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

The reciprocal connection of 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 phenotype under different tradeoff conditions are still not fully understood. Here, we designed a distinct heterogeneous electric surface potential gradient of piezoelectric biomaterial to decouple the density-dependent migration/proliferation dichotomy. We found that surface potential gradient accelerated both individual and collective cell migration but reduced proliferation through G0/G1 cell cycle arrest via integrin/cytoskeleton signaling axis in low density. Interestingly, the initial cell density encodes proliferative potential independent of the substrate feature. While in high density, surface potential gradient ceased cell proliferation mainly via E-cadherin/beta-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/proliferation, and also provide a new paradigm of materiobiology.