Intercellular signaling drives robust cell fate and patterning in multicellularsystems

Abstract

Cells do not act in isolation; they communicate with each other through a complex network of signals. In multicellular organisms, cell signaling buffers against fluctuations in gene expression. Its effect, however, on multistability--the ability of genetically identical cells to take on and maintain diverse stable states or phenotypes--is unclear. We develop spatially explicit stochastic models that couple fine-grained gene regulatory dynamics with intercellular signaling to study cell fate control in multicellular tissues. We show that intercellular signaling acts as a switch-like controller of cell fate, driving transitions from transient to stable states across tissues. Even weak signaling stabilizes short-lived expression states, and we derive mathematical expressions for the threshold signaling strength required to trigger tissue-wide stabilization. We also derive a universal spatial limit: stable region size grows only sublinearly with signaling strength, implying that large stable regions are prohibitively costly to maintain. The resulting trade-off between robustness and signaling in cell fate control highlights the delicate balance required during developmental processes to maintain spatial precision and provides insight into how organisms regulate tissue structure. OverviewCell fate decisions in developing tissues are governed by gene regulatory networks, but how communication between neighboring cells influences these decisions is poorly understood. We develop a mathematical framework showing that intercellular signaling acts as a controller of cell fate, suppressing spontaneous switching, and inducing stable, coordinated behaviors across tissues. Even weak signaling induces a sharp transition from unstable to stable population-wide dynamics. We also derive fundamental scaling laws showing that the size of stable regions increases sublinearly with signaling strength, revealing a trade-off between developmental robustness and resource cost. These results offer insight into how organisms achieve reliable spatial organization during development, despite molecular noise, and provide design principles for engineering synthetic tissues that balance stability, scalability, and resource efficiency.