The mechanical and cytoskeletal basis of lung morphogenesis

The development of complex tissues with characteristic three-dimensional (3D) morphology is made possible through tight temporal and spatial coordination of cell proliferation. This occurs within an embryonic environment filled with various types of soluble growth factors and insoluble extracellular matrix (ECM) molecules, in addition to being mechanically active. For example, formation of branching epithelium in the lung (1) and many other tissues (2) is driven by local differentials in cell growth that promote outward tissue expansion (i.e., epithelial bud formation) relative to neighboring quiescent regions of the same tissue. Localized production of growth factors may promote directional branching in the developing lung by influencing the general site where new branches will form (3). However, the sharp growth differentials responsible for tissue patterning often have abrupt boundaries, with growth being activated in an all-or-none manner within neighboring groups of cells only separated by a few micrometers. Moreover, normal branching morphogenesis in the lung requires the presence ofECMas well as growth factors (4). Gradients of soluble mitogens alone therefore cannot account for how these critical growth differentials are established.