Rufo Joseph, Qiu Chongxu, Han Dasol, Baxter Naomi, Daley Gabrielle, Wilson Maxwell Z
Department of Molecular, Cellular, and Developmental Biology, University of California Santa Barbara, Santa Barbara, CA, USA.
Center for BioEngineering, University of California Santa Barbara, Santa Barbara, CA, USA.
bioRxiv. 2024 Sep 23:2024.09.20.614192. doi: 10.1101/2024.09.20.614192.
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.
人类原肠胚形成是一个关键的发育阶段，由于机制尚不清楚，许多妊娠在此阶段失败。我们使用二维类原肠胚（一种人类原肠胚形成的干细胞模型），结合高通量药物扰动和数学建模，创建了一个可解释的类原肠胚形态空间图谱。该图谱概述了对各种扰动的模式形成结果，并确定了经典模式形成和失败模式的变化。我们对形态发生素动力学进行建模，将模拟的类原肠胚嵌入实验确定的形态空间中，以解释发育参数如何驱动模式形成。我们的模型预测并验证了模式形成差异的两个最大来源：基于细胞密度对Wnt信号和SOX2稳定性的调节。将这些参数作为形态空间的轴赋予了可解释性。为了证明其效用，我们预测了在斑马鱼中得到验证的新型致畸剂。总体而言，我们展示了发育干细胞模型如何用于构建对发育结果集的全面且可解释的理解。
