The New York Stem Cell Foundation Research Institute, New York, NY 10019, USA.
Neuroscience Institute, NYU Langone School of Medicine, New York, NY 10016, USA.
Neuron. 2020 Aug 5;107(3):436-453.e12. doi: 10.1016/j.neuron.2020.05.014. Epub 2020 Jun 1.
New methods for investigating human astrocytes are urgently needed, given their critical role in the central nervous system. Here we show that CD49f is a novel marker for human astrocytes, expressed in fetal and adult brains from healthy and diseased individuals. CD49f can be used to purify fetal astrocytes and human induced pluripotent stem cell (hiPSC)-derived astrocytes. We provide single-cell and bulk transcriptome analyses of CD49f hiPSC-astrocytes and demonstrate that they perform key astrocytic functions in vitro, including trophic support of neurons, glutamate uptake, and phagocytosis. Notably, CD49f hiPSC-astrocytes respond to inflammatory stimuli, acquiring an A1-like reactive state, in which they display impaired phagocytosis and glutamate uptake and fail to support neuronal maturation. Most importantly, we show that conditioned medium from human reactive A1-like astrocytes is toxic to human and rodent neurons. CD49f hiPSC-astrocytes are thus a valuable resource for investigating human astrocyte function and dysfunction in health and disease.
鉴于星形胶质细胞在中枢神经系统中的关键作用，我们迫切需要新的方法来研究人类星形胶质细胞。在这里，我们表明 CD49f 是一种新型的人类星形胶质细胞标志物，在健康和患病个体的胎儿和成人脑中均有表达。CD49f 可用于纯化胎儿星形胶质细胞和人诱导多能干细胞 (hiPSC) 衍生的星形胶质细胞。我们提供了 CD49f hiPSC-星形胶质细胞的单细胞和批量转录组分析，并证明它们在体外具有关键的星形胶质细胞功能，包括对神经元的营养支持、谷氨酸摄取和吞噬作用。值得注意的是，CD49f hiPSC-星形胶质细胞对炎症刺激有反应，获得类似于 A1 的反应状态，在此状态下，它们的吞噬作用和谷氨酸摄取受损，并且无法支持神经元成熟。最重要的是，我们表明来自人类反应性 A1 样星形胶质细胞的条件培养基对人和啮齿动物神经元有毒性。因此，CD49f hiPSC-星形胶质细胞是研究人类星形胶质细胞在健康和疾病中的功能和功能障碍的有价值的资源。
