02301nas a2200265   4500000000100000008004100001260001500042100001700057700001900074700001700093700001800110700002900128700002700157700002200184700001700206700002200223700001700245700001900262700001500281245012000296856006100416300001300477490000700490520153800497       2025                            d  c2025-09-101 aSimona Lange1 aMartin Ebeling1 aAthéna Loye1 aFlorian Wanke1 aJuliane Siebourg-Polster1 aTania J. J. Sudharshan1 aFranziska Völlmy1 aJakub Kralik1 aBérengère Vidal1 aKerstin Hahn1 aLynette C. Foo1 aJan Hoeber00aHuman myelinated brain organoids with integrated microglia as a model for myelin repair and remyelinating therapies  uhttps://www.science.org/doi/10.1126/scitranslmed.adp7047  aeadp70470 v173 aOligodendrocytes, 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.