Nam, Ye Rim Kang, Minji Kim, Minji Seok, Min Jong Yang, Yunseon Han, Young-Eun Oh, Soo-Jin Kim, Do Gyeong Son, Hyeon Chang, Mi-Yoon Lee, Sang-Hun 2024-11-28T11:00:27Z 2024-11-28T11:00:27Z 2024-11-27 2025-03 2090-1232 https://pubs.kist.re.kr/handle/201004/151163 Introduction 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. Methods 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). Results Through a comprehensive series of in-vitro and in-vivo 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. Conclusion 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 in-vitro studies using human cells and in-vivo 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. English Cairo University Preparation of human astrocytes with potent therapeutic functions from human pluripotent stem cells using ventral midbrain patterning Article 10.1016/j.jare.2024.03.012 1 Journal of Advanced Research, v.69, pp.181 - 196 Journal of Advanced Research 69 181 196 Y scie scopus 001440692400001 Multidisciplinary Sciences Science & Technology - Other Topics Article HUMAN DOPAMINERGIC-NEURONS ALPHA-SYNUCLEIN DISEASE INFLAMMATION GENERATION PROGENITOR PATHOLOGY RATHER BRAIN LMX1B Astrocyte Transplantation a-synuclein Amyloid beta Parkinson&apos s disease Alzheimer&apos s disease