Localized hypoxia within the subgranular zone determines the early survival of newborn hippocampal granule cells.
Localized hypoxia within the subgranular zone determines the early survival of newborn hippocampal granule cells.
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DOI：
10.7554/elife.08722
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发表时间：
2015-10-17
期刊：
影响因子：
7.7
通讯作者：
Westbrook GL
中科院分区：
文献类型：
--
作者：
Chatzi C;Schnell E;Westbrook GL
大多数成年海马新生细胞在从中间祖细胞（IPC）向未成熟神经元分化的早期过程中死亡。体内神经干细胞处于相对低氧的环境中，低氧可促进其在体外的存活、增殖和干细胞化。因此，我们假设IPC从SGZ内的缺氧区迁移可能导致氧化损伤，从而触发细胞死亡。沿着SGZ观察到由成体NSC和早期IPC组成的低分化小生境，相邻的晚期IPC和成神经细胞中存在氧化副产物。在体外的神经球和体内的新生SGZ细胞中，用二甲基氧烯丙基甘氨酸稳定缺氧诱导因子-1 α可以增加早期存活，但不能增加增殖或分化。在Escherichia fl/flmutants中的拯救实验支持这些结果。我们认为，局部缺氧的SGZ内的神经原性微环境，并决定了早期，活性独立的成年海马新生细胞的生存。http://dx.doi.org/10.7554/eLife.08722.001海马体是哺乳动物大脑中的一个区域，与新记忆的形成有关。这个过程涉及到新神经元的诞生，在年轻成年小鼠的海马体中，新神经元以每天4000个的速度产生。然而，这些细胞中只有一小部分存活下来形成成熟的神经元。这些细胞主要以两种方式死亡-第一种发生在它们形成后几天，第二种发生在几周后，当它们作为未成熟的神经元整合到大脑中时。在后一波中，新的神经元变得活跃，如果它们与其他神经细胞连接，它们就会存活，如果它们不连接，就会死亡。但是对于导致早期细胞死亡的原因知之甚少。与其他组织相比，含有新神经元前体的组织通常具有较低的氧气水平。这意味着，当这些细胞开始成为神经元并离开这些部位时，它们必须面对更高水平的氧气，并可能遭受“氧化”损伤。这使得Chatzi等人提出这样的问题：这种氧化损伤是否可能导致海马体中新神经元的早期丢失。首先，研究人员发现，海马体中含有前体细胞的部分（称为颗粒下区或SGZ）有片状低氧区。进一步的实验表明，可能导致氧化损伤的化学物质存在于附近已经开始成为新神经元的细胞中。Chatzi等人随后测试了化学稳定一种名为缺氧诱导因子-1 α（Hypoxia Inducible Factor-1α，简称HIF 1 α）的蛋白质是否可以增加SGZ中细胞的存活率，这种蛋白质可以自然地帮助细胞适应低氧环境。高水平的HIF 1 α确实增加了这些细胞的存活率。这些发现表明，SGZ中的新生细胞在支持早期前体的低氧环境和周围较高的氧气水平之间走钢丝，这些氧气水平可能对开始成为神经元的细胞有毒。对HIF 1 α下游作用的蛋白质和分子的进一步研究可以揭示增强这些新生成神经元存活的方法。DOI：http://dx.doi.org/10.7554/eLife.08722.002网站
The majority of adult hippocampal newborn cells die during early differentiation from intermediate progenitors (IPCs) to immature neurons. Neural stem cells in vivo are located in a relative hypoxic environment, and hypoxia enhances their survival, proliferation and stemness in vitro. Thus, we hypothesized that migration of IPCs away from hypoxic zones within the SGZ might result in oxidative damage, thus triggering cell death. Hypoxic niches were observed along the SGZ, composed of adult NSCs and early IPCs, and oxidative byproducts were present in adjacent late IPCs and neuroblasts. Stabilizing hypoxia inducible factor-1α with dimethyloxallyl glycine increased early survival, but not proliferation or differentiation, in neurospheres in vitro and in newly born SGZ cells in vivo. Rescue experiments in Baxfl/flmutants supported these results. We propose that localized hypoxia within the SGZ contributes to the neurogenic microenvironment and determines the early, activity-independent survival of adult hippocampal newborn cells. DOI: http://dx.doi.org/10.7554/eLife.08722.001 The hippocampus is a region in the mammalian brain that has been implicated in the formation of new memories. This process involves the birth of new neurons, which are created at a rate of ∼4000 a day in the hippocampus of a young adult mouse. Yet only a fraction of these cells survive to form mature neurons. These cells die in two main waves – the first occurs days after they form, and the second several weeks later when as immature neurons they integrate into the brain. During this later wave, new neurons become active and survive if they connect with other nerve cells and die if they don’t. But little is known about what causes the earlier wave of cell death. The tissues that contain the precursors of new neurons often have lower oxygen levels compared to other tissues. This means that when these cells start to become neurons and leave these sites, they have to face higher levels of oxygen and may undergo “oxidative” damage. This led Chatzi et al. to ask whether such oxidative damage might cause the early loss of new neurons in the hippocampus. First, the part of the hippocampus that contains the precursor cells (called the subgranular zone or SGZ) was found to have patchy areas of low oxygen. Further experiments then revealed that chemicals that may cause oxidative damage were present in the nearby cells that had already started on the path to become new neurons. Chatzi et al. then tested whether chemically stabilizing a protein called Hypoxia Inducible Factor-1α (or HIF1α for short), which naturally helps cells to adapt to low oxygen environments, might increase the survival of the cells in the SGZ. Higher levels of HIF1α did indeed increase the survival of these cells. These findings suggest that newborn cells in the SGZ walk a tightrope between a low oxygen environment that supports the early precursors and the surrounding higher oxygen levels that can be toxic to those cells that start to become neurons. Further studies of the proteins and molecules that act downstream of HIF1α could shed light on ways to enhance the survival of these newly-generated neurons. DOI: http://dx.doi.org/10.7554/eLife.08722.002