Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition

During morphogenesis, the intestine undergoes significant structural remodeling, transitioning from a simple tube of immature epithelium into a complex crypt-villus architecture housing mature cell types. However, the relationship between these structural changes and epithelial maturation has remained enigmatic. Using engineered scaffolds that replicate crypt-like geometries, we establish a robust platform for guiding the morphogenesis and differentiation of fetal intestinal cells into mature engineered tissues that mimic their in vivo counterparts. Mechanistically, tissue maturation is driven by cell crowding, leading to reduced YAP1 activation. Modulating YAP signaling in both engineered tissues and the developing mouse intestine alters epithelial lineage specification. These findings uncover a geometry-dependent mechanism that links tissue architecture to cell fate transitions. Our work provides a platform for modeling aspects of intestinal development and offers insights for refining stem cell differentiation protocols and regenerative strategies for intestinal disorders. • Crypt-like geometry promotes maturation of fetal intestinal epithelial cells • Engineered tissues display multi-lineage differentiation and epithelial organization • Cell crowding reduces YAP1 activity to drive epithelial maturation • YAP activity modulates cell lineage specification in vivo Using engineered scaffolds mimicking intestinal crypts, Maimets et al. show that tissue geometry drives epithelial maturation by regulating YAP activity. Crypt-like structures promote differentiation of fetal cells, providing insight into how form guides function and offering a platform for modeling intestinal development and repair.