干细胞生态位对于调节干细胞的行为至关重要。果蝇神经干细胞(神经母细胞,NBs)被胶质细胞紧密包裹,但目前尚不清楚神经胶质细胞是否能调节NBs的自我更新和分化。这里,我们发现由胶质细胞产生的铁蛋白,与Zip13合作将铁运输到NB中用于能源生产,这对NB的自我更新和增殖至关重要。神经胶质铁蛋白编码基因的敲除通过下调乌头酸酶活性和NAD+水平导致NBs能量短缺,这导致Prospero进入细胞核介导的NBs的低增殖和过早分化。更重要的是,铁蛋白是肿瘤抑制的潜在靶点。此外,胶质铁蛋白的产生水平受NBs状态的影响,建立双细胞铁稳态。在这项研究中,我们证明神经胶质细胞对维持NBs的自我更新是必不可少的,揭示了NB胶质细胞在大脑发育过程中的新作用。
铁是几乎所有生物体的必需营养素。例如,铁有助于DNA的复制,细胞内能量的产生,以及氧气在身体周围的运输。缺铁是所有营养缺乏中最常见的,影响全世界超过40%的儿童。这会导致贫血,也会损害大脑和神经系统的发育,可能导致长期的认知损伤,即使在缺乏治疗之后。人们对铁如何促进大脑和神经系统的发育知之甚少。特别是,它是否以及如何支持神经干细胞(或简称NSC),这些神经干细胞在成熟的大脑中产生各种神经类型。为了调查,Maetal.通过实验降低了果蝇幼虫发育中大脑中铁蛋白(一种储存铁的蛋白质)的水平。铁蛋白的这种减少导致NSC的数量减少和大脑变小。出乎意料的是,当支持神经干细胞并向神经干细胞发送信号的神经胶质细胞中铁蛋白水平降低时,这种作用最大,而不是干细胞本身。Maetal.然后用荧光显微镜证实胶质细胞制造并含有大量的铁蛋白,这些铁蛋白可以转运到神经干细胞。在缺乏铁蛋白的果蝇的饮食中添加铁补充剂不会导致发育中的果蝇大脑中的干细胞数量正常,而添加减少铁含量的化合物导致干细胞数量减少。一起,这表明铁蛋白将铁从神经胶质细胞转运至神经干细胞。没有铁蛋白和铁,NSC无法产生足够的能量来分裂和制造新的干细胞。这导致神经干细胞失去干细胞的特征,并过早地转变为其他类型的神经元或神经胶质细胞。一起,这些发现表明,当铁不能从神经胶质细胞转移到神经干细胞时,这将导致大脑发育的缺陷。未来的实验将必须测试在哺乳动物发育中的大脑中是否也发生类似的铁从支持细胞到神经干细胞的运输。以及这种机制是否适用于身体其他部位的干细胞。
Stem cell niche is critical for regulating the behavior of stem cells. Drosophila neural stem cells (Neuroblasts, NBs) are encased by glial niche cells closely, but it still remains unclear whether glial niche cells can regulate the self-renewal and differentiation of NBs. Here, we show that ferritin produced by
glia, cooperates with Zip13 to transport iron into NBs for the energy production, which is essential to the self-renewal and proliferation of NBs. The knockdown of glial ferritin encoding genes causes energy shortage in NBs via downregulating aconitase activity and NAD+ level, which leads to the low proliferation and premature differentiation of NBs mediated by Prospero entering nuclei. More importantly, ferritin is a potential target for tumor suppression. In addition, the level of glial ferritin production is affected by the status of NBs, establishing a bicellular iron homeostasis. In this study, we demonstrate that glial cells are indispensable to maintain the self-renewal of NBs, unveiling a novel role of the NB glial niche during brain development.
Iron is an essential nutrient for almost all living organisms. For example, iron contributes to the replication of DNA, the generation of energy inside cells, and the transport of oxygen around the body. Iron deficiency is the most common of all nutrient deficiencies, affecting over 40% of children worldwide. This can lead to anemia and also impair how the brain and nervous system develop, potentially resulting in long-lasting cognitive damage, even after the deficiency has been treated. It is poorly understood how iron contributes to the development of the brain and nervous system. In particular, whether and how it supports nerve stem cells (or NSCs for short) which give rise to the various neural types in the mature brain. To investigate, Ma et al. experimentally reduced the levels of ferritin (a protein which stores iron) in the developing brains of fruit fly larvae. This reduction in ferritin led to lower numbers of NSCs and a smaller brain. Unexpectedly, this effect was largest when ferritin levels were reduced in glial cells which support and send signals to NSCs, rather than in the stem cells themselves. Ma et al. then used fluorescence microscopy to confirm that glial cells make and contain a lot of ferritin which can be transported to NSCs. Adding iron supplements to the diet of flies lacking ferritin did not lead to normal numbers of stem cells in the brains of the developing fruit flies, whereas adding compounds that reduce the amount of iron led to lower numbers of stem cells. Together, this suggests that ferritin transports iron from glial cells to the NSCs. Without ferritin and iron, the NSCs could not produce enough energy to divide and make new stem cells. This caused the NSCs to lose the characteristics of stem cells and prematurely turn into other types of neurons or glial cells. Together, these findings show that when iron cannot move from glial cells to NSCs this leads to defects in brain development. Future experiments will have to test whether a similar transport of iron from supporting cells to NSCs also occurs in the developing brains of mammals, and whether this mechanism applies to stem cells in other parts of the body.