Development and function of human astrocytes

描述(申请人提供)：星形胶质细胞是人脑中最丰富的细胞类型，几乎参与大脑功能的方方面面，经常是疾病进展。星形胶质细胞在正常和异常脑发育中的作用以及疾病发病机制的确定一直受到缺乏/缺乏针对星形胶质祖细胞和更成熟的星形胶质细胞谱系的标志物，以及那些可能表明星形胶质细胞在不同脑区功能多样性的标志物的显著阻碍。在我们将人类多能干细胞(HPSCs)分化为神经亚型的过程中，我们发现了一种神经胶质前体，它可以生成星形胶质细胞，但不能生成神经元和少突胶质细胞。我们将使用这些假定的星形胶质前体细胞来发现星形胶质前体细胞的特异性标志物，从而首次实现对星形胶质细胞前体细胞的前瞻性鉴定。建立在我们的 凭借十年来将PSCs定向为区域特定神经元亚型的经验，我们成功地产生了丰富的区域特定星形胶质细胞亚型种群。我们将利用这些星形胶质细胞亚型来揭示区域星形胶质细胞的功能特征，为进一步探讨星形胶质细胞在动态平衡和病理条件下对特定脑区神经元功能的影响奠定基础。作为一项原则证明，我们将描述脆性X综合征(FXS)皮质星形胶质细胞的转录组，功能障碍的星形胶质细胞可能在FXS中发挥作用，我们已经为FXS建立了IPSCs，并识别FXS背后的星形胶质细胞对神经元功能障碍的潜在功能贡献。在拟议的研究中，我们将建立工具和资源(例如，星形胶质细胞的转录图谱、报告/转基因系)，以加强对星形胶质细胞谱系发育及其在发病机制中的作用的研究，并通过靶向星形胶质细胞来实现精神障碍的治疗开发。

DESCRIPTION (provided by applicant): Astrocytes, the most abundant cell type in the human brain, participate in virtually every aspect of brain function and often disease progression. Defining the roles of astrocytes in normal and abnormal brain development as well as disease pathogenesis has been significantly hampered by the lack / scarcity of markers that are specific to progenitors and more mature cells of the astroglial lineage as well as those that may signal functional diversity of astrocytes in different brain regions. During our differentiation of human pluripotent stem cells (hPSCs) to neural subtypes, we discovered a glial precursor that generates astrocytes but not neurons and oligodendrocytes. We will use these putative astroglial progenitors to discover markers that are specific to astroglial progenitors, thus enabling prospective identification of astroglial progenitors for the first time. Building upon our decade's experience in directing PSCs to region-specific neuronal subtypes, we have successfully generated enriched populations of region-specific astrocyte subtypes. We will use these astrocyte subtypes to uncover the functional characteristics of regional astrocytes, setting up the foundation for further exploring the effects of astrocytes on neuronal function in particula brain regions under homeostatic and pathological conditions. As a proof-of-principle, we will profile the transcriptome of cortical astrocytes from Fragile X Syndrome (FXS) in which dysfunctional astrocytes may play a role and for which we have established iPSCs, and discern potential functional contribution of astrocytes to neuronal dysfunction that underlies FXS. Along the proposed study, we will establish tools and resources (e.g., transcription profiles, reporter/transgenic lines for astroglial cells) that will enhance studies on astroglial lineage development and their contribution to pathogenesis, and enable therapeutic development for mental disorders by targeting astroglial cells.