Research

Designing biological systems

Cells and tissues are sophisticated biological systems developed by long-time evolution. There are a lot of things we need to learn from such natural systems, but at the same time, we try to reconstitute artificial biological systems by design to test our understandings and expand potentials of biological systems for medical and industrial applications.

Programming multicellular structures by synthetic cell-cell communications that control cell adhesion

Recently, the synthetic receptor system called synthetic Notch receptor (synNotch) has been developed, which allows us to construct customized cell-cell communications that induce user-defined gene expression in the mammalian cells (Morsut et al. , Cell 164, 780-91 (2016)). We used synNotch receptors to design cell-cell signaling circuits that control the expression of cell adhesion molecule cadherin, allowing cells to spontaneously arrange themselves and create various multilayered structures (Science. 361, 156-162 (2018)). Tissue development processes can be created by designing what cells sense and how cells respond in the cell-cell communications. This system allows us to analyze the generation of multilayer structures, the increase in cell types, the formation of asymmetric structures and the regeneration after injury.

Programming multicellular patterns using synthetic morphogens

In addition to cell arrangement by adhesion, cell positions are regulated by secreted factors called morphogens. It's known that morphogens form concentration gradients and induce pattern formation in embryos, but to understand the principles of how randomly-diffusing secreted proteins can encode multicellular patterns, we developed an artificial morphogen system in which GFP, a fluorescent molecule with no physiological effect, acts as a morphogen (Science. 370, 327-331 (2020)). We engineered cell-cell signaling circuits where cells secrete GFP and respond to it by trapping, inhibiting or receiving it, and analyzed the regulatory principles of gradient shape and dynamics. We use synthetic morphogens as a model to explore the mechanisms of precision, robustness and autonomy of multicellular pattern formation and to engineer tissues and organs by adding new positional information for cell fate control.

Creating "self-growing tissue" in a multicellular model system

Looking at organismal development and embryogenesis, a lot of questions arise: e.g. how do cells create lumens or tubes? how do cells correct noise/variability to form beautiful patterns? how do cells keep the tissue size constant? how did complex tissue structures evolve? Our goal is to identify the cell-cell interaction rules that enable the formation of such complex and dynamic multicellular structures and to be able to freely design tissue structures.

Manipulating organoid structures

Thanks to recent advances in organoid technologies, we can culture stem cells to form various "mini-organs" on a culture dish such as intestine, liver and brain. The inherent ability of stem cells allow cells to form organ-like structures in vitro, but to apply organoids to transplantation therapy and drug screening, more sophisticated control is required to add cell types, manipulate organoid morphologies and increase organoid uniformity. Therefore, we aim to design gene expression patterns in organoids to manipulate organoid morphology and cell composition for regenerative medicine applications.