Biology subjects

Vetter, R.

Publications and source records attributed to Vetter, R..

16 recordsLinked to original sources

bioRxiv2026

OptiCell3D: Precise inference of mechanical cell properties from microscopy imaging

We introduce OptiCell3D, an open-source image-based framework for inferring cellular mechanical properties directly from 3D microscopy data. By integrating short physical simulations with gradient-based optimization via backpropagation, our method substantially improves accuracy compared to existing approaches. Moreover, OptiCell3D enables mechanical inference in tissues that are too large to be fully imaged, extending its applicability to more complex biological systems. We demonstrate the power of our approach by applying OptiCell3D to five morphologically diverse mouse epithelial tissues. By combining inferred parameters with simulations and morphometric analysis, we find that the ratio of apical to lateral surface tension predicts cell aspect ratio across epithelial subtypes, linking a single mechanical parameter to the broad morphological diversity of epithelia. Finally, we apply our framework to stratified tissues, finding greater variability in pressure and surface tension between cells and tension gradients along the apico-basal axis.

biophysics↗

bioRxiv2026

Determinants of the Transition Zone Width of Morphogen Readouts

In tissue patterning, cell fate boundaries often form transition zones with mixed or gradual fates rather than sharp demarcations. Traditionally, such zones in morphogen-driven systems were attributed to fluctuations in morphogen concentrations, especially at low molecule numbers. Here, we present experimental data from the mouse neural tube, the precursor of the central nervous system, which challenges this view. Contrary to expectations, we find that the transition zone width (TZW) does not increase with distance from the morphogen source. By combining experiments, theory, and computational modelling, we identify key factors shaping the TZW. Our findings suggest that cellular readout noise, rather than morphogen fluctuations, determine the TZW. The inferred variability in the parameters defining morphogen dynamics and cellular readout remains within previously reported physiological ranges. This discovery adds to earlier findings that morphogen gradients maintain higher-than-expected patterning precision over long distances, offering new insights into the robustness of developmental processes.

developmental biology↗

bioRxiv2025

Directed cell migration is a versatile mechanism for rapid developmental pattern formation

The evolution of multicellular organisms hinges on self-organization mechanisms that generate tissues with diverse functions. A central process is the breaking of symmetry to form spatial patterns from initially uniform conditions. Among the various mechanisms proposed, directed cell migration--driven by chemotaxis, durotaxis, differential adhesion or other processes--offers a compelling strategy to organize tissues rapidly and robustly. Here, we unify these concepts into a general mathematical framework and show that it can produce diverse spatial patterns across one-, two-, and three-dimensional domains. Using numerical simulations and stability theory, we characterize the emergence, geometry, and formation speed of these patterns. Our findings provide a mechanistic understanding of morphogenesis beyond the traditional chemical or mechanical patterning paradigms and offer a quantitative foundation to guide pattern formation in tissue engineering and regenerative medicine.

developmental biology↗

bioRxiv2025

The emergence of the fractal bronchial tree

The fractal design of the bronchial tree, as described by the Hess-Murray law, facilitates energy-efficient lung ventilation, yet its developmental origins remain unclear. Here, we quantify the rearrangement of the embryonic bronchial tree into its fractal architecture, using SkelePlex, a new neural network-based image processing pipeline, and elucidate the biophysical principles governing its formation. We find that the branch shapes are such that pressure drop, shear, axial and hoop stress are equal across all branches. The seemingly random diameter of sister branches reflects the different number of tips they connect to in the asymmetric lung tree. By analysing lungs after pneumonectomy and those affected by chronic obstructive pulmonary disease (COPD), we show the same principles to persist in adulthood and disease, potentially providing quantitative biomarkers for disease progression and therapeutic guidance.

developmental biology↗

bioRxiv2023

Morphogen gradients can convey position and time in growing tissues

During embryonic development, cells coordinate fate decisions based on both position and time. While morphogen gradients have long been recognized as a source of positional information, how timing is synchronized across developing tissues remains unclear. We propose a simple mechanism by which morphogen dynamics can also encode time. If the morphogen source expands with a uniformly growing tissue and the gradient maintains a constant decay length, cells experience transient, hump-shaped signals that convey timing cues. Moreover, when two opposing exponential gradients with equal lengths--such as those in the vertebrate neural tube--interact, their product forms a uniform signal that can synchronize fate decisions across the entire tissue. With increasing gradient amplitudes, cells encounter a transient signal; with constant amplitudes, the signal decays--a feature of a depletion timer. This mechanism provides a generalizable principle by which morphogen gradients may coordinate both spatial and temporal aspects of patterning during development.

developmental biology↗

bioRxiv2023

Morphometry and mechanical instability at the onset of epithelial bladder cancer

Malignancies of epithelial tissues, called carcinomas, account for the majority of cancer cases. Much cancer research has focused on genetic alterations and their relation to different carcinoma phenotypes. Besides a rewiring in the signalling networks, carcinoma progression is accompanied by mechanical changes in the epithelial cells and the extracellular matrix. Here, we reveal intricate morphologies in the basement membrane at the onset of bladder cancer, and propose that they emerge from a mechanical buckling instability upon epithelial overgrowth. Using a combination of microscopy imaging of the mouse and human bladder tissue, elasticity theory, and numerical simulations of differential growth in the bladder mucosa, we find that aberrant tissue morphologies can emerge through stiffness changes in the different mucosa layers. The resulting thickening, wrinkles and folds exhibit qualitative and quantitative similarity with imaged early papillary tumors and carcinomas in situ. Atomic force microscopy indeed reveals local stiffness changes in the pathological basement membrane. Our findings suggest a mechanical origin of the different carcinoma subtypes in the bladder, which have vastly different clinical prognosis. They might provide the basis for a new line of attack in medical carcinoma treatment and prophylaxis.

cancer biology↗

bioRxiv2023

3D Simulation of Tissue Mechanics with Cell Polarization

The 3D organisation of cells determines tissue function and integrity, and changes dramatically in development and disease. Cell-based simulations have long been used to define the underlying mechanical principles. However, large computational costs have so far limited simulations to either simplified cell geometries or small tissue patches. Here, we present SimuCell3D, a highly efficient open-source program to simulate large tissues in 3D with subcellular resolution, growth, proliferation, extracellular matrix, fluid cavities, nuclei, and non-uniform mechanical properties, as found in polarised epithelia. Spheroids, vesicles, sheets, tubes, and other tissue geometries can readily be imported from microscopy images and simulated to infer biomechanical parameters. Doing so, we show that 3D cell shapes in layered and pseudostratified epithelia are largely governed by a competition between surface tension and intercellular adhesion. SimuCell3D enables the large-scale in silico study of 3D tissue organization in development and disease at an unprecedented level of detail.

bioinformatics↗

bioRxiv2023

2D Effects Enhance Precision of Gradient-Based Tissue Patterning

Robust embryonic development requires pattern formation with high spatial accuracy. In epithelial tissues that are patterned by morphogen gradients, the emerging patterns achieve levels of precision that have recently been explained by a simple one-dimensional reaction-diffusion model with kinetic noise. Here, we show that patterning precision is even greater if transverse diffusion effects are at play in such tissues. The positional error, a measure for spatial patterning accuracy, decreases in wider tissues but then saturates beyond a width of about ten cells. This demonstrates that the precision of gradient-based patterning in two- or higher-dimensional systems can be even greater than predicted by 1D models, and further attests to the potential of noisy morphogen gradients for high-precision tissue patterning.

developmental biology↗

bioRxiv2022

Patterning precision under non-linear morphogen decay and molecular noise

Morphogen gradients can instruct cells about their position in a patterned tissue. Non-linear morphogen decay has been suggested to increase gradient precision by reducing the sensitivity to variability in the morphogen source. Here, we use cell-based simulations to quantitatively compare the positional error of gradients for linear and non-linear morphogen decay. While we confirm that non-linear decay reduces the positional error close to the source, the reduction is very small for physiological noise levels. Far from the source, the positional error is much larger for non-linear decay in tissues that pose a flux barrier to the morphogen at the boundary. In light of this new data, a physiological role of morphogen decay dynamics in patterning precision appears unlikely.

developmental biology↗

bioRxiv2022

Geometric Effects Position Renal Vesicles During Kidney Development

During kidney development, reciprocal signalling between the epithelium and the mesenchyme coordinates nephrogenesis with branching morphogenesis of the collecting ducts. The mechanism that positions the renal vesicles, and thus the nephrons, relative to the branching ureteric buds has remained elusive. By combining computational modelling and experiments, we show that geometric effects concentrate the key regulator, WNT9b, at the junctions between parent and daughter branches where renal vesicles emerge, even when uniformly expressed in the ureteric epithelium. This curvature effect might be a general paradigm to create non-uniform signalling in development.

developmental biology↗

bioRxiv2022

Impact of cell size on morphogen gradient precision

Tissue patterning during embryonic development is remarkably precise. We numerically determine the impact of the cell diameter, gradient length, and the morphogen source on the variability of morphogen gradients and show that the positional error increases with the gradient length relative to the size of the morphogen source, and with the square root of the cell diameter and the readout position. We provide theoretical explanations for these relationships, and show that they enable high patterning precision over developmental time for readouts that scale with expanding tissue domains, as observed in the Drosophila wing disc. Our analysis suggests that epithelial tissues generally achieve higher patterning precision with small cross-sectional cell areas. An extensive survey of measured apical cell areas shows that they are indeed small in developing tissues that are patterned by morphogen gradients. Enhanced precision may thus have led to the emergence of pseudostratification in epithelia, a phenomenon for which the evolutionary benefit had so far remained elusive.

developmental biology↗

bioRxiv2021

Hingepoint emergence in mammalian spinal neurulation

Neurulation is the process in early vertebrate embryonic development during which the neural plate folds to form the neural tube. Spinal neural tube folding in the posterior neuropore changes over time, first showing a median hingepoint, then both the median hingepoint and dorsolateral hingepoints, followed by dorsolateral hingepoints only. The biomechanical mechanism of hingepoint formation in the mammalian neural tube is poorly understood. Here, we employ a mechanical finite element model to study neural tube formation. The computational model mimics the mammalian neural tube using microscopy data from mouse and human embryos. While intrinsic curvature at the neural plate midline has been hypothesized to drive neural tube folding, intrinsic curvature was not sufficient for tube closure in our simulations. We achieved neural tube closure with an alternative model combining mesoderm expansion, non-neural ectoderm expansion and neural plate adhesion to the notochord. Dorsolateral hingepoints emerged in simulations with low mesoderm expansion and zippering. We propose that zippering provides the biomechanical force for dorsolateral hingepoint formation in settings where the neural plate lateral sides extend above the mesoderm. Together, these results provide a new perspective on the biomechanical and molecular mechanism of mammalian spinal neurulation.

developmental biology↗

bioRxiv2021

Inference of Morphogen Gradient Precision from Molecular Noise Data

During development, morphogen gradients provide spatial information for tissue patterning. Gradients and readout mechanisms are inevitably variable, yet the resulting patterns are strikingly precise. Measurement limitations currently preclude precise detection of morphogen gradients over long distances. Here, we develop a new formalism to estimate gradient precision along the entire patterning axis from measurements close to the source. Using numerical simulations, we infer gradient variability from measured molecular noise levels in morphogen production, decay, and diffusion. The predicted precision is much higher than previously measured--precise enough to allow even single gradients to define the central progenitor boundaries during neural tube development. Finally, we show that the patterning mechanism is optimized for precise progenitor cell numbers, rather than precise boundary positions, as the progenitor domain size is particularly robust to gradient alterations. We conclude that single gradients can yield the observed developmental precision, which provides new prospects for tissue engineering.

developmental biology↗

bioRxiv2021

3D Cell Neighbour Dynamics in Growing Pseudostratified Epithelia

During morphogenesis, epithelial sheets remodel into complex geometries. How cells dynamically organize their contact with neighbouring cells in these tightly packed tissues is poorly understood. We have used light-sheet microscopy of growing mouse embryonic lung explants, three-dimensional cell segmentation, and physical theory to unravel the principles behind 3D cell organization in growing pseudostratified epithelia. We find that cells have highly irregular 3D shapes and exhibit numerous neighbour intercalations along the apical-basal axis as well as over time. Despite the fluidic nature, the cell packing configurations follow fundamental relationships previously described for apical epithelial layers, i.e., Eulers formula, Lewis law, and Aboav-Weaires law, at all times and across the entire tissue thickness. This arrangement minimizes the lateral cell-cell surface energy for a given cross-sectional area variability, generated primarily by the distribution and movement of nuclei. We conclude that the complex 3D cell organization in growing epithelia emerges from simple physical principles.

cell biology↗

bioRxiv2020

The Biomechanical Basis of Biased Epithelial Tube Elongation

During lung development, epithelial branches expand preferentially in longitudinal direction. This bias in outgrowth has been linked to a bias in cell shape and in the cell division plane. How this bias arises is unknown. Here, we show that biased epithelial outgrowth occurs independent of the surrounding mesenchyme, of preferential turn-over of the extracellular matrix at the bud tips, and of FGF signalling. There is also no evidence for actin-rich filopodia at the bud tips. Rather, we find epithelial tubes to be collapsed during early lung and kidney development, and we observe fluid flow in the narrow tubes. By simulating the measured fluid flow inside segmented narrow epithelial tubes, we show that the shear stress levels on the apical surface are sufficient to explain the reported bias in cell shape and outgrowth. We use a cell-based vertex model to confirm that apical shear forces, unlike constricting forces, can give rise to both the observed bias in cell shapes and tube elongation. We conclude that shear stress may be a more general driver of biased tube elongation beyond its established role in angiogenesis. Summary StatementWe systematically analysed the requirements for biased elongating outgrowth of epithelial tubes during lung and kidney development, and provide evidence that fluid-flow induced shear stress drives their biased elongation.

developmental biology↗

bioRxiv2019

Aboave-Weaire’s law in epithelia results from an angle constraint in contiguous polygonal lattices

It has long been noted that the cell arrangements in epithelia, regardless of their origin, exhibit some striking regularities: first, the average number of cell neighbours at the apical side is (close to) six. Second, the average apical cell area is linearly related to the number of neighbours, such that cells with larger apical area have on average more neighbours, a relation termed Lewis law. Third, Aboav-Weaires (AW) law relates the number of neighbours that a cell has to that of its direct neighbours. While the first rule can be explained with topological constraints in contiguous polygonal lattices, and the second rule (Lewis law) with the minimisation of the lateral contact surface energy, the driving forces behind the AW law have remained elusive. We now show that also the AW law emerges to minimise the lateral contact surface energy in polygonal lattices by driving cells to the most regular polygonal shape, but while Lewis law regulates the side lengths, the AW law controls the angles. We conclude that global apical epithelial organization is the result of energy minimisation under topological constraints.

biophysics↗