Synthetic developmental biology - cross-species comparison and manipulation 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…
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 the rabbit, marmoset, cow and rhinoceros, setting up a ‘stem cell zoo’ in the lab (Figure 3). The combination of the stem cell zoo and new organoids will enable the quantitative comparison of tissue morphogenesis, including tissue mechanics and morphometry, across species.
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 4). By manipulating the shape of organoids, we are now investigating the interplay between tissue shape and function.