Fish primary embryonic stem cells self-assemble into retinal tissue mirroringin vivoearly eye development

Organoids derived from pluripotent stem cells promise the solution to current challenges in basic and biomedical research. Further progress and widespread applications are however limited by long developmental time, variable success, and lack of direct comparison to anin vivoreference. To overcome those limitations, we derived organoids from rapidly developing teleosts. We demonstrate how primary embryonic stem cells from zebrafish and medaka efficiently self-organize into anterior neural structures, particularly retina. Within four days, blastula-stage cell aggregates reproducibly execute key steps of eye development: retinal specification, morphogenesis and differentiation. The number of aggregated cells as well as genetic factors crucially impacted upon the concomitant morphological changes that were intriguingly reflecting thein vivosituation. High reproducibility and rapid development of fish-derived organoids in combination with advanced genome editing techniques immediately allow addressing aspects of development and disease, and systematically probing the impact of the physical environment on morphogenesis and differentiation.