Research

Organoids are self-organizing cells that are grown from stem cells in vitro and are widely used to model organ development and disease. In organoids, while cell growth and hence proliferation are mechanically constrained due to the geometrical requirements to keep maintaining the cell cluster, various morphologies of organoids are achieved. However, it remains elusive how such mechanical constraint can affect organoid growth and the final morphology. In this study, we investigate the influences of mechanical constraint on organoid morphogenesis by numerical simulations with a multicellular phase-field model. In this mathematical model, we can isolate out mechanical interaction from other biological processes. More specifically, we examine the pattern formations of organoids emerging when changing luminal fluid pressure and proliferation time. Even if most organoids seem to be the same in the initial phase, they have distinctive features in the later phase in this numerical model. The patterns in the later phase include spheroid-like shape, star-like shape, and so on. Although all cells have identical natures, in the star-like organoid, cells that can divide are spatially fixed and show behavior like spontaneous differentiation. Classifying the patterns of organoids by several indexes, we discuss the mechanisms which generate the different pattern.

We found that strong steric interaction produces perfect alignment of a pair of colliding filaments but nonetheless prevents global alignment and rather forms clusters. Surprisingly, weaker steric interactions that allow microtubules to overlap can form global alignment. To explain this discrepancy of microscopic and macroscopic alignment behaviors, statics of binary collision of microtubules were examined. It appears that a pair of microtubules change their orientation nematically after collision in both strong and weak steric interaction cases. Based on this result, numerical simulations were also performed, which reproduced this observation. Furthermore, our experimental system showed various other collective behaviors, including order-disorder coexistence, global rotation, and looping.

In previous studies on collective motion in various systems, such as bacteria gliding on agar, bacteria swimming in thin chambers and cytoskeletal filaments driven by motor proteins, global aligning or clustering patterns have been reported. These two patterns are discernible by nematic order and density distribution, although the symmetries of particles of motion and alignment interaction in those system are the same. Our study shows this difference of pattern can be produced by the subtle difference of steric interaction, i.e. whether moving particles can overlap or not. This will provide new insights that those discernible patterns can be reproduced by changing the strength parameter of steric interaction.

The characteristic of our experimental system is that both microtubule density and strength of steric interaction can be controlled. It enables us to obtain the phase diagram of collective motion in microtubule-and-kinesin motility assay system.