SysBio Talk of Hiro Eto - October 24 2025

Multicellular tissues maintain remarkably precise architectures, requiring mechanisms that robustly coordinate proliferation, differentiation, and self-organisation. In the small intestine, this process is especially demanding: stem cells must continuously replenish multiple specialised cell types while preserving a regular spatial pattern. Although the molecular components of intestinal signalling pathways are well established, the dynamical principles by which these pathways regulate tissue organisation remain unclear. Recent work in cell lines has shown that signalling pathways can use dynamic signal encoding—where features such as pulse duration, wave propagation, or oscillation frequency (e.g., in calcium, NF-κB, or ERK signalling) transmit information beyond static activity levels. Whether tissues exploit such temporal codes to regulate composition has remained an open question.

Here, we investigate Notch signalling, a canonical pathway that governs the choice between absorptive and secretory fates. Using a fluorescent Notch activity reporter in a transgenic mouse model, we performed live-cell imaging of intestinal organoids combined with single-cell tracking. We discovered that Notch signalling in progenitor cells does not operate as a static on/off switch, but rather exhibits oscillatory dynamics.

To test whether these dynamics are functional, we developed a microfluidic system enabling the external modulation of Notch activity in real time. By tuning the oscillation frequency, we found that specific dynamic regimes biased cell fate outcomes—shaping the proportion of progenitor versus differentiated secretory cells. Thus, the encoding of information in the temporal frequency of signalling directly determines tissue composition.

This research reveals a new mechanism of how Notch regulates cell fate decisions in the intestine. It also establishes a new in vitro platform technology to control signalling processes in multicellular systems.