Biology subjects

Manning, M. L.

Publications and source records attributed to Manning, M. L..

8 recordsLinked to original sources

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↗

bioRxiv2026

Tissue-scale mechanics controls differentiation strategy and dynamics of epithelial multilayering

Generating and maintaining multilayered epithelia requires coordinated cell division, differentiation, and tissue architecture, yet the precise mechanisms of multilayering remain unclear. Using the developing mouse epidermis, we show that basal stem cells adopt distinct multilayering strategies depending on tissue mechanics. Combining quantitative morphometry, embryo live imaging and physical modeling, we observe that early in development, the epidermis is fluid-like, allowing undifferentiated cells to move suprabasally through perpendicular divisions or basal detachment before differentiating. As the tissue matures and rigidifies, a mechanical barrier is established that only allows upward movement of basal cells that have committed to differentiation. The final step of this commitment is delamination that requires Notch signaling, triggered by increased tissue stiffness and jamming. This mechanical regulation orchestrates a feedback loop that induces cell upward motion precisely when the basal layer becomes crowded. Together, our findings identify tissue mechanics as the key determinant of how tissues drive multilayering and reveal mechanically regulated Notch signaling as a driver of epidermal delamination.

cell biology↗

bioRxiv2025

Epithelial convergent extension as a tuning process

Self-tuning--the ability of disordered systems to develop desired collective behaviors by tuning internal couplings in response to feedback--has recently emerged as a powerful framework for understanding adaptation in amorphous solids, mechanical metamaterials, and electrical networks. These systems can learn desired responses, encode memory, and robustly reorganize under repeated stimuli, much like artificial neural networks but without requiring processors to adjust their weights. Here, we extend this paradigm to morphogenesis and show that the epithelium can be viewed as tunable matter and that epithelial convergent extension (CE) can be understood as a self-tuning process. Using a vertex model with active interfacial tensions, we systematically compare distinct tension-update strategies, including externally imposed shear, global gradient descent optimization, and decentralized local feedback rules. We find that while all methods can generate tissue elongation, only local orientation- and length-sensitive rules reproduce key experimental features of CE, such as supracellular actomyosin pattern formation, cell shape changes, and junctional alignment. In contrast, global optimization produces homogeneous tension patterns and mechanically fragile states. By interpreting CE through the lens of tuning, our framework bridges the physics of tunable matter with developmental biology, revealing how simple, local rules enable tissues to efficiently orchestrate complex morphogenetic outcomes through decentralized mechanical adaptation.

biophysics↗

bioRxiv2024

Dynamical forces drive organ morphology changes during embryonic development

Cells, tissues, and organs must change shape in precise ways during embryonic development to execute their functions. Multiple mechanisms including biochemical signaling pathways and biophysical forces help drive these morphology changes, but it has been difficult to tease apart their contributions, especially from tissue-scale dynamic forces that are typically ignored. We use a combination of mathematical models and in vivo experiments to study a simple organ in the zebrafish embryo called Kupffers vesicle. Modeling indicates that dynamic forces generated by tissue movements in the embryo produce shape changes in Kupffers vesicle that are observed during development. Laser ablations in the zebrafish embryo that alter these forces result in altered organ shapes matching model predictions. These results demonstrate that dynamic forces sculpt cell and organ shape during embryo development. Significance StatementWe aim to understand the mechanisms that control precise cell and tissue shape changes required for organ function. Many studies focused on cell shapes have ignored the role of dynamic forces self-generated by slow tissue flows, but recent work showing tissues are near a jamming transition with diverging relaxation timescales suggests slow motion could give rise to large forces. Through a combination of mathematical modeling, imaging, and mechanical perturbations to in vivo experiments, our work demonstrates that tissue-scale dynamic forces are sculpting the shape of an epithelial organ in the zebrafish embryo called Kupffers vesicle (KV). Because there are many processes during development that occur at similarly slow rates, this suggests that self-generated dynamic forces should be investigated more broadly.

developmental biology↗

bioRxiv2021

Effect of cellular rearrangement time delays on the rheology of vertex models for confluent tissues

Large-scale tissue deformation during biological processes such as morphogenesis requires cellular rearrangements. The simplest rearrangement in confluent cellular monolayers involves neighbor exchanges among four cells, called a T1 transition, in analogy to foams. But unlike foams, cells must execute a sequence of molecular processes, such as endocytosis of adhesion molecules, to complete a T1 transition. Such processes could take a long time compared to other timescales in the tissue. In this work, we incorporate this idea by augmenting vertex models to require a fixed, finite time for T1 transitions, which we call the "T1 delay time". We study how variations in T1 delay time affect tissue mechanics, by quantifying the relaxation time of tissues in the presence of T1 delays and comparing that to the cell-shape based timescale that characterizes fluidity in the absence of any T1 delays. We show that the molecular-scale T1 delay timescale dominates over the cell shape-scale collective response timescale when the T1 delay time is the larger of the two. We extend this analysis to tissues that become anisotropic under convergent extension, finding similar results. Moreover, we find that increasing the T1 delay time increases the percentage of higher-fold coordinated vertices and rosettes, and decreases the overall number of successful T1s, contributing to a more elastic-like - and less fluid-like - tissue response. Our work suggests that molecular mechanisms that act as a brake on T1 transitions could stiffen global tissue mechanics and enhance rosette formation during morphogenesis.

biophysics↗

bioRxiv2019

Cell division Rate Controls Cell Shape Remodeling in Epithelia

Epithelia have distinct cellular architectures, which are established in development, re-established after wounding, and maintained during tissue homeostasis despite cell turnover and mechanical perturbations. In turn, cell shape also controls tissue function as a regulator of cell differentiation, proliferation, and motility. Here we investigate cell shape changes in a model epithelial monolayer. After the onset of confluence, cells continue to proliferate and change shape over time, eventually leading to a final architecture characterized by arrested motion and more regular cell shapes. Such monolayer remodeling is robust, with qualitatively similar evolution in cell shape and dynamics observed across disparate perturbations. Here we quantify differences in monolayer remodeling guided by the active vertex model to identify underlying order parameters controlling epithelial architecture. When monolayers are formed atop extracellular matrix with varied stiffness, we find the cell density at which motion arrests varies significantly but the cell shape remains constant, consistent with the onset of tissue rigidity. In contrast, pharmacological perturbations can significantly alter the cell shape at which tissue dynamics is arrested, consistent with varied amounts of active stress within the tissue. Across all experimental conditions the final cell shape is well correlated to the cell proliferation rate, and cell cycle inhibition immediately arrests cell motility. Finally, we demonstrate cell-cycle variation in junctional tension as a source of active stress within the monolayer. Thus, the architecture and mechanics of epithelial tissue can arise from an interplay between cell mechanics and stresses arising from cell cycle dynamics. SIGNIFICANCE STATEMENTThe morphology of biological tissue is determined by the shape and density of constituent cells. Here we measure the dynamics of cells in model epithelial tissues to study the evolution of their shape and density over time. Guided by a mathematical model, we find that cell shape is controlled by rigidity and active stresses within the tissue. We then show that cell cycle dynamics are the source of active stress that drives epithelial remodeling.

biophysics↗

bioRxiv2019

Anisotropy links cell shapes to a solid-to-fluid transition during convergent extension

Within developing embryos, tissues flow and reorganize dramatically on timescales as short as minutes. This includes epithelial tissues, which often narrow and elongate in convergent extension movements due to anisotropies in external forces or in internal cell-generated forces. However, the mechanisms that allow or prevent tissue reorganization, especially in the presence of strongly anisotropic forces, remain unclear. We study this question in the converging and extending Drosophila germband epithelium, which displays planar polarized myosin II and experiences anisotropic forces from neighboring tissues, and we show that in contrast to isotropic tissues, cell shape alone is not sufficient to predict the onset of rapid cell rearrangement. From theoretical considerations and vertex model simulations, we predict that in anisotropic tissues two experimentally accessible metrics of cell patterns--the cell shape index and a cell alignment index--are required to determine whether an anisotropic tissue is in a solid-like or fluid-like state. We show that changes in cell shape and alignment over time in the Drosophila germband indicate a solid-to-fluid transition that corresponds to the onset of cell rearrangement and convergent extension in wild-type embryos and are also consistent with more solid-like behavior in bnt mutant embryos. Thus, the onset of cell rearrangement in the germband can be predicted by a combination of cell shape and alignment. These findings suggest that convergent extension is associated with a transition to more fluid-like tissue behavior, which may help accommodate tissue shape changes during rapid developmental events.

developmental biology↗

bioRxiv2018

Tissue flow induces cell shape changes during organogenesis

In embryonic development, cell shape changes are essential for building functional organs, but in many cases the mechanisms that precisely regulate these changes remain unknown. We propose that fluid-like drag forces generated by the motion of an organ through surrounding tissue could generate changes to its structure that are important for its function. To test this hypothesis, we study the zebrafish left-right organizer, Kupffers vesicle (KV), using experiments and mathematical modeling. During development, monociliated cells that comprise the KV undergo region-specific shape changes along the anterior-posterior axis that are critical for KV function: anterior cells become long and thin, while posterior cells become short and squat. Here, we develop a mathematical vertex-like model for cell shapes, which incorporates both tissue rheology and cell motility, and constrain the model parameters using previously published rheological data for the zebrafish tailbud [Serwane et al.] as well as our own measurements of the KV speed. We find that drag forces due to dynamics of cells surrounding the KV could be sufficient to drive KV cell shape changes during KV development. More broadly, these results suggest that cell shape changes could be driven by dynamic forces not typically considered in models or experiments.

biophysics↗