Cells were first cultured in glass dishes over a century ago (, ), a technology still used with only minimal changes. Yet, cells on glass or tissue culture plastic, so-called two-dimensional (2D) culture, often fail to reflect in vivo function. The ability to grow cells within extracellular matrix (ECM) gels (3D culture) was a major advance that recapitulated in vivo cellular behaviors, ranging from differentiated function to maintenance of stem cell niches (–). The question of how cells distinguish between 2D and 3D environments to determine gene expression, cell behavior, and morphogenesis is of much interest to cell biologists and tissue engineers. However, cells do not sense "dimensionality" directly as an independent variable; rather, it is ascertained through its effects on various cell processes.