Astrocytes are glial-type cells that protect neurons from toxic insults and support neuronal functions and metabolism in a healthy brain. Leveraging these physiological functions, transplantation of astrocytes or their derivatives has emerged as a potential therapeutic approach for neurodegenerative disorders. To substantiate the clinical application of astrocyte-based therapy, we aimed to prepare human astrocytes with potent therapeutic capacities from human pluripotent stem cells (hPSCs). To that end, we used ventral midbrain patterning during the differentiation of hPSCs into astrocytes, based on the roles of midbrain-specific factors in potentiating glial neurotrophic/anti-inflammatory activity. To assess the therapeutic effects of human midbrain-type astrocytes, we transplanted them into mouse models of Parkinson's disease (PD) and Alzheimer's disease (AD). Through a comprehensive series of and experiments, we were able to establish that the midbrain-type astrocytes exhibited the abilities to effectively combat oxidative stress, counter excitotoxic glutamate, and manage pathological protein aggregates. Our strategy for preparing midbrain-type astrocytes yielded promising results, demonstrating the strong therapeutic potential of these cells in various neurotoxic contexts. Particularly noteworthy is their efficacy in PD and AD-specific proteopathic conditions, in which the midbrain-type astrocytes outperformed forebrain-type astrocytes derived by the same organoid-based method. The enhanced functions of the midbrain-type astrocytes extended to their ability to release signaling molecules that inhibited neuronal deterioration and senescence while steering microglial cells away from a pro-inflammatory state. This success was evident in both studies using human cells and experiments conducted in mouse models of PD and AD. In the end, our human midbrain-type astrocytes demonstrated remarkable effectiveness in alleviating neurodegeneration, neuroinflammation, and the pathologies associated with the accumulation of α-synuclein and Amyloid β proteins.

中文翻译：

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利用腹侧中脑图案化从人多能干细胞中制备具有有效治疗功能的人星形胶质细胞

星形胶质细胞是神经胶质细胞，可以保护神经元免受毒性损伤，并支持健康大脑中的神经元功能和新陈代谢。利用这些生理功能，星形胶质细胞或其衍生物的移植已成为神经退行性疾病的潜在治疗方法。为了证实基于星形胶质细胞的治疗的临床应用，我们的目标是从人类多能干细胞（hPSC）中制备具有有效治疗能力的人类星形胶质细胞。为此，我们根据中脑特异性因子在增强神经胶质神经营养/抗炎活性中的作用，在 hPSC 分化为星形胶质细胞的过程中使用腹侧中脑模式。为了评估人类中脑型星形胶质细胞的治疗效果，我们将其移植到帕金森病（PD）和阿尔茨海默病（AD）的小鼠模型中。通过一系列全面的实验，我们能够确定中脑型星形胶质细胞表现出有效对抗氧化应激、对抗兴奋毒性谷氨酸和管理病理性蛋白质聚集体的能力。我们制备中脑型星形胶质细胞的策略取得了有希望的结果，证明了这些细胞在各种神经毒性环境中的强大治疗潜力。特别值得注意的是它们在 PD 和 AD 特异性蛋白质病理条件下的功效，其中中脑型星形胶质细胞的表现优于通过相同的基于类器官的方法衍生的前脑型星形胶质细胞。中脑型星形胶质细胞功能的增强延伸到它们释放信号分子的能力，这些信号分子抑制神经元退化和衰老，同时引导小胶质细胞远离促炎症状态。这一成功在使用人类细胞的研究以及在 PD 和 AD 小鼠模型中进行的实验中都是显而易见的。最终，我们的人类中脑型星形胶质细胞在减轻神经退行性变、神经炎症以及与 α-突触核蛋白和淀粉样蛋白 β 蛋白积累相关的病理学方面表现出显着的有效性。