Computational mechanics simulations on epithelial folding (Strengths, insights, and future challenges)

Abstract

Epithelial folding is a fundamental process governing the transformation of flat epithelial sheets into intricate three-dimensional structures during morphogenesis. This phenomenon plays a pivotal role in the development of various organs across biological systems. Despite its importance, the underlying mechanisms of epithelial folding remain incompletely understood due to its dynamic and complex nature. In recent years, computational simulations have emerged as powerful tools to study epithelial folding, providing a means to test theories, generate predictions, and integrate data from various sources. The basic workflow of simulation-based research involves formulating hypotheses grounded in insights derived from experimental observations, constructing mechanical models based on these hypotheses, conducting simulations, and subsequently comparing simulation results with experimental observations. This review encompasses studies exploring how spatial distributions of contractile cells and temporal histories of growth and contraction contribute to the three-dimensionalization of epithelial sheets by modeling the mechanics of tissue growth and cell contractile forces. Additionally, it addresses the studies examining the impact of asymmetry in physical constraints imposed by the surrounding structures of epithelial sheets and the non-uniformity of growth on the undulation pattern formation of epithelial sheets by modeling the mechanical interaction between the growing tissue and the surrounding structures. Furthermore, a recent advancement proposes a new framework where computations are employed for initial stages of hypothesis formation by inferring the causality. In this context, we also discuss a recent study that quantitatively infers differential growth, causing the morphogenesis, solely from pre-and post-growth shape data. Through this comprehensive review, we demonstrate the utility of simulations in studying epithelial folding, emphasizing their potential for synergistic integration with various perspectives and exploring synergistic opportunities.