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

Tissue morphogenesis is an emergent phenomenon: macroscopic structures cannot be predicted from a mere list of genes and cells. We examine here how digits arise from a spherical limb bud and present a framework linking microscopic cellular behavior to morphogenesis. To extract digit morphogenesis in vitro, we created a limb-mesenchyme organoid that breaks symmetry and forms digit-like cartilage. Analyzing cell behavior, iterating between experimental evidence and cellular-based models, shows that microscopic mechanisms like differential adhesion between distal and proximal autopod cells, chemotaxis toward Fgf8b, and biased traction can drive tissue-wide deformations by convergent extension that eventually lead to the formation of digit structures. Taking the continuum limit of these microscopic rules yields a modified Cahn–Hilliard equation, that is well known to describe fluid interfaces and so-called fingering instabilities, but that is shown here to recapitulate well organoid morphogenesis. Taken together, this work suggests that the emergence of “fingers” can be explained in a theoretical framework as a type of fingering instability.