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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. 

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.