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Long-term live imaging and multiscale analysis identify heterogeneity and core principles of epithelial organoid morphogenesis.

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Hof, Lotta 
Moreth, Till 
Koch, Michael 
Liebisch, Tim 
Kurtz, Marina 


BACKGROUND: Organoids are morphologically heterogeneous three-dimensional cell culture systems and serve as an ideal model for understanding the principles of collective cell behaviour in mammalian organs during development, homeostasis, regeneration, and pathogenesis. To investigate the underlying cell organisation principles of organoids, we imaged hundreds of pancreas and cholangiocarcinoma organoids in parallel using light sheet and bright-field microscopy for up to 7 days. RESULTS: We quantified organoid behaviour at single-cell (microscale), individual-organoid (mesoscale), and entire-culture (macroscale) levels. At single-cell resolution, we monitored formation, monolayer polarisation, and degeneration and identified diverse behaviours, including lumen expansion and decline (size oscillation), migration, rotation, and multi-organoid fusion. Detailed individual organoid quantifications lead to a mechanical 3D agent-based model. A derived scaling law and simulations support the hypotheses that size oscillations depend on organoid properties and cell division dynamics, which is confirmed by bright-field microscopy analysis of entire cultures. CONCLUSION: Our multiscale analysis provides a systematic picture of the diversity of cell organisation in organoids by identifying and quantifying the core regulatory principles of organoid morphogenesis.


Funder: Giersch Foundation


Animals, Cell Division, Cholangiocarcinoma, Epithelium, Humans, Mice, Microscopy, Morphogenesis, Organoids, Pancreas

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BMC Biol

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Springer Science and Business Media LLC
Horizon 2020 Framework Programme (668350-2)
Deutsche Forschungsgemeinschaft (CEF-MC2)
Bundesministerium für Bildung und Forschung (114027003)
Hessisches Ministerium für Wissenschaft und Kunst (LOEWE DynaMem, CMMS, DynaMem, CMMS)