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.
The proposed study will uncover markers for cells of the astroglial lineage, generate resources and tools pertaining astrocyte research, and identify faulty astrocyte genes in patients with autism spectrum disorders, thus opening a new avenue for treating autism spectrum disorders.
|Tao, Yunlong; Zhang, Su-Chun (2016) Neural Subtype Specification from Human Pluripotent Stem Cells. Cell Stem Cell 19:573-586|
|Jones, Jeffrey R; Zhang, Su-Chun (2016) Engineering human cells and tissues through pluripotent stem cells. Curr Opin Biotechnol 40:133-8|
|Chen, Yuejun; Xiong, Man; Dong, Yi et al. (2016) Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson's Disease. Cell Stem Cell 18:817-26|
|Huang, Cindy Tzu-Ling; Tao, Yunlong; Lu, Jianfeng et al. (2016) Time-Course Gene Expression Profiling Reveals a Novel Role of Non-Canonical WNT Signaling During Neural Induction. Sci Rep 6:32600|
|Lu, Jianfeng; Zhong, Xuefei; Liu, Huisheng et al. (2016) Generation of serotonin neurons from human pluripotent stem cells. Nat Biotechnol 34:89-94|
|Chen, Hong; Qian, Kun; Chen, Wei et al. (2015) Human-derived neural progenitors functionally replace astrocytes in adult mice. J Clin Invest 125:1033-42|
|Chen, Yuejun; Cao, Jingyuan; Xiong, Man et al. (2015) Engineering Human Stem Cell Lines with Inducible Gene Knockout using CRISPR/Cas9. Cell Stem Cell 17:233-44|
|Du, Zhong-Wei; Chen, Hong; Liu, Huisheng et al. (2015) Generation and expansion of highly pure motor neuron progenitors from human pluripotent stem cells. Nat Commun 6:6626|
|Williams, Emily Cunningham; Zhong, Xiaofen; Mohamed, Ahmed et al. (2014) Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons. Hum Mol Genet 23:2968-80|
|Qian, Kun; Huang, Cindy Tzu-Ling; Huang, CindyTzu-Ling et al. (2014) A simple and efficient system for regulating gene expression in human pluripotent stem cells and derivatives. Stem Cells 32:1230-8|
Showing the most recent 10 out of 12 publications