Autocrine inhibition of cell motility can drive epithelial branching morphogenesis in absence of growth

Abstract

Epithelial branching morphogenesis drives the development of organs such as the lung, salivary gland, kidney and the mammary gland. It involves cell proliferation, cell differentiation and cell migration. An elaborate network of chemical and mechanical signals between the epithelium and the surrounding mesenchymal tissues regulates the formation and growth of branching organs. Surprisingly, when cultured in isolation from mesenchymal tissues, many epithelial tissues retain the ability to exhibit branching morphogenesis even in absence of proliferation. In this work, we propose a simple, experimentally-plausible mechanism that can drive branching morphogenesis in absence of proliferation and cross-talk with the surrounding mesenchymal tissue. The assumptions of our mathematical model derive from in vitro observations of the behavior of mammary epithelial cells. These data show that autocrine secretion of the growth factor TGFβ1 inhibits the formation of cell protrusions, leading to curvature dependent inhibition of sprouting. Our hybrid cellular Potts and partial-differential equation model correctly reproduces the experimentally observed tissue-geometry dependent determination of the sites of branching, and it suffices for the formation of self-avoiding branching structures in absence and also in presence of cell proliferation.