Cell–ECM Interactions and the Regulation of Epithelial Branching Morphogenesis

Branching morphogenesis is a crucial mechanism in embryonic development for establishing the architecture of many mammalian epithelial organs, including the salivary gland, lung, kidney, and mammary gland. It substantially expands the epithelial surface area available for secretion or absorption within many organs. Studies in three-dimensional ex vivo organ culture, including early tissue recombination studies, have revealed that cell interactions with the interstitial extracellular matrix (ECM) and the basement membrane associated with epithelial cells play a critical role in the branching process. Here, we review the dynamic mechanisms by which cell–ECM interactions regulate the morphogenesis and organization of branched epithelial tissue structures. We highlight several general biological principles by which cell interactions with the ECM and basement membrane regulate epithelial branching morphogenesis; these include ECM-mediated or -induced alterations in tissue shape and stimulation of dynamic cell motility, proliferative outgrowth and expansion of the epithelium regulated by growth factors and proteolytic degradation of the ECM, and basement membrane roles in coordinating organization of epithelial tissue architecture. Because an in-depth understanding of cell interactions with the ECM will be important for developing novel approaches to disease therapy, we conclude with a discussion of the implications of these findings for the rational design of bioengineered scaffolds in regenerative medicine strategies, as well as their potential relevance to epithelial cancer progression.