Emergent stable tissue shapes from the regulatory feedback between morphogens and cell growth.

The development and regeneration of multicellular organisms require dynamic coordination between cellular behaviors and mechanochemical signals to achieve precise and stable tissue shapes. Plastic organisms, such as planarians, can regenerate, grow, and degrow as adults while maintaining precise whole-body and organ tissue shapes. However, the mechanisms underlying the pathways that coordinate and integrate these signals into the correct balance between cellular growth, mitosis, and apoptosis to form emergent target tissue shapes remain poorly understood. Here, we present a systematic theoretical study of the biological drivers controlling the feedback mechanisms between tissue growth and morphogen signaling. The approach is based on lattice-free, center-based simulations of cell size dynamics, mitosis, and apoptosis governed by both intercellular diffusible morphogen concentrations and mechanical stress between cells to drive their spatial organization. The results demonstrate how different morphogen properties and tissue mechanics form a feedback loop that is essential for the robust regulation of target tissue shapes. Furthermore, we show that stable tissue shapes can emerge and regenerate from self-regulated patterning processes, such as Turing systems, controlling cellular growth dynamics. A stable feedback loop can form between the emergent morphogen patterns and the dynamics of cellular growth they regulate, as the tissue dynamics define the domain in which morphogens diffuse and hence pattern. Overall, this study highlights the essential role of the feedback loop between morphogen patterning and cellular growth in the regulation of tissue dynamics for stable shape formation. Moreover, this work establishes a framework for further experiments to understand the regulatory dynamics of whole-body development and regeneration using models with high spatiotemporal resolution. SIGNIFICANCE: Tight coordination and interpretation of the multitude of signals at different biological scales- from intracellular signals to mechanical interactions-are essential during the development and regeneration of multicellular organisms. In this work, we investigate the leading role of the feedback between mechanochemical signaling networks and tissue shape through cellular behaviors such as growth, proliferation, and apoptosis. This study demonstrates the interdependence between tissue growth and pattern formation mechanisms in the regulation of stable tissue shapes. Overall, this research provides novel mechanistic insights into the formation of tissue shapes through the regulatory feedback interaction between cell growth and patterning dynamics.