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bioRxiv · 10.64898/2026.05.24.727552

A novel reaction-diffusion architecture for engineering self-organized patterns in mammalian cells

Swedlund, B.·Danan, J. J.·Jiang, T.-X.·Ben Tahar, S.·Poon, K.·Bhamidipati, P. S.·Kreiger, Z. A.·Murillo, S.·Kunnan, M.·Pearce, D. J. G.·Chuong, C.-M.·Ehrenreich, I. M.·Morsut, L.
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Abstract

Reaction-diffusion circuits generate self-organized spatial patterns through local activation and long-range inhibition, but synthetic implementations in mammalian cells have been limited by the differential-diffusion requirement. Here, we introduce a novel architecture, juxtacrine activation with paracrine inhibition (JAPI), where the activator propagates through cell-cell contacts rather than diffusion. We demonstrate mathematically and numerically that JAPI accesses the same patterning regimes as classical diffusion-based circuits with one fewer free parameter. We then engineer compact synNotch-based JAPI circuits in mammalian fibroblasts and demonstrate their sufficiency for self-organized patterning through tunable, size-limited signal propagation. Functionalized to spatially control morphogen secretion, these circuits perturb feather bud formation on adjacent embryonic chicken epidermis. Finally, we develop a library-based approach to explore coupled, dual-JAPI circuits with tunable cross-inhibition, enabling programmable interactions between patterns and access to a broad morphospace of spatial states. Together, JAPI provides a compact, modular platform for programming self-organized multicellular patterning. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/727552v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@fae8c9org.highwire.dtl.DTLVardef@c8eddborg.highwire.dtl.DTLVardef@177d08corg.highwire.dtl.DTLVardef@11cc952_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Swedlund, B., Danan, J. J., Jiang, T.-X., Ben Tahar, S., Poon, K., Bhamidipati, P. S., Kreiger, Z. A., Murillo, S., Kunnan, M., Pearce, D. J. G., Chuong, C.-M., Ehrenreich, I. M., Morsut, L.. 2026-05-25. A novel reaction-diffusion architecture for engineering self-organized patterns in mammalian cells. https://doi.org/10.64898/2026.05.24.727552

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