Collective Organization Behaviors of Multi-Cell Systems Induced by Engineered ECM-Cell Mechanical Coupling

Cells in vivo are surrounded by fibrous extracellular matrix (ECM), which can mediate the propagation of active cellular forces through stressed fiber bundles and regulate various biological processes. However, the mechanisms for multi-cellular organization and collective dynamics induced by cell-ECM mechanical couplings, which are crucial for the development of novel ECM-based biomaterial for cell manipulation and biomechanical applications, remain poorly understood. Herein, the authors design an in vitro quasi-3D experimental system and demonstrate a transition between spreading and aggregating in collective organizational behaviors of discrete multi-cellular systems, induced by engineered ECM-cell mechanical coupling, with the observed phenomena and underlying mechanisms differing fundamentally from those of cell monolayers. During the process of collective cell organization, the collagen substrate undergoes reconstruction into a dense fiber network structure, which is correlated with local cellular density and consistent with observed enhanced cells' motility; and the weakening of fiber bundle formation within the hydrogel reduces cells’ movement. Moreover, cells can respond to the curvature and shape of the original cell population and form different aggregation patterns. These results elucidate important physical factors involved in collective cell organization and provide important references for potential applications of biomaterials in new therapies and tissue engineering.