Predicting and Controlling Collective Fate in Multicellular Systems

Heydari, T.; Bashth, O.; Fernandes, J.; Sabbineni, B.; Aguilar-Hidalgo, D.; Chen, J.; Shakiba, N.; Edelstein-Keshet, L.; Zandstra, P. W.

doi:10.64898/2025.12.11.693804

bioRxiv · 10.64898/2025.12.11.693804

Predicting and Controlling Collective Fate in Multicellular Systems

Heydari, T.·Bashth, O.·Fernandes, J.·Sabbineni, B.·Aguilar-Hidalgo, D.·Chen, J.·Shakiba, N.·Edelstein-Keshet, L.·Zandstra, P. W.

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Abstract

Collective behavior is a defining property of multicellular systems, where coordinated outcomes emerge from local cell-cell interactions. Yet the quantitative rules linking single-cell decision-making to tissue-scale organization remain poorly resolved. Here, we develop a quantitative framework that defines an order parameter predicting when initially disordered colonies undergo a transition to ordered fate alignment and when minimal, localized inputs can redirect their collective state. This analysis reveals a distinct control regime in which multicellular assemblies become susceptible to a single engineered "guide" cell. We validate these predictions by introducing guide cells that integrate into unperturbed colonies and redirect fate patterns within the theoretically defined control windows. Together, these results connect single-cell decision rules to emergent tissue-level organization and establish a generalizable biological control strategy in which a minority engineered subset can reliably redirect the developmental trajectory of a much larger multicellular population. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/693804v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@37baeforg.highwire.dtl.DTLVardef@d1d86aorg.highwire.dtl.DTLVardef@d7375eorg.highwire.dtl.DTLVardef@1741e9a_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOSummary figure:C_FLOATNO Emergence, Scaling, and Control of Multicellular Collective Order. (A) Cell-number-dependent collective order. Sparse colonies lack coordination and yield disordered fate distributions; dense colonies exhibit coordinated, ordered outcomes. (B) Collective order rises with colony compactness ({propto} cell density) and collapses across colony radii R onto a single curve. (C) Once coordination emerges, a single "guide cell" can steer fate-analogous to a sheepdog guiding a flock. The herding efficacy exhibits a biphasic window versus cell number. C_FIG

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Heydari, T., Bashth, O., Fernandes, J., Sabbineni, B., Aguilar-Hidalgo, D., Chen, J., Shakiba, N., Edelstein-Keshet, L., Zandstra, P. W.. 2025-12-15. Predicting and Controlling Collective Fate in Multicellular Systems. https://doi.org/10.64898/2025.12.11.693804

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