An explainable map of human gastruloid morphospace reveals gastrulation failure modes and predicts teratogens

Abstract

Human gastrulation is a critical stage of development where many pregnancies fail due to poorly understood mechanisms. Using the 2D gastruloid, a stem cell model of human gastrulation, we combined high-throughput drug perturbations and mathematical modelling to create an explainable map of gastruloid morphospace. This map outlines patterning outcomes in response to diverse perturbations and identifies variations in canonical patterning and failure modes. We modeled morphogen dynamics to embed simulated gastruloids into experimentally-determined morphospace to explain how developmental parameters drive patterning. Our model predicted and validated the two greatest sources of patterning variance: cell density-based modulations in Wnt signaling and SOX2 stability. Assigning these parameters as axes of morphospace imparted interpretability. To demonstrate its utility, we predicted novel teratogens that we validated in zebrafish. Overall, we show how stem cell models of development can be used to build a comprehensive and interpretable understanding of the set of developmental outcomes.