Mechanical control of tissue morphogenesis in the developing embryo
Chemical and Biological Engineering, Princeton University
April 9, 2015
Foege N130A, Wallace H. Coulter Seminar Room
Space-filling, branched networks form the basic architecture for numerous organs in the body, such as the lung, kidney and mammary gland. In the early embryo, these complex structures originate as epithelial tubes — simple geometries that are molded by a sequence of branching events, patterned in both space and time. In most cases, branching involves reciprocal signaling between the branching epithelium and surrounding layer of mesenchyme. In the developing mouse lung, airway branching is highly stereotyped and regulated in part by fibroblast growth factor (FGF) signaling. New epithelial branches emerge at locations adjacent to focal expression of FGF10 in the mesenchyme. This pre-pattern of FGF10 is thought to specify the locations of new branches. Interestingly, however, when the mesenchyme is removed, and reciprocal signaling is effectively disrupted, isolated epithelial explants still branch in culture. In the absence of a mesenchymal FGF template, it is unclear how the epithelial branching pattern is specified.
Here, using a combination of experiments and mathematical modeling, I show that a growth-induced mechanical instability defines the relative locations of branches within the embryonic airway epithelium in the absence of mesenchyme. We removed the mesenchyme from developing mouse lungs, embedded isolated epithelia in three-dimensional (3D) gels of reconstituted basement membrane protein, and performed time-lapse culture experiments. New epithelial branches formed simultaneously, with the airway epithelium cast into a folded geometry with characteristic wavelength ?. To quantitatively investigate the mechanics of this process, I constructed a simple theoretical model for the growing airway epithelium embedded within a viscoelastic gel. These results indicate that a growth-induced viscoelastic folding instability underlies epithelial branching in the absence of mesenchyme. The dominant wavelength of this instability defines the overall branching pattern, and is controlled by epithelial growth rates. Taken together, these data suggest that physical mechanisms control the spatially patterned cell behaviors that govern epithelial morphogenesis.
Dr. Victor Varner is currently a Postdoctoral Research Associate with the Department of Chemical and Biological Engineering at Princeton University, where he is working with Celeste Nelson on the mechanics of branching morphogenesis in the developing mouse lung. Before coming to Princeton, he earned a B.S. in Mechanical Engineering from Texas A&M University and worked with the Human Research Facility at the NASA Johnson Space Center in Houston. He then received his Ph.D. from the Department of Biomedical Engineering at Washington University in St. Louis, under the direction of Larry Taber, where he investigated the biomechanics of early heart and brain development in the chick embryo. This work was supported by a fellowship from the American Heart Association.