Cell‐cell signaling by direct contact increases cell proliferation via a PI3K‐dependent signal

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Abstract
We report a novel mechanism of cellular growth control. Increasing the density of endothelial or smooth muscle cells in culture increased cell‐cell contact and decreased cell spreading, leading to growth arrest. Using a new method to independently control cell‐cell contact and cell spreading, we found that introducing cell‐cell contact positively regulates proliferation, but that contact‐mediated proliferation can be masked by changes in cell spreading: Round cells with many contacts proliferated less than spread cells with none. Physically blocking cell‐cell contact or inhibiting PI3K signaling abrogated cell‐cell induced proliferation, but inhibiting diffusible paracrine signaling did not. Thus, direct cell‐cell contact induces proliferation in these cells.