Self-organized fingering instabilities drive the emergence of tissue morphogenesis in digit organoids

Tissue morphogenesis is an emergent phenomenon: macroscopic structures cannot be predicted from a parts list of genes and cells. We examined how digits arise from a spherical limb bud and present a framework linking microscopic behaviors to morphogenesis. To extract digit morphogenesis in vitro , we created a limb-mesenchyme organoid that breaks symmetry and forms digit-like cartilage. Analyzing cell behaviors and iterating with cellular-based models identified sufficient microscopic mechanisms: differential adhesion between Distal and Proximal cells, chemotaxis toward Fgf8b and Wnt3a, and biased traction driving convergent extension. Taking the continuum limit of these behaviors yielded a modified Cahn–Hilliard equation that can describe fingering instability, recapitulating organoid morphogenesis. Taken together, this work suggests that the emergence of “fingers” can be explained as fingering instability.