Negi, R. S. | Search bioRxiv

bioRxiv2026

A Predictive Model for Coupling Cell Division Orientation to Tissue Mechanics During Epithelial Morphogenesis

Stratified epithelial tissues such as the skin epidermis maintain barrier integrity during development and homeostasis through the coordinated action of cell proliferation, differentiation, delamination, and tissue-scale mechanical forces. During development, the orientation of cell division within the basal layer plays a pivotal role in tissue stratification; however, the mechanical principles linking the orientation of the division plane to these processes across developmental stages remain poorly understood. Here, we expand a recently developed three-dimensional vertex model for stratified epithelia, composed of the basement membrane, basal, and suprabasal layers, to study the mechanical and structural impact of cell divisions with a wider range of orientations. The model integrates developmental stage via specific changes in heterotypic interfacial tensions (arising from actomyosin cortical contractility and adhesion molecules at the basal-suprabasal interface) and tissue stiffness that have been quantified previously in experiments. By systematically varying background mechanical parameters, we investigate how heterotypic tension, division orientation, and tissue fluidity collectively influence the outcome of cell division. Our goal is to uncover the strategies that the embryo may employ to generate stratified phenotypes at different developmental stages, recognizing that these strategies might evolve over time. Although our focus is on the embryonic developmental stages of the epidermis, this framework may also be extended to investigate transformed cells, such as in cancer, to explore how altered division orientation contributes to precancerous or transformed phenotypes.

biophysics↗

bioRxiv2025

Sparse mesenchymal cell networks as a fluid under tension

Sparse mesenchymal cellular networks are ubiquitous across animals, shaping both embryonic and adult structures through dynamic interactions with epithelia. Yet, the physical principles underlying their collective behaviors remain elusive, as their stellate cells and large extracellular spaces--filled with matrix or interstitial fluid--pose significant experimental and computational challenges. Here, we demonstrate that the avian presomitic mesoderm (PSM), a canonical embryonic mesenchymal tissue, behaves as a fluid under tension, exhibiting structural organization that cannot be explained by simple Brownian-like cell motion. Through quantitative modeling, we identify contact inhibition of locomotion (CIL)--where cells actively retract and move away upon contact--as a key mechanism that enables sparse mesenchymal networks to sustain macroscopic tension while flowing like a fluid. Simple continuum equations relate observable cell-scale parameters to the emergent remodeling dynamics observed in both experiments and simulations. Together, these findings put forward an unrecognized mechanical role for CIL, extending its influence beyond collective migration, and establish the fluid-under-tension state as a distinct class of tissue behavior that describes key developing embryonic tissues and may illuminate how matrix-rich adult tissues become fluidized during tumorigenesis.

biophysics↗