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

胶质细胞HIF-α在缺氧/缺血诱导的少突胶质细胞病理中的作用机制 妊娠37周前的早产影响到10个婴儿中的1个，对公共卫生造成巨大负担。 由于早产儿的呼吸系统和脑白色物质脉管系统的不成熟， 缺氧/缺血（H/I）引起弥漫性白色物质损伤（WTH）在早产儿脑中经常发生。干扰 髓鞘形成是弥漫性髓鞘病的标志性病理特征。产生髓鞘的分化受损 少突胶质细胞从少突胶质细胞祖细胞分化（称为OPC分化）是一个主要的罪魁祸首 髓鞘形成紊乱目前还没有临床治疗方法用于促进受脑缺血影响的早产儿的髓鞘形成。 - 是的因此，研究卵巢癌中OPC分化停滞的分子机制具有重要意义 并有助于设计用于治疗早产儿髓鞘形成不足的髓鞘形成疗法。这个项目 目的是确定弥漫性脑脊髓炎中髓鞘形成紊乱的分子机制，重点是 胶质细胞HIFα在OPC分化和髓鞘形成中的作用及机制。发育中枢 神经系统（CNS）暴露于生理低氧环境，在该环境下低氧可诱导 α因子HIFα（HIF 1 α和HIF 2 α）是瞬时稳定的，以调节神经发育。HIFα的作用 在神经胶质细胞发育中的作用仍然是未知的，直到一项开创性的研究报告了少突胶质细胞HIFα 稳定化通过激活自分泌Wnt信号传导干扰正常OPC分化（Yuen等，2014 Cell）。然而，我们最近的体内研究（Zhang等人，2020 Nature Communications）弱化了这一概念， 阐明了胶质细胞类型特异性HIFα-Wnt调节：少突胶质细胞HIFα不调节Wnt信号传导 而星形胶质细胞HIFα却令人惊讶地具有这种功能。我们提交的研究（Zhang et al.，2020 BioRxiv， doi：10.1101/2020.03.30.015131）进一步证明了HIFα在正常人中的自分泌Wnt非依赖性作用。 发现了一个新的HIFα靶点，其激活抑制OPC分化。 在接下来的研究中，我们发现神经胶质细胞中持续的HIFα激活，有趣的是， HIFα激活减轻弥漫性脑梗死动物模型中髓鞘形成障碍。建立在这些 大量的数据，我们提出了一个总体假设，即在海马神经元中，少突胶质细胞HIFα调节 OPC分化以独立于先前认为的自分泌Wnt信号传导的方式（在目标1中测试）， 相反，通过激活SOX 9，我们发现了一个新的非经典HIFα靶点（在目标2中进行了测试）， 星形胶质细胞通过HIFα激活的旁分泌Wnt信号传导控制OPC分化（在Aim 3中测试）。我们将 使用神经胶质类型特异性和时间条件遗传突变体和早产人脑等效小鼠 模型来检验我们的假设。这个项目可能会推进我们的基本机制 了解胶质细胞HIFα在少突胶质细胞生物学和病理学中的作用，并为治疗提供新的数据。 胶质细胞HIFα在克服弥漫性脑梗死影响的早产儿髓鞘形成障碍中的潜力

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.