The differential adhesion hypothesis attributes sorting-out behavior of embryonic cells to differences in the strengths of their intercellular adhesions. It suggests that cells in mixed populations rearrange themselves to minimize their total adhesive free energy. The final configuration adopted is viewed as approaching a moststable or equilibrium configuration, with the less cohesive cell/population tending to envelop the more cohesive one.
The hypothesis enables two predictions to be made. First, if the final configuration adopted by a mixed cell population indeed approximates an equilibrium configuration, the same final configuration should be approached irrespective of the starting configuration. Second, comparison of the equilibrium configurations for all possible pair-combinations of a series of cell populations of different types should reveal a hierarchy of “preference” for the internal position, reflecting a hierarchy of cellular cohesiveness.
These predictions have been tested and confirmed. First, any particular pair of tissues approaches the same final configuration, irrepective of whether the cells are initially randomly intermixed or tissue fragments are laterally joined. Second, the predicted hierarchy of preference for the internal position has been found, consistent with a hierarchy of cellular cohesiveness.
An effort has been made to clarify confusions that have arisen concerning the differential adhesion hypothesis. It is particularly stressed that the hypothesis offers an explanation for cell population behavior in terms of relative strengths of cell adhesions and makes no proposals concernnig the chemistry of adhesion. However, the value of equilibrium configurations in guiding biochemical investigations of cell surface adhesives is pointed out, as is the relevance of the present observations to natural morphogenetic events.