Genomics Analysis of Metabolic Pathways of Human Stem Cell-Derived Microglia-Like Cells and the Integrated Cortical Spheroids
Genomics Analysis of Metabolic Pathways of Human Stem Cell-Derived Microglia-Like Cells and the Integrated Cortical Spheroids
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DOI：
10.1155/2019/2382534
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发表时间：
2019-11-18
影响因子：
4.3
通讯作者：
Li, Yan
中科院分区：
文献类型：
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作者：
Bejoy, Julie;Yuan, Xuegang;Li, Yan
来源于人多能干细胞（hiPSC）的脑球状体或类器官仍然不能在体内完全重现人脑组织，并且限制之一是缺乏小胶质细胞。为了增加内置的免疫功能，在我们的研究中进行了背侧前脑球状体与同基因小胶质细胞样细胞（D-MG）的共培养。分析三维D-MG球状体的转录组，并与同基因小胶质细胞样细胞（MG）进行比较。含有小胶质细胞样细胞的皮质球状体显示不同的代谢程序，这可能会影响相关的表型。与糖酵解和缺氧信号相关的基因在共培养的D-MG球状体中的表达增加，表明代谢向有氧糖酵解转变，这有利于小胶质样细胞的M1极化。此外，还分析了细胞增殖、细胞死亡、PIK 3/AKT/mTOR信号通路、真核起始因子2通路、Wnt和Notch通路等代谢途径和信号通路。结果证实了mTOR和p53信号传导的激活、Notch配体表达的增加、NF-κ B和经典Wnt途径的抑制以及共培养的D-MG球状体中细胞周期基因表达的降低。该分析表明，生理三维微环境可以重塑体外皮质球体的免疫力，并更好地再现体内脑组织功能，用于疾病建模和药物筛选。
Brain spheroids or organoids derived from human pluripotent stem cells (hiPSCs) are still not capable of completely recapitulating in vivo human brain tissue, and one of the limitations is lack of microglia. To add built-in immune function, coculture of the dorsal forebrain spheroids with isogenic microglia-like cells (D-MG) was performed in our study. The three-dimensional D-MG spheroids were analyzed for their transcriptome and compared with isogenic microglia-like cells (MG). Cortical spheroids containing microglia-like cells displayed different metabolic programming, which may affect the associated phenotype. The expression of genes related to glycolysis and hypoxia signaling was increased in cocultured D-MG spheroids, indicating the metabolic shift to aerobic glycolysis, which is in favor of M1 polarization of microglia-like cells. In addition, the metabolic pathways and the signaling pathways involved in cell proliferation, cell death, PIK3/AKT/mTOR signaling, eukaryotic initiation factor 2 pathway, and Wnt and Notch pathways were analyzed. The results demonstrate the activation of mTOR and p53 signaling, increased expression of Notch ligands, and the repression of NF-kappa B and canonical Wnt pathways, as well as the lower expression of cell cycle genes in the cocultured D-MG spheroids. This analysis indicates that physiological 3-D microenvironment may reshape the immunity of in vitro cortical spheroids and better recapitulate in vivo brain tissue function for disease modeling and drug screening.