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自组装人诱导多能干细胞衍生的神经皮质类器官作为脑缺血神经毒性研究模型。

Neural cortical organoids from self-assembling human iPSC as a model to investigate neurotoxicity in brain ischemia.

机构信息

Biology of Neurodegenerative Diseases Lab, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.

Acute Brain Injury and Therapeutic Strategies Lab, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.

出版信息

J Cereb Blood Flow Metab. 2023 May;43(5):680-693. doi: 10.1177/0271678X231152023. Epub 2023 Jan 18.

DOI:10.1177/0271678X231152023
PMID:36655331
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10108182/
Abstract

Brain ischemia is a common acute injury resulting from impaired blood flow to the brain. Translation of effective drug candidates from experimental models to patients has systematically failed. The use of human induced pluripotent stem cells (iPSC) offers new opportunities to gain translational insights into diseases including brain ischemia. We used a human 3D self-assembling iPSC-derived model (human cortical organoids, hCO) to characterize the effects of ischemia caused by oxygen-glucose deprivation (OGD). hCO exposed to 2 h or 8 h of OGD had neuronal death and impaired neuronal network complexity, measured in whole-mounting microtubule-associated protein 2 (MAP-2) immunostaining. Neuronal vulnerability was reflected by a reduction in mRNA levels, and increased release of neurofilament light chain (NfL) in culture media, proportional to OGD severity. Glial fibrillary acidic protein (GFAP) gene or protein levels did not change in hCO, but their release in medium increased after prolonged OGD. In conclusion, this human 3D iPSC-based model of brain ischemic injury is characterized by marked neuronal injury reflected by the release of the translational biomarker NfL which is relevant for testing neuroprotective strategies.

摘要

脑缺血是一种常见的急性损伤，是由于大脑血流受损引起的。有效的药物候选物从实验模型向患者的转化系统地失败了。人类诱导多能干细胞（iPSC）的使用为包括脑缺血在内的疾病提供了获得转化见解的新机会。我们使用了一种人类 3D 自组装 iPSC 衍生模型（人皮质类器官，hCO）来描述由氧葡萄糖剥夺（OGD）引起的缺血的影响。暴露于 2 小时或 8 小时 OGD 的 hCO 具有神经元死亡和神经元网络复杂性受损，通过全 mounting 微管相关蛋白 2（MAP-2）免疫染色来测量。神经元易损性反映在 mRNA 水平降低，以及培养物中神经丝轻链（NfL）的释放增加，与 OGD 严重程度成正比。hCO 中的神经胶质纤维酸性蛋白（GFAP）基因或蛋白水平没有改变，但在长时间 OGD 后，它们在培养基中的释放增加。总之，这种基于人类 3D iPSC 的脑缺血损伤模型的特点是明显的神经元损伤，这反映在翻译生物标志物 NfL 的释放上，这对于测试神经保护策略是相关的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/4a7e0c24106a/10.1177_0271678X231152023-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/2bd5671c7d0a/10.1177_0271678X231152023-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/dd43e40eaccf/10.1177_0271678X231152023-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/cef4dcd8861b/10.1177_0271678X231152023-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/1d152e3c6a56/10.1177_0271678X231152023-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/4a7e0c24106a/10.1177_0271678X231152023-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/2bd5671c7d0a/10.1177_0271678X231152023-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/dd43e40eaccf/10.1177_0271678X231152023-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/cef4dcd8861b/10.1177_0271678X231152023-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/1d152e3c6a56/10.1177_0271678X231152023-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0ff4/10108182/4a7e0c24106a/10.1177_0271678X231152023-fig5.jpg

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