Decoding the origins of cellular self-organization for engineered biology.

Cellular self-organization reflects an evolutionary leap in which multicellular coordination became essential. Driven by fundamental constraints like oxygen and nutrient transport, physical laws generate inevitable collective behaviors such as cavitation, folding and branching. These behaviors couple mechanics, signaling and gene regulation to build tissues and organs with spatiotemporal precision through the iterative layering of simple rules. Stem cell-based models of embryogenesis and organogenesis make these principles experimentally tractable, revealing canonical developmental routes and alternative trajectories and failure modes that expose bottlenecks and constraints. In this Perspective, we trace self-organization from evolutionary origins to biophysical inevitability and discuss how emerging tools in stem cell biology and bioengineering are beginning to translate these insights into regenerative strategies. Decoding the rules of morphogenesis will open possibilities to reimagine, simulate and rationally engineer the architecture of living tissues.