Abstract
Organoids derived from pluripotent stem cells promise the solution to current challenges in basic and biomedical research. Mammalian organoids are however limited by long developmental time, variable success, and lack of direct comparison to an in vivo reference. To overcome these limitations and address species-specific cellular organization, we derived organoids from rapidly developing teleosts. We demonstrate how primary embryonic pluripotent cells from medaka and zebrafish efficiently assemble into anterior neural structures, particularly retina. Within 4 days, blastula-stage cell aggregates reproducibly execute key steps of eye development: retinal specification, morphogenesis, and differentiation. The number of aggregated cells and genetic factors crucially impacted upon the concomitant morphological changes that were intriguingly reflecting the in vivo situation. High efficiency and rapid development of fish-derived organoids in combination with advanced genome editing techniques immediately allow addressing aspects of development and disease, and systematic probing of impact of the physical environment on morphogenesis and differentiation.
Highlights
Organ development is a complex process of orchestrated events of tissue specification, morphogenesis, and differentiation in specialized cell types
Retinal development is initiated during early neurulation, when the eye field is specified by the coordinated expression of eye field transcription factors Rx, Lhx2, Pax6, Six3, and Otx2 within the region of the anterior neural plate (Li et al, 1997; Loosli et al, 1999; Zuber et al, 2003)
We used primary embryonic pluripotent cells derived from blastula-stage embryos of medaka (Oryzias latipes) as a source of pluripotent cells and established the conditions to generate the anterior neural structures, retinal tissue
Summary
Organ development is a complex process of orchestrated events of tissue specification, morphogenesis, and differentiation in specialized cell types. Rx3-deficient cells are excluded from OV domains in fish (Loosli et al, 2003) and embryonic mouse chimeras (Medina-Martinez et al, 2009), demonstrating the crucial role of Rx3 in early retina development and morphogenesis. We demonstrate that primary embryonic pluripotent cells derived from medaka and zebrafish form aggregates of neuroepithelial identity. These aggregates adopt retinal fate following the species-specific pace of development. Within only 4 days of culture, fish-derived primary embryonic pluripotent cells efficiently proceed through retinal differentiation, OV morphogenesis, and the onset of retinal differentiation, offering new ways to address multiple aspects of development and to systematically probe the dependence of organogenesis on variable physical environments
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