Tissue spreading on implantable substrates is a competitive outcome of cell-cell vs. cell-substratum adhesivity

While the interactions of cells with polymeric substrata are widely studied , the influence of cell-cell cohesivity on tissue spreading has not been ri gorously investigated. Here we demonstrate that the rate of tissue spreadin g over a two-dimensional substratum reflects a competition or "tug-of-war" between cell-cell and cell-substratum adhesions. We have generated both a " library" of structurally related copolymeric substrata varying in their adh esivity to cells and a library of genetically engineered cell populations v arying only in cohesivity. Cell-substratum adhesivity was varied through th e poly(ethylene glycol) content of a series of copolymeric substrata, where as cell-cell cohesivity was varied through the expression of the hemophilic cohesion molecules Nand R-cadherin by otherwise noncohesive L929 cells. In the key experiment, multicellular aggregates containing about 600 cells we re allowed to spread onto copolymeric surfaces. We compared the spreading b ehavior of aggregates having different levels of cell-cell cohesivity on a series of copolymeric substrata having different levers of cell-substratum adhesivity. In these experiments, cell-cell cohesivity was measured by tiss ue surface tensiometry, and cell-substratum adhesivity was assessed by a di stractive method. Tissue spreading was assayed by confocal microscopy as th e rate of cell emigration from similar-sized, fluorescence-labeled, multice llular aggregates deposited on each of the substrata. We demonstrate that e ither decreasing substratum adhesivity or increasing cell-cell cohesivity d ramatically slowed the spreading rate of cell aggregates.