Glial HIFa: mechanisms and implications in hypoxia/ischemia-induced oligodendroglial pathology

胶质细胞HIFA：机制及其在缺氧/缺血诱导的少突胶质细胞病理中的意义 37周前的早产影响十分之一的婴儿，对公共卫生是一个巨大的负担。 由于早产儿呼吸系统和脑白质血管的不成熟， 缺氧/缺血(H/I)所致的弥漫性脑白质损伤(WMI)常见于早产儿脑内。烦躁不安 髓鞘形成是弥漫性WMI的一个显著病理特征。髓鞘生成的分化障碍 少突胶质细胞前体细胞(称为OPC分化)是主要的罪魁祸首 治疗髓鞘形成障碍。目前尚无促进早产儿髓鞘形成的临床疗法。 WMI。因此，研究WMI中OPC分化受阻的分子机制具有重要意义。 并有助于设计治疗早产儿髓鞘过少的髓鞘疗法。这个项目 旨在确定弥漫性WMI中髓鞘形成障碍的分子机制，重点是 胶质细胞缺氧诱导因子α在骨肉瘤分化和髓鞘形成中的作用及机制。发展中的中心 神经系统(CNS)暴露在低氧的生理环境中，在这种环境下，低氧可诱导 HIFα(HIF1α和HIF2α)是调节神经发育的暂时性稳定因子。低氧诱导因子α的作用 直到一项开创性的研究报道了少突胶质细胞缺氧诱导因子α的概念 稳定化通过激活自分泌Wnt信号干扰了正常的OPC分化(袁等人，2014 单元格)。然而，我们最近的活体研究(Zhang等人，2020自然通讯)削弱了这一概念和 破解胶质细胞类型特异性缺氧诱导因子α-Wnt调节：少突胶质细胞缺氧诱导因子α不调节Wnt信号 而星形胶质细胞的缺氧诱导因子α出人意料地做到了这一点。我们提交的研究(Zhang等人，2020 BioRxiv， DOI：10.1101/2020.03.30.015131)进一步证实了HIFα在正常脑组织中的自分泌WNT非依赖性作用 发现了一种新的缺氧诱导因子α靶点，其激活抑制了OPC的分化。 展望wmi，我们发现在胶质细胞中持续的低氧诱导因子α激活，有趣的是，抑制这种 缺氧诱导因子α的激活减轻了弥漫性白质心肌梗死动物模型中的髓鞘形成障碍。建立在这些基础上 大量数据，我们提出了一个重要的假设，即在腰腿痛下，少突胶质细胞HIFα调节 以与先前认为的自分泌Wnt信号无关的方式进行OPC区分(在目标1中测试)， 取而代之的是，通过激活SOX9，我们识别的一个新的非规范的HIFα靶标(在Aim 2中进行了测试)，并且 星形胶质细胞通过缺氧诱导因子α激活的旁分泌Wnt信号调控OPC的分化(在AIM 3中进行了测试)。我们会 使用神经胶质类型特定和时间条件的遗传突变体和早产的人脑等效小鼠 弥漫WMI模型来验证我们的假设。这个项目可能会推进我们的基本机制 了解胶质细胞缺氧诱导因子α在少突胶质细胞生物学和病理学中的作用，为治疗提供新的数据 胶质细胞缺氧诱导因子α在克服弥漫性白质心肌梗死影响的早产儿髓鞘形成障碍方面的潜力。

Glial HIFa: mechanisms and implications in hypoxia/ischemia-induced oligodendroglial pathology Preterm birth before 37th gestational week affects 1 of 10 infants and is an enormous burden on public health. Due to the immaturity of the respiratory system and the brain white matter vasculature of preterm infants, hypoxia/ischemia (H/I)-elicited diffuse white matter injury (WMI) frequently occurs in preterm brain. Disturbed myelination is a hallmark pathological feature in diffuse WMI. Impaired differentiation of myelin-producing oligodendrocytes from oligodendrocyte progenitor cells (referred to as OPC differentiation) is a primary culprit for disturbed myelination. No clinical therapies exist for promoting myelination in preterm infants affected by WMI. Therefore, studying molecular mechanisms underlying arrested OPC differentiation in WMI is important and instrumental in designing myelination therapies for treating hypomyelination in preterm infants. This project aims to define molecular mechanisms underlying the disturbed myelin formation in diffuse WMI with a focus on the function and mechanisms of glial HIFα in OPC differentiation and myelination. The developing central nervous system (CNS) is exposed to a physiologically hypoxic environment under which hypoxia inducible factor alpha, HIFα (HIF1α and HIF2α) is transiently stabilized to regulate neural development. The role of HIFα in glial cell development remains unknown until a seminal study reported a concept that oligodendroglial HIFα stabilization disturbed normal OPC differentiation through activating autocrine Wnt signaling (Yuen et al., 2014 Cell). However, our recent in vivo study (Zhang et al., 2020 Nature Communications) weakens the concept and unraveled a glial type-specific HIFα-Wnt regulation: oligodendroglial HIFα does not regulate Wnt signaling while astroglial HIFα surprisingly does. Our submitted study (Zhang et al., 2020 BioRxiv, doi:10.1101/2020.03.30.015131) further demonstrated an autocrine Wnt-independent role of HIFα in normal oligodendroglial development and discovered a novel HIFα target whose activation inhibits OPC differentiation. Going forward to WMI, we found persistent HIFα activation in glial cells and interestingly, dampening such HIFα activation mitigated myelination disturbance in an animal model for diffuse WMI. Built on these substantive data, we propose an overarching hypothesis that, under WMI, oligodendroglial HIFα regulates OPC differentiation in a manner independent of autocrine Wnt signaling as previously thought (tested in Aim 1), instead, through activating SOX9, a new non-canonical HIFα target we identified (tested in Aim 2) and that astrocytes control OPC differentiation through HIFα-activated paracrine Wnt signaling (tested in Aim 3). We will use glial type-specific and time-conditional genetic mutants and a preterm human brain-equivalent mouse model for diffuse WMI to test our hypothesis. This project will likely advance our fundamental mechanism knowledge of glial HIFα in oligodendroglial biology and pathology and provide new data into the therapeutic potential of glial HIFα in overcoming disturbed myelination in preterm infants affected by diffused WMI.