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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 biophysical mechanism of interspecies differences in developmental tempo, we make organoids from pluripotent stem cells. Organoids offer an ideal in vitro platform to compare different species under the same experimental conditions.

As a model system of developmental tempo, we have focused on the segmentation clock: the oscillatory gene expression that regulates the timing of somite formation during embryogenesis. We recapitulated oscillations of the segmentation clock from human and mouse stem cells, demonstrating that the oscillation period of the human segmentation clock is approximately 5 hours, while that of mice is approximately 2 hours (Figure 1). By quantitatively measuring and mathematically modeling the dynamics of the in vitro segmentation clocks, we found that several biochemical reactions of the segmentation clock network are slower in human cells as compared with mouse cells. Namely, slower protein degradation and slower gene expression processes in human cells result in the slower oscillation of the human segmentation clock. Now the obvious question is the mechanism by which these biochemical reactions are slower in humans. So our quest will continue until we find out the ultimate cause of species-specific tempo…

Developing new organoids and the stem cell zoo

Not only the segmentation clock but also the formation of 3D somites can be recapitulated from pluripotent stem cells. We have recently created human embryonic organoids, termed somitoids, that periodically form pairs of somite-like structures according to the segmentation clock (Figure 2). Furthermore, in addition to human and mouse stem cells, we now use several mammalian species, including rabbits, cattle and rhinoceroses, setting up a ‘stem cell zoo’ in the lab. The combination of the stem cell zoo and new organoids will enable the quantitative comparison of tissue morphogenesis across species.

Manipulation of organoids

After finding out the biophysical mechanisms underlying species-specific developmental tempo and morphology, we want to manipulate the mechanisms. Ultimately, we want to make a mouse tissue that displays human time and shape, for instance. That is why we develop genetic tools to manipulate organoids. We have recently developed an optogenetic tool to induce apical constriction in mammalian cells. Optogenetic manipulation of apical constriction caused multiple types of tissue deformation, including neuroepithelial thickening and apical lumen shrinkage of neural organoids (Figure 3). By manipulating the shape of organoids, we are now investigating the interplay between tissue shape and function.

Future projects and goals

  • Cross-species comparison by using the organoid zoo.
  • Investigation of the biophysical mechanisms underlying inter-species differences.
  • Development of optogenetic tools to manipulate the time and shape of organoids.

Technologies in the lab

  • Stem cell zoo (ES and iPS cells of several mammalian species)
  • Multiple types of organoids (embryonic organoids, brain organoids, cardiac organoids)
  • Quantitative measurements of biochemical and biophysical parameters
  • Mathematical modeling
  • Optogenetic tools and artificial gene circuits

ERC INVESTIGATOR (ERC CoG – ALLOCHRONY)

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: Human embryonic organoids that periodically form somite-like structures. The spheroid of human iPS cells elongates and starts forming pairs of somites according to the segmentation clock. Related to Sanaki-Matsumiya et al., Nat Commun, 2022.

Figure 3: 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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