Tissue dynamics play a crucial role in biological processes ranging from inflammation to morphogenesis. However, these noisy multicellular dynamics are notoriously hard to predict. Here, we introduce a biomimetic machine learning framework capable of inferring noisy multicellular dynamics directly from experimental movies. This generative model combines graph neural networks, normalizing flows and WaveNet algorithms to represent tissues as neural stochastic differential equations where cells are edges of an evolving graph. Cell interactions are encoded in a dual signaling graph capable of handling signaling cascades. The dual graph architecture of our neural networks reflects the architecture of the underlying biological tissues, substantially reducing the amount of data needed for training, compared to convolutional or fully-connected neural networks. Taking epithelial tissue experiments as a case study, we show that our model not only captures stochastic cell motion but also predicts the evolution of cell states in their division cycle. Finally, we demonstrate that our method can accurately generate the experimental dynamics of developmental systems, such as the fly wing, and cell signaling processes mediated by stochastic ERK waves, paving the way for its use as a digital twin in bioengineering and clinical contexts.
翻译:组织动力学在从炎症到形态发生的生物过程中起着至关重要的作用。然而,这些噪声多细胞动力学极难预测。本文提出了一种仿生机器学习框架,能够直接从实验影像中推断噪声多细胞动力学。该生成模型结合图神经网络、归一化流和WaveNet算法,将组织表示为神经随机微分方程,其中细胞是演化图的边。细胞相互作用被编码在一个能够处理信号级联的双重信号图中。我们神经网络的双重图架构反映了底层生物组织的结构,与卷积或全连接神经网络相比,显著减少了训练所需的数据量。以上皮组织实验为例,我们证明该模型不仅能捕捉随机细胞运动,还能预测细胞在分裂周期中状态的演化。最后,我们展示了该方法能够准确生成发育系统(如果蝇翅膀)的实验动力学,以及由随机ERK波介导的细胞信号过程,为其在生物工程和临床环境中作为数字孪生体的应用铺平了道路。