Human myelinated brain organoids with integrated microglia as a model for myelin repair and remyelinating therapies

IF 14.6 1区 医学 Q1 CELL BIOLOGY
Simona Lange, Martin Ebeling, Athéna Loye, Florian Wanke, Juliane Siebourg-Polster, Tania J. J. Sudharshan, Franziska Völlmy, Jakub Kralik, Bérengère Vidal, Kerstin Hahn, Lynette C. Foo, Jan Hoeber
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Abstract

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.
整合小胶质细胞的人髓鞘类脑器官作为髓鞘修复和髓鞘再生治疗的模型
少突细胞是中枢神经系统(CNS)的髓鞘形成细胞,对髓鞘的形成至关重要,对维持轴突的完整性和传导至关重要。这些细胞及其产生的髓鞘的破坏是脱髓鞘疾病的标志,如多发性硬化症或某些药物副作用导致的脱髓鞘疾病,导致严重的神经损伤。在这项研究中,我们创造了一个人脑类器官,包括神经元、星形胶质细胞和髓鞘少突胶质细胞。通过整合诱导多能干细胞衍生的小胶质细胞,我们赋予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)能够在人类环境中研究脱髓鞘和再髓鞘形成(髓鞘再生的过程)。在毒素诱导脱髓鞘后,我们观察到髓磷脂减少,随后是自我驱动的再髓鞘形成。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clemastine、XAV939和BQ3020的应用进一步增强了MHBOs +MG的髓鞘再生,但在没有小胶质细胞的情况下无效。我们的研究结果在小鼠小脑切片培养中进行了交叉验证,证实了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。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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