Emergent Tissue Shapes from the Regulatory Feedback between Morphogens and Cell Growth

Patterning and morphogenesis in multicellular organisms require precise dynamic coordination between cellular behaviors and mechano-chemical signals. However, the mechanisms underlying the pathways that coordinate and integrate these signals into emergent cellular behaviors and tissue shapes remain poorly understood. Here, we present a cell-centered agent-based mathematical approach to shed light on the feedback mechanisms underlying tissue growth and pattern formation. The model includes cell size dynamics governed by both intercellular diffusible morphogen concentrations and mechanical stress between cells to control their spatial organization, and does not require the use of any superimposed lattice, increasing its applicability and performance. The results show how the precise integration of the feedback loop between cellular behaviors and mechano-chemical signaling is essential for the regulation of shape and spatial patterns across the tissue scale. Furthermore, the regulation of cellular dynamics by patterning processes, such as Turing activator-inhibitor systems, can drive the formation of emergent stable tissue shapes, which, in turn, specify the domain for morphogen patterning? closing the self-regulated loop between tissue shape and morphogenetic signals. Overall, this study highlights the importance of the feedback loop between morphogen patterning and cellular behaviors in regulating tissue growth dynamics and stable shape formation. Moreover, this study establishes a framework for further experiments to understand the regulatory dynamics of whole-body development and regeneration using high spatiotemporal resolution models.Significance Tight coordination and interpretation of the multitude of signals at different biological scales are essential during the development of multicellular organisms to control their shape, size, and pattern. In this work, we investigated the leading role of the feedback between mechano-chemical signaling networks and tissue shape through cellular behaviors such as growth, proliferation, and apoptosis. The model explains the interdependence between tissue growth and pattern formation mechanisms in regulating the fundamental properties of morphogenesis. Overall, this study provides mechanistic insights into the regulatory feedback interactions between tissue morphogenesis and patterning dynamics.