Human Stem Cell-derived Aggregates of Forebrain Astroglia Respond to Amyloid Beta Oligomers
Human Stem Cell-derived Aggregates of Forebrain Astroglia Respond to Amyloid Beta Oligomers
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DOI：
10.1089/ten.tea.2019.0227
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发表时间：
2020-05-01
影响因子：
4.1
通讯作者：
Li, Yan
中科院分区：
文献类型：
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作者：
Griffin, Kyle;Bejoy, Julie;Li, Yan
星形胶质细胞是神经元回路的重要组成部分，越来越多的证据表明这些细胞的功能障碍与许多中枢神经系统疾病有关。过去，由于人类大脑的有限访问，研究这些细胞在人类大脑功能中的作用一直很困难。在这项研究中，人诱导多能干细胞分化成星形胶质细胞球使用混合平板接种方法，有或没有双重SMAD抑制。对衍生的细胞进行星形胶质细胞标志物、脑区域特性、吞噬作用、钙瞬时信号传导、活性氧产生和免疫应答的评估。通过用淀粉样蛋白-β（A β）42寡聚体刺激来模拟神经变性。最后，将衍生的星形球与同基因神经球进行共培养。结果表明，衍生的星形胶质细胞表达具有前脑背侧皮质特性的星形胶质细胞标志物，分泌细胞外基质，并且能够吞噬氧化铁颗粒并响应A β 42刺激（较高的氧化应激，较高的TNF-α和IL-6表达）。RNA测序结果揭示了对星形胶质细胞标志物、趋化因子和脑区域身份的A β 42刺激应答的衍生细胞的不同转录组。共培养实验显示神经元的突触活动和星形胶质细胞的神经保护能力增强。这项研究提供了有关脑星形胶质细胞的作用，异型细胞-细胞相互作用，以及体外工程神经元突触形成的知识。其意义在于神经系统疾病建模，药物筛选，以及研究神经退行性变的进展和干细胞微环境的作用。Impact StatementHuman pluripotent stem cell derived astrocytes are a powerful tool for disease modeling and drug screening.然而，关于脑区域的身份和神经变性刺激的免疫反应的属性还没有得到很好的表征。本研究的结果表明，衍生的星形胶质细胞表达具有前脑背侧皮质身份的星形胶质细胞标志物，分泌细胞外基质（ECM），并能够吞噬氧化铁颗粒和响应淀粉样蛋白β寡聚体，显示星形胶质细胞标志物，趋化因子和脑区域身份的不同转录组。这项研究提供了有关脑星形胶质细胞的作用，异型细胞-细胞相互作用，以及体外工程神经组织的知识。
Astrocytes are vital components in neuronal circuitry and there is increasing evidence linking the dysfunction of these cells to a number of central nervous system diseases. Studying the role of these cells in human brain function in the past has been difficult due to limited access to the human brain. In this study, human induced pluripotent stem cells were differentiated into astrospheres using a hybrid plating method, with or without dual SMAD inhibition. The derived cells were assessed for astrocytic markers, brain regional identity, phagocytosis, calcium-transient signaling, reactive oxygen species production, and immune response. Neural degeneration was modeled by stimulation with amyloid-beta (A beta) 42 oligomers. Finally, co-culture was performed for the derived astrospheres with isogenic neurospheres. Results indicate that the derived astroglial cells express astrocyte markers with forebrain dorsal cortical identity, secrete extracellular matrix, and are capable of phagocytosing iron oxide particles and responding to A beta 42 stimulation (higher oxidative stress, higher TNF-alpha, and IL-6 expression). RNA-sequencing results reveal the distinct transcriptome of the derived cells responding to A beta 42 stimulation for astrocyte markers, chemokines, and brain regional identity. Co-culture experiments show the synaptic activities of neurons and the enhanced neural protection ability of the astroglial cells. This study provides knowledge about the roles of brain astroglial cells, heterotypic cell-cell interactions, and the formation of engineered neuronal synapses in vitro. The implications lie in neurological disease modeling, drug screening, and studying progression of neural degeneration and the role of stem cell microenvironment.Impact StatementHuman pluripotent stem cell-derived astrocytes are a powerful tool for disease modeling and drug screening. However, the properties regarding brain regional identity and the immune response to neural degeneration stimulus have not been well characterized. Results of this study indicate that the derived astroglial cells express astrocyte markers with forebrain dorsal cortical identity, secrete extracellular matrix (ECM), and are capable of phagocytosing iron oxide particles and responding to amyloid-beta oligomers, showing the distinct transcriptome in astrocyte markers, chemokines, and brain regional identity. This study provides knowledge about the roles of brain astroglial cells, heterotypic cell-cell interactions, and engineering neural tissues in vitro.