Lange Simona, Ebeling Martin, Loye Athéna, Wanke Florian, Siebourg-Polster Juliane, Sudharshan Tania J J, Völlmy Franziska, Kralik Jakub, Vidal Bérengère, Hahn Kerstin, Foo Lynette C, Hoeber Jan
Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland.
Sci Transl Med. 2025 Sep 10;17(815):eadp7047. doi: 10.1126/scitranslmed.adp7047.
Oligodendrocytes, the myelinating cells of the central nervous system (CNS), are essential for the formation of myelin sheaths and pivotal for maintaining axonal integrity and conduction. Disruption of these cells and the myelin sheaths they produce is a hallmark of demyelinating conditions like multiple sclerosis or those resulting from certain drug side effects, leading to profound neurological impairments. In this study, we created a human brain organoid comprising neurons, astrocytes, and myelinating oligodendrocytes. By integrating induced pluripotent stem cell-derived microglia, we endowed these myelinated human brain organoids (MHBOs) with immune characteristics. MHBOs with microglia (MHBOs +MG) enabled the investigation of demyelination and remyelination-a process in which myelin sheaths are regenerated-in a human context. After toxin-induced demyelination, we observed a reduction in myelin followed by subsequent self-driven remyelination. Proteomic and transcriptomic analyses provided a molecular signature of demyelination and myelin recovery indicating a central role for microglia in the remyelination process. Furthermore, the application of the pro-remyelinating compounds clemastine, XAV939, and BQ3020 further enhanced remyelination in MHBOs +MG but was ineffective in the absence of microglia. Cross-validation of our findings in mouse cerebellar slice cultures confirmed that the pro-remyelinating compounds were effective ex vivo, suggesting the translational potential of our MHBOs +MG model.
少突胶质细胞是中枢神经系统（CNS）的髓鞘形成细胞，对于髓鞘的形成至关重要，并且对维持轴突完整性和传导起着关键作用。这些细胞及其产生的髓鞘的破坏是脱髓鞘疾病（如多发性硬化症）或某些药物副作用导致的疾病的标志，会导致严重的神经功能障碍。在本研究中，我们创建了一种包含神经元、星形胶质细胞和有髓鞘形成能力的少突胶质细胞的人脑类器官。通过整合诱导多能干细胞衍生的小胶质细胞，我们赋予了这些有髓鞘的人脑类器官（MHBOs）免疫特性。带有小胶质细胞的MHBOs（MHBOs +MG）能够在人体环境中研究脱髓鞘和髓鞘再生过程，即髓鞘再生的过程。在毒素诱导脱髓鞘后，我们观察到髓鞘减少，随后是自我驱动的髓鞘再生。蛋白质组学和转录组学分析提供了脱髓鞘和髓鞘恢复的分子特征，表明小胶质细胞在髓鞘再生过程中起核心作用。此外，促髓鞘再生化合物氯马斯汀、XAV939和BQ3020的应用进一步增强了MHBOs +MG中的髓鞘再生，但在没有小胶质细胞的情况下无效。我们在小鼠小脑切片培养物中的研究结果的交叉验证证实，促髓鞘再生化合物在体外是有效的，这表明我们的MHBOs +MG模型具有转化潜力。
