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Recent advances in three dimensional (3D) culture systems have led to the generation of brain organoids that share resemblance to different parts of the human brains; however, a 3D organoid model of the midbrain that contains functional midbrain dopaminergic (mDA) neurons has not been reported. In this study, we develop a method to differentiate human PSCs into a large multicellular organoid-like structure that contains distinct layers of neuronal cells with a transcriptomic profile that resembles human prenatal midbrain. Importantly, we detected electrically active and functionally mature mDA neurons, and dopamine production in our 3D midbrain-like organoids (MLOs). In contrast to human mDA neurons generated using non-3D methods or in the MLOs generated from mouse embryonic stem cells, our human MLOs uniquely produced neuromelanin-like granules that were structurally similar to those isolated from human substantia nigra tissues. Thus our MLOs bearing features of the human midbrain may provide a novel tractable in vitro system to study the human midbrain and its related diseases. |