铁对生命很重要,缺铁会损害发育,但是铁水平是否调节神经分化仍然难以捉摸。在这项研究中,铁调节蛋白(IRP)敲除的胚胎干细胞(ESC)显示严重缺铁,我们发现,诱导神经分化后,IRP1-/-IRP2-/-ESCs中的Pax6-和Sox2阳性神经元前体细胞和Tuj1纤维明显减少。始终如一,体内研究表明,IRP1在IRP2-/-胎鼠体内的敲除显著影响神经元前体的分化和神经元的迁移。这些发现表明低细胞内铁状态显著抑制神经分化。当用铁补充IRP1-/-IRP2-/-ESC时,这些ESC可以正常分化。进一步的研究表明,潜在的机制与铁的低水平和铁-硫簇蛋白ISCU的下调引起的活性氧(ROS)产生的增加有关,which,反过来,影响干细胞的增殖和分化。因此,适量的铁对于维持正常的神经分化(称为铁分化)至关重要。
Iron is important for life, and iron deficiency impairs development, but whether the iron level regulates neural differentiation remains elusive. In this study, with iron-regulatory proteins (IRPs) knockout embryonic stem cells (
ESCs) that showed severe iron deficiency, we found that the Pax6- and Sox2-positive neuronal precursor cells and Tuj1 fibers in IRP1-/-IRP2-/-
ESCs were significantly decreased after inducing neural differentiation. Consistently, in vivo study showed that the knockdown of IRP1 in IRP2-/- fetal mice remarkably affected the differentiation of neuronal precursors and the migration of neurons. These findings suggest that low intracellular iron status significantly inhibits neurodifferentiation. When supplementing IRP1-/-IRP2-/-
ESCs with iron, these
ESCs could differentiate normally. Further investigations revealed that the underlying mechanism was associated with an increase in reactive oxygen species (ROS) production caused by the substantially low level of iron and the down-regulation of iron-sulfur cluster protein ISCU, which, in turn, affected the proliferation and differentiation of stem cells. Thus, the appropriate amount of iron is crucial for maintaining normal neural differentiation that is termed ferrodifferentiation.