Stochastic simulations of self-organized elastogenesis in the developing lung

In the normal lung, the dominant cable is an elastic “line element” composed of elastin fibers bound to a protein scaffold. The cable line element maintains alveolar geometry by balancing surface forces within the alveolus and changes in lung volume with exercise. Recent work in the postnatal rat lung has suggested that the process of cable development is self-organized in the extracellular matrix. Early in postnatal development, a blanket of tropoelastin (TE) spheres appear in the primitive lung. Within 7 to 10 days, the TE spheres are incorporated into a distributed protein scaffold creating the mature cable line element. To study the process of extracellular assembly, we used cellular automata (CA) simulations. CA simulations demonstrated that the intermediate step of tropoelastin self-aggregation into TE spheres enhanced the efficiency of cable formation more than 5-fold. Similarly, the rate of tropoelastin production had a direct impact on the efficiency of scaffold binding. The binding affinity of the tropoelastin to the protein scaffold, potentially reflecting heritable traits, also had a significant impact on cable development. In contrast, the spatial distribution of TE monomer production, increased Brownian motion and variations in scaffold geometry did not significantly impact simulations of cable development. We conclude that CA simulations are useful in exploring the impact of concentration, geometry, and movement on the fundamental process of elastogenesis.Author summary: The dominant cable in a healthy lung is made up of elastin fibers bound to a protein scaffold and helps maintain alveolar shape and lung volume during exercise. Recent research on postnatal rat lungs indicates that elastogenesis, the development of this cable, is a self-organized process within the extracellular matrix. Elastogenesis is difficult to study by conventional approaches but can be usefully explored by cellular automata simulations. First, elastogenesis involves discrete interactive variables—such as TE monomers and TE spheres—that bind to a protein scaffold. Conceptualizing large mutually interactive populations, particularly difficult in the compressed timeframe of the cable development, is enhanced with simulations. Second, the length scale and geometry of our simulations is a reasonable reflection of the primary septa and the protein scaffold. This scale consistency suggests that the short-range planar interactions in our simulations will faithfully contribute to the large-scale 3-dimensional patterns observed in the developing lung. Finally, elastogenesis appears to be a self-organized process independent of supervised interactions. The simple rules explored in these simulations may not only reflect normal development but also suggest perturbations potentially associated with congenital lung diseases.