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Ebisuya Group

Synthetic developmental biology - cross-species comparison and manipulation of organoids

The Ebisuya group recapitulates developmental mechanisms in vitro to study how we humans are different from other species, and develops novel tools to manipulate tissue shape and function.

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Previous and current research

Cross-species comparisons of organoids

Human development is in general slower than mouse development, …but why? To study the mechanism of interspecies differences in developmental time scale, we recapitulate developmental processes in vitro through making organoids from pluripotent stem cells. The in vitro tissues offer an ideal platform to compare different species under the same experimental conditions. As a model system of interspecies differences, we have focused on the segmentation clock: the oscillatory gene expression that regulates the timing of somite formation during embryogenesis. Interestingly, the oscillation period of the human segmentation clock is approximately 5 hours, while that of mice is approximately 2 hours (Figure 1). We have found that several biochemical reactions of the segmentation clock are slower in human cells as compared with mouse cells. To expand the research, we are now exploring other organoids that display inter-species differences. We are also working on several mammalian species, including rabbits, cattle and rhinoceroses, setting up a ‘stem cell zoo’ in the lab.

Manipulation of organoids

In parallel, we develop genetic tools to manipulate organoids, as in vitro tissues are amenable to quantitative measurements and manipulation. We have recently developed an optogenetic tool to induce apical constriction in mammalian cells. Optogenetic manipulation of apical constriction caused several types of tissue deformation, including neuroepithelial thickening and apical lumen shrinkage of neural organoids (Figure 2). By manipulating the shape of organoids, we are now investigating the interplay between tissue shape and function.

Future projects and goals

  • Recapitulation of developmental mechanisms and cross-species comparison by using the stem cell zoo.
  • Investigation of the ultimate causes of inter-species differences.
  • Development of novel genetic tools to manipulate the shape and function of organoids.
Figure 1: The mouse and human segmentation clocks were recapitulated from pluripotent stem cells. The mouse segmentation clock showed faster biochemical reactions and a shorter oscillation period (2 hours) whereas that of human showed slower reactions and a longer period (5 hours).
Related to Matsuda et al., Science, 2020.
Figure 2: Optogenetic manipulation of organoid shapes. Our optogenetic tool induces apical constriction in mammalian cells (left). Illumination of an optic vesicle organoid caused shrinkage of the apical lumen (right). Related to Martinez-Ara et al., bioRxiv, 2021.
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