Cerebral organoids provide an accessible system for investigations of cellular composition, interactions, and organization but have lacked oligodendrocytes, the myelinating glia of the central nervous system. Here we reproducibly generated oligodendrocytes and myelin in 'oligocortical spheroids' derived from human pluripotent stem cells. Molecular features consistent with those of maturing oligodendrocytes and early myelin appeared by week 20 in culture, with further maturation and myelin compaction evident by week 30. Promyelinating drugs enhanced the rate and extent of oligodendrocyte generation and myelination, and spheroids generated from human subjects with a genetic myelin disorder recapitulated human disease phenotypes. Oligocortical spheroids provide a versatile platform for studies of myelination of the developing central nervous system and offer new opportunities for disease modeling and therapeutic development.

Highlights d CD49f is a novel, reactivity-independent marker for human astrocytes d CD49f can be used to purify human fetal astrocytes and iPSCderived astrocytes d CD49f + hiPSC-astrocytes acquire an A1-like reactive state upon cytokine stimulation d CD49f + A1-like reactive astrocytes are dysfunctional and toxic to neurons in vitro

Induced pluripotent stem cells (iPSCs) enable the generation of previously unattainable, scalable quantities of disease-relevant tissues from patients suffering from essentially any genetic disorder. This cellular material has proven instrumental for drug screening efforts on these disorders, and has facilitated the identification of novel therapeutics for patients. Here we will review the foundational technologies that have enabled iPSCs, the power and limitations of iPSC-based compound screens along with screening guidelines, and recent examples of screening efforts. Additionally we will provide a brief commentary on the future scientific roadmap using pluripotent- and 3D organoid-based, combinatorial approaches.

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