影响的与能量消耗和G2/M细胞周期进程相关的基因。综上所述，母体缺氧诱导的IUGR与胎儿NSC细胞周期进程的缺陷相关，并对后代的认知发育产生长期影响。