The differences in cellular behavior underlying morphogenesis are governed by signaling interactions in the growing tissue. In lung branching morphogenesis, for instance, the high sensitivity of cells to the distribution of diffusive signals within the developing tissue is considered to be the principle mechanism guiding shape change. The cellular response to a concentration gradient of signals has been investigated in many ways at the single-cell level. However, the degree to which cell-cell interactions affect gradient sensing and behavior at the mesoscopic level is poorly understood. This study aims to provide greater understanding of the mesoscopic response of epithelial tissue to a signaling gradient via a combination of experimental and theoretical approaches.

This study uses three different techniques; construction of a microfluidics device for three dimensional tissue culture, imaging of live mouse fetal lung, and mathematical modeling of epithelial shape formation. First, a microfluidics device is constructed that enables the imaging of live lung explants within an ECM gel chamber exposed to a sustained FGF diffusion gradient. The spatiotemporal patterns of cell movement, proliferation, and signaling activity downstream of FGF are measured from imaging data. These aspects of cell behavior are quantified and the data subsequently fed into a mathematical model. The model, which considers the mechanical interactions between epithelial cells, explores the ways in which the coupling of single-cell movement gives rise to mesoscopic behavior.

This interdisciplinary study will provide new insights into how epithelial tissue responds to a concentration gradient of signaling factors. It has recently been proposed that mechanical interactions between cells drive shape change within the growing epithelial sheet. My mathematical model incorporates this concept, and is applied to the study of collective cell migration to determine how responses at the single-cell level are linked to overall tissue shape change.