Decoupling of Density-Dependent Migration/Proliferation Dichotomy on Surface Potential Gradient

The reciprocal connection between cell migration and proliferation relies on the intertwined contributions from substrate-associated and intercellular cues in the microenvironment. However, how cells perceive the substrates, make contact with their neighbors, and switch phenotypes under different trade-off conditions are still not fully understood. Here, we designed a distinct heterogeneous electric surface potential gradient of piezoelectric biomaterials to decouple the density-dependent migration/proliferation dichotomy. We found that the surface potential gradient accelerated both individual and collective cell migration but reduced proliferation through G0/G1 cell cycle arrest via the integrin/cytoskeleton signaling axis in low density. Interestingly, the initial cell density encodes the proliferative potential independent of the substrate feature. While in high density, the surface potential gradient ceased cell proliferation mainly via the E-cadherin/β-catenin signaling axis. Taken together, these results shed light on the underlying mechanism of the intertwined contributions of cell-material and cell-cell cross-links on migration and proliferation and also provide a new paradigm of materiobiology.