Glia in Neurodegenerative Diseases: a Human Glial Chimeric Mouse Model

研究目的：我的研究目标是来自iPSC衍生的星形胶质细胞的外泌体，iPSC分化为星形胶质细胞和神经元以及小鼠神经祖细胞的植入。目的是在体外研究可以解释这种特殊神经退行性疾病Kii ALS/PDC的机制，并在体内开发可用于药物测定的嵌合小鼠模型，以支持Kii ALS/PDC患者的研究。研究结果：2022财年是完成实验、撰写文章和修订的一年。我可以成功地在对照供体的人脊髓中观察到一种对星形胶质细胞线粒体呼吸至关重要的蛋白质，并可以评估Kii ALS/PDC患者中该蛋白质的减少。我还可以在RNA水平上定量Tau同种型的显著减少，这取决于Kii ALS/PDC患者的临床分层。我还可以使用我们实验室发表的方法将来自3名健康供体和6名患者的iPSC区分为几种神经元亚型（Sato et al. Neurosci Lett 2021）。最后，我给几只NOD/SCID小鼠移植了神经胶质祖细胞，并进行了行为实验。在对iPSC衍生的星形胶质细胞进行外泌体分析后，蛋白质组分析揭示了一组指示在iPS衍生的Kii ALS/PDC-星形胶质细胞中的有害作用的基因，这与先前发表的结果（提交的文章）相一致。我还移植了来自3个对照系和3个患者的神经祖细胞，并进行了行为分析。

Research aim:My research targets exosomes from iPSC-derived astrocytes, iPSC differentiation into astrocytes and neurons and engraftment of neural progenitors in mice. The purpose is to investigate in vitro a mechanistic that could explain this peculiar neurodegenerative disease Kii ALS/PDC is, and in vivo to develop a chimeric mouse model which could be used for drugs assays, in order to support research to Kii ALS/PDC-patients.Research results:FY2022 has been the year of finalization of the experiments, writing of the article and revisions too. I could successfully visualize in human spinal cord from control-donors a protein paramount for astrocytic-mitochondria respiration and could assess a decrease of it in Kii ALS/PDC-patients. I could also quantify at RNA level a significant decrease in Tau isoforms depending on the clinical stratification of Kii ALS/PDC-patients. I could also differentiate iPSC from 3 healthy donors and 6 patients into several sub-type of neurons using a method published in our Lab (Sato et al. Neurosci Lett 2021). Finally, I have engrafted several NOD/SCID mice with glial progenitors and performed behavioral experiments. After having performed exosomes analysis from iPSC-derived astrocytes, proteome analysis revealed a set of genes indicative of a deleterious effect in iPS-derived Kii ALS/PDC-astrocytes, concomitant with previous published results (article in submission). I also engrafted neural progenitors from 3 control lines and 3 patients and performed behavioral analysis.