Development and function of human astrocytes

描述（由申请人提供）：星形胶质细胞是人脑中最丰富的细胞类型，几乎参与脑功能的各个方面，并经常参与疾病进展。星形胶质细胞在正常和异常脑发育以及疾病发病机制中的作用，由于缺乏星形胶质细胞谱系的祖细胞和更成熟的细胞特异性标记物，以及那些可能表明不同脑区域星形胶质细胞功能多样性的标记物，而受到严重阻碍。在我们将人多能干细胞（hPSCs）分化为神经亚型的过程中，我们发现了一种胶质前体，它能产生星形胶质细胞，但不能产生神经元和少突胶质细胞。我们将利用这些假定的星形胶质祖细胞来发现星形胶质祖细胞特有的标记物，从而首次实现对星形胶质祖细胞的前瞻性鉴定。以我们的

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.