TY - JOUR
AU - Simona Lange
AU - Martin Ebeling
AU - Athéna Loye
AU - Florian Wanke
AU - Juliane Siebourg-Polster
AU - Tania J. J. Sudharshan
AU - Franziska Völlmy
AU - Jakub Kralik
AU - Bérengère Vidal
AU - Kerstin Hahn
AU - Lynette C. Foo
AU - Jan Hoeber
AB - 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.
BT - Science Translational Medicine
DA - 2025-09-10
DO - 10.1126/scitranslmed.adp7047
IS - 815
N2 - 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.
PY - 2025
EP - eadp7047
T2 - Science Translational Medicine
TI - Human myelinated brain organoids with integrated microglia as a model for myelin repair and remyelinating therapies
UR - https://www.science.org/doi/10.1126/scitranslmed.adp7047
VL - 17
Y2 - 2025-12-01
ER -