A multiscale chemical-mechanical model predicts impact of morphogen spreading on tissue growth

Abstract

The exact mechanism controlling cell growth remains a grand challenge in developmental biology and regenerative medicine. The Drosophila wing disc tissue serves as an ideal biological model to study mechanisms involved in growth regulation. Most existing computational models for studying tissue growth focus specifically on either chemical signals or mechanical forces. Here we developed a multiscale chemical-mechanical model to investigate the growth regulation mechanism based on the dynamics of a morphogen gradient. By comparing the spatial distribution of dividing cells and the overall tissue shape obtained in model simulations with experimental data of the wing disc, it is shown that the size of the domain of the Dpp morphogen is critical in determining tissue size and shape. A larger tissue size with a faster growth rate and more symmetric shape can be achieved if the Dpp gradient spreads in a larger domain. Together with Dpp absorbance at the peripheral zone, the feedback regulation that downregulates Dpp receptors on the cell membrane allows for further spreading of the morphogen away from its source region, resulting in prolonged tissue growth at a more spatially homogeneous growth rate.

Morphogen gradients are regulated by porous media characteristics of the developing tissue

“…This could then be combined with Wnt signaling at the blastoderm margin, inhibiting cell detachment and maintaining stiff tissue mechanics [82]. Fully coupling morphogen gradient formation, geometry evolution, tissue mechanics, and hydrodynamics would constitute an important step towards understanding morphogenesis as a fully self-organized mechano-chemical process [58, 86].…”

Reverse engineering morphogenesis through Bayesian optimization of physics-based models

“…Further, this framework can be extended to studying other physical and biochemical processes such as embryogenesis 77 , 78 and models of plant development 79 . Of note, it can also be used to study any models of organogenesis as it is independent of the modeling framework or package used in the physics-based simulation, which makes it attractive for more complex computational models that incorporate subcellular elements 22 , 30 , 80 , 81 . In summary, this computational framework enables the systematic elucidation of generalizable biological rules of the morphogenesis of multicellular systems.…”

Balancing competing effects of tissue growth and cytoskeletal regulation during Drosophila wing disc development

“…Future developments of our multi-scale computational model will include a more detailed, microscale stochastic description of the interaction between the actin filaments and myosin motors such that the directionality of the contractile forces can be explicitly incorporated and the mitotic rounding process along with cell division be extended to include a complete representation of mechanistic details. Developing fully chemical-mechanical models based on the approach from Ramezani et al will also enable a fully integrated perspective of organ size control 47 . The experimentally calibrated computational framework opens avenues for exploring feedback loops between tissue shape and cell proliferation.…”