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During developmental processes such as embryogenesis, how a group of cells self-organizes into specific structures is a central question in biology. However, it remains a major challenge to understand and predict the behavior of every cell within the living tissue over time during such intricate processes. Here we present MultiCell, a geometric deep learning method that can accurately capture the highly convoluted interactions among cells. We demonstrate that multicellular data can be represented with both granular and foam-like physical pictures through a unified graph data structure, considering both cellular interactions and cell junction networks. Using this method, we achieve interpretable four-dimensional morphological sequence alignment and predict single-cell behaviors before they occur at single-cell resolution during Drosophila embryogenesis. Furthermore, using neural activation map and model ablation studies, we demonstrate that cell geometry and cell junction networks are essential features for predicting cell behaviors during morphogenesis. This method sets the stage for data-driven quantitative studies of dynamic multicellular developmental processes at single-cell precision, offering a proof-of-concept pathway toward a unified morphodynamic atlas. 

Within multicellular living systems, cells coordinate their positions with spatiotemporal accuracy to form various tissue structures and control development. These arrangements can be regulated by tissue geometry, biochemical cues, as well as mechanical perturbations. However, how cells pack during dynamic three-dimensional multicellular architectures formation remains unclear. Here, examining a growing spherical multicellular system, human lung alveolospheres, we observe an emergence of hexagonal packing order and a structural transition of cells that comprise the spherical epithelium. Surprisingly, the cell packing behavior on the spherical surface of lung alveolospheres resembles hard-disks packing on spheres, where the less deformable cell nuclei act as effective “hard disks” and prevent cells from getting too close. Nucleus-to-cell size ratio increases during lung spheroids growth; as a result, we find more hexagon-concentrated cellular packing with increasing bond orientational order. Furthermore, by osmotically changing the compactness of cells on alveolospheres, we observe a more ordered packing when nucleus-to-cell size ratio increases, and vice versa. These more ordered cell packing characteristics are consistent with reduced cell dynamics, together suggesting that better cellular packing stabilizes local cell neighborhoods and may regulate more complex biological functions such as cellular maturation and tissue morphogenesis. 

The cytoskeleton is a complex network of interconnected biopolymers consisting of actin filaments, microtubules, and intermediate filaments. These biopolymers work in concert to transmit cell-generated forces to the extracellular matrix required for cell motility, wound healing, and tissue maintenance. While we know cell-generated forces are driven by actomyosin contractility and balanced by microtubule network resistance, the effect of intermediate filaments on cellular forces is unclear. Using a combination of theoretical modeling and experiments, we show that vimentin intermediate filaments tune cell stress by assisting in both actomyosin-based force transmission and reinforcement of microtubule networks under compression. We show that the competition between these two opposing effects of vimentin is regulated by the microenvironment stiffness. These results reconcile seemingly contradictory results in the literature and provide a unified description of vimentin’s effects on the transmission of cell contractile forces to the extracellular matrix. 

Collective cell migration is an essential process throughout the lives of multicellular organisms, for example in embryonic development, wound healing and tumour metastasis. Substrates or interfaces associated with these processes are typically curved, with radii of curvature comparable to many cell lengths. Using both artificial geometries and lung alveolospheres derived from human induced pluripotent stem cells, here we show that cells sense multicellular-scale curvature and that it plays a role in regulating collective cell migration. As the curvature of a monolayer increases, cells reduce their collectivity and the multicellular flow field becomes more dynamic. Furthermore, hexagonally shaped cells tend to aggregate in solid-like clusters surrounded by non-hexagonal cells that act as a background fluid. We propose that cells naturally form hexagonally organized clusters to minimize free energy, and the size of these clusters is limited by a bending energy penalty. We observe that cluster size grows linearly as sphere radius increases, which further stabilizes the multicellular flow field and increases cell collectivity. As a result, increasing curvature tends to promote the fluidity in multicellular monolayer. Together, these findings highlight the potential for a fundamental role of curvature in regulating both spatial and temporal characteristics of three-dimensional multicellular systems.