Designing complex organoids through developmental principles

Principles of developmental biology have inspired efforts for directed differentiation of human pluripotent stem cells (hPSCs), leading to the first generation of organoids that are now well established as models of human development and disease. However, first-generation organoid models were missing many cell types that would be needed to study normal and pathological processes. Here, we discuss how designing next-generation organoids with increased cellular complexity has been possible by better reproducing developmental processes in play during organogenesis in vivo. We focus on recent conceptual and technical advances in reconstructing appropriate cellular diversity in organoids, dissecting the importance of tissue-tissue interactions and specialized cell addition, and how engineering technologies can further enhance our ability to control how cells are brought together to mimic human development in vitro.