Adipose stroma induces branching morphogenesis of engineered epithelial tubules

The mammary gland and other treelike organs develop their characteristic fractal geometries through branching morphogenesis, a process in which the epithelium bifurcates and invades into the surrounding stroma. Controlling the pattern of branching is critical for engineering these organs. In vivo, the branching process is instructed by stromal-epithelial interactions and adipocytes form the largest component of the fatty stroma that surrounds the mammary epithelium. Here, we used microlithographic approaches to engineer a three-dimensional culture model that enables analysis of the effect of adipocytes on the pattern of branching morphogenesis of mammary epithelial cells. We found that adipocyte-rich stroma induces branching through paracrine signals, including hepatocyte growth factor, but does not affect the branching pattern per se. This tissue engineering approach can be expanded to other organs, and should enable piecemeal analysis of the cellular populations that control patterning during normal development.