An interplay of geometry and signaling enables robust lung branching morphogenesis

Abstract

Early branching events during lung development are stereotyped. Although key regulatory components have been defined, the branching mechanism remains elusive. We have now used a developmental series of 3D geometric datasets of mouse embryonic lungs as well as time-lapse movies of cultured lungs to obtain physiological geometries and displacement fields. We find that only a ligand-receptor-based Turing model in combination with a particular geometry effect that arises from the distinct expression domains of ligands and receptors successfully predicts the embryonic areas of outgrowth and supports robust branch outgrowth. The geometry effect alone does not support bifurcating outgrowth, while the Turing mechanism alone is not robust to noisy initial conditions. The negative feedback between the individual Turing modules formed by fibroblast growth factor 10 (FGF10) and sonic hedgehog (SHH) enlarges the parameter space for which the embryonic growth field is reproduced. We therefore propose that a signaling mechanism based on FGF10 and SHH directs outgrowth of the lung bud via a ligand-receptor-based Turing mechanism and a geometry effect.

Visualizing Morphogenesis with the Processing Programming Language

“…Branching morphogenetic processes that could be modeled encompass lung morphogenesis (Menshykau et al, 2014), establishment of blood vascular networks (Boas and Merks 2015), and branching of tumors (Miura 2015;Takaki 2005). Blender (www.blender.org), an open source 3D animation and graphics software, could also be used to model morphogenesis.…”

Simulation Frameworks for Morphogenetic Problems

“…This approach has been used to study the ability of a Turing-type signalling mechanism to control the branching of embryonic lungs [6]; an example is given in Figure 1A.…”

“…Instead of either using cell-based or continuous approaches, they vote for the derivation of continuous formulations based on discrete models to understand a problem on different scales. [6]); (B) Spheroid model of a liver lobule (reprinted with permission from [7]); (C) Vertex model to study epithelial dynamics (reprinted by permission of Elsevier from [8]); (D) Cellular Potts model of blood vessel growth (reprinted with permission from [9]); (E) Immersed Boundary cell model of a proliferating tissue; (F) Subcellular Element model of a single cell subject to a stretching force (reproduced by permission of IOP Publishing from [10]). …”

4D Biofabrication of Branching Multicellular Structures: A Morphogenesis Simulation Based on Turing’s Reaction-Diffusion Dynamics

“…The reaction-diffusion (RD) model based on Turing-type mechanism has shown its potential power on simulating the dynamic process of molecules and tissue morphogenesis [16][17][18] with time. This is a suitable method to guide the 4D biofabrication via predicting the dynamic evolution of 3D self-organized microstructures.…”