Sunny Donna Elizabeth, Hammer Elke, Strempel Sebastian, Joseph Christy, Manchanda Himanshu, Ittermann Till, Hübner Stephanie, Weiss Frank Ulrich, Völker Uwe, Heckmann Matthias
Department of Neonatology and Pediatric Intensive Care, University of Medicine Greifswald, Ferdinand-Sauerbruchstrasse, 17475, Greifswald, Germany.
Department of Functional Genomics, University of Medicine Greifswald, Greifswald, Germany.
Mol Cell Pediatr. 2020 Aug 25;7(1):10. doi: 10.1186/s40348-020-00102-8.
Hyperoxia is a well-known cause of cerebral white matter injury in preterm infants with male sex being an independent and critical risk factor for poor neurodevelopmental outcome. Sex is therefore being widely considered as one of the major decisive factors for prognosis and treatment of these infants. But unfortunately, we still lack a clear view of the molecular mechanisms that lead to such a profound difference. Hence, using mouse-derived primary oligodendrocyte progenitor cells (OPCs), we investigated the molecular factors and underlying mechanisms behind the differential response of male and female cells towards oxidative stress.
We demonstrate that oxidative stress severely affects cellular functions related to energy metabolism, stress response, and maturation in the male-derived OPCs, whereas the female cells remain largely unaffected. CNPase protein level was found to decline following hyperoxia in male but not in female cells. This impairment of maturation was accompanied by the downregulation of nucleoporin and nuclear lamina proteins in the male cells. We identify Nup133 as a novel target protein affected by hyperoxia, whose inverse regulation may mediate this differential response in the male and female cells. Nup133 protein level declined following hyperoxia in male but not in female cells. We show that nuclear respiratory factor 1 (Nrf1) is a direct downstream target of Nup133 and that Nrf1 mRNA declines following hyperoxia in male but not in female cells. The female cells may be rendered resistant due to synergistic protection via the estrogen receptor alpha (ERα) which was upregulated following hyperoxia in female but not in male cells. Both Nup133 and ERα regulate mitochondrial function and oxidative stress response by transcriptional regulation of Nrf1.
These findings from a basic cell culture model establish prominent sex-based differences and suggest a novel mechanism involved in the differential response of OPCs towards oxidative stress. It conveys a strong message supporting the need to study how complex cellular processes are regulated differently in male and female brains during development and for a better understanding of how the brain copes up with different forms of stress after preterm birth.
高氧是早产婴儿脑白质损伤的一个众所周知的原因，男性是神经发育不良结局的独立且关键的危险因素。因此，性别被广泛认为是这些婴儿预后和治疗的主要决定性因素之一。但不幸的是，我们仍然不清楚导致这种巨大差异的分子机制。因此，我们使用小鼠来源的原代少突胶质前体细胞（OPC），研究了雄性和雌性细胞对氧化应激的不同反应背后的分子因素和潜在机制。
我们证明氧化应激严重影响雄性来源的OPC中与能量代谢、应激反应和成熟相关的细胞功能，而雌性细胞基本不受影响。发现男性细胞在高氧后CNPase蛋白水平下降，而女性细胞则没有。这种成熟障碍伴随着男性细胞中核孔蛋白和核纤层蛋白的下调。我们确定Nup133是受高氧影响的一种新的靶蛋白，其反向调节可能介导雄性和雌性细胞中的这种差异反应。男性细胞在高氧后Nup133蛋白水平下降，而女性细胞则没有。我们表明核呼吸因子1（Nrf1）是Nup133的直接下游靶点，并且男性细胞在高氧后Nrf1 mRNA下降，而女性细胞则没有。雌性细胞可能由于雌激素受体α（ERα）的协同保护而具有抗性，雌激素受体α在雌性细胞高氧后上调，而在雄性细胞中没有。Nup133和ERα都通过对Nrf1的转录调节来调节线粒体功能和氧化应激反应。
这些来自基本细胞培养模型的发现确立了显著的性别差异，并提示了一种参与OPC对氧化应激不同反应的新机制。它传达了一个强烈的信息，支持研究在发育过程中男性和女性大脑中复杂的细胞过程如何受到不同调节以及更好地理解早产后脑如何应对不同形式应激的必要性。
