Biology subjects

Jensen, O. E.

Publications and source records attributed to Jensen, O. E..

14 recordsLinked to original sources

bioRxiv2026

Physics-informed stereology for estimating placental diffusive exchange capacity

IntroductionStereological estimates of villous membrane thickness and surface area are widely used to infer the diffusive exchange capacity of the human placenta. A key geometric determinant of exchange capacity can be expressed as an effective diffusive length scale. Here we combine virtual histological sections with computational modelling in realistic villous geometries to assess the accuracy of classical stereological estimates of this diffusive length scale. MethodsTwo terminal villi, reconstructed from three-dimensional imaging, were digitally sectioned to generate random two-dimensional geometries containing fetal capillaries and surrounding villous tissue. For each section, we simulated steady diffusive transport between the fetal-capillary and intervillous-space boundaries to obtain a physics-based diffusive length scale as a reference case. Using the same geometries, we applied standard line-intercept stereology to measure harmonic-mean barrier thickness and boundary-length densities, from which a stereological estimate of diffusive length scale was derived. ResultsAcross both villi, stereology systematically overestimated the diffusive length scale by approximately 15-25%, depending on villus and section. We identified sources of this discrepancy, including interface curvature and assumptions underpinning the stereological correction factors, using idealised models of villous structure. ConclusionThese findings highlight the need for stereological approaches that account for curvature when interpreting placental structure-function relationships.

biophysics↗

bioRxiv2026

The impact of placental structure on haemodynamics and fetal oxygen uptake

The placenta is a fundamental organ for human reproduction, facilitating fetal growth via the exchange of oxygen, nutrients and waste products between mother and fetus, by means of a dense network of fetal villi bathed in maternal blood that flows through the intervillous space (IVS). However, despite its role in adverse pregnancy outcomes associated with impaired maternal-fetal transfer, the influence of placental structure on maternal haemodynamics and the delivery of oxygen and nutrients to the developing fetus is not well understood. This study employs computational fluid dynamics within physiologically informed 2D and 3D whole-organ-scale placental geometries, whose features are informed by recent ex vivo experimental and {micro}CT data, to examine comprehensively the influence of placental anatomy on maternal flow and transport in the IVS. In particular, we consider in detail the impact of the number and placement of maternal decidual arteries and veins that supply and drain the IVS, the location and height of so-called septal walls that loosely separate the placenta into functional units (cotyledons) and sub-units (lobules), and the density of the fetal villous trees as reflected in the rate of uptake of dissolved solutes from the maternal blood and the resistance to flow. We first exploit the computational efficiency of simulation in a representative 2D geometry to study in detail the sensitivity of haemodynamic markers to these parameters. These results guide our 3D study which reveals that the flow, transport and oxygen uptake are strongly influenced by placental structure, and exposes the vein-to-artery ratio as a key indicator of placental efficiency, regulating a trade-off between a preferential maternal flow environment and fetal oxygen uptake. Conversely, the location and height of the septal walls, a feature that is not well studied, have minimal systematic impact on the macroscopic haemodynamic and transport measures considered here. We also introduce a reduced model, for which analytical progress can be made, and demonstrate its utility in exposing key drivers of maternal-fetal transport. Author summaryIn our study, we explored how placental structure affects maternal blood flow and the delivery of oxygen to the fetus. The placenta is a complex and vital organ, but we do not fully understand how its morphology influences its functional efficiency. This is a critical gap in our knowledge as placental blood flow is implicated in serious pregnancy complications such as fetal growth restriction and pre-eclampsia. To investigate the effect of structure, we used detailed 2D and 3D models of the placenta. These models allowed us to simulate maternal blood flow and oxygen transport therein while changing various structural features, such as the number and location of placental veins and the density of the intervillous space. We found that the ratio of veins to arteries is a key factor in determining the maternal blood flow speed and the amount of oxygen the fetus receives. A higher number of veins relative to arteries helps create the slow-flow environment necessary for a healthy pregnancy, but an excessive ratio can reduce the efficiency of oxygen uptake. Our findings suggest that the vein-to-artery ratio could be an important indicator of placental health, offering a new perspective for understanding and enabling effective early intervention treatments of pregnancy complications.

physiology↗

bioRxiv2025

Umbilical cord structure shapes feto-maternal heat exchange across mammals

The umbilical cord exhibits striking structural diversity across placental mammals; however, the consequences of such variation on physiological function are poorly understood. Combining comparative anatomy across 130 mammal species with ancestral-trait reconstruction, multimodal imaging, and physics-based transport modelling, we show that the human umbilical cord structure is uncommon in other mammals and that the ancestral umbilical cord was unspiralled, with three vessels and an allantoic duct. Across species, vessel number and cord length correlate with birth weight: four-vessel cords and the persistence of an allantoic duct occur in species with heavier neonates, while two-vessel cords are confined to small muroid rodents. Mathematical modelling predicts that oxygen delivery remains near maximal across all cord architectures, but placental heat removal depends strongly on umbilical flow, and moderately on cord length and coiling. Scaling of umbilical flow with birth weight implies that larger species approach near-maximal heat-removal capacity, while smaller species are less efficient. Finally, three-dimensional imaging of the human cord reveals a triple-helix configuration of umbilical vessels, rather than arteries simply twisting around a central vein. This, and other observed cross-sectional vessel configurations in mammals and atypical human cords, aligns with theoretically predicted arrangements that minimize inter-vessel shunting, supporting an adaptive role for cord geometry in thermal regulation function. Together, these findings reframe the umbilical cord as a heat-exchange system and link its structural diversity to evolutionary history, neonatal mass, and maternal investment, with implications for fetal resilience to environmental stress.

physiology↗

bioRxiv2025

Morphological determinants of glycosylation efficiency in Golgi cisternae

The Golgi apparatus has an intricate spatial structure characterized by flattened membrane-bound compartments, known as cisternae. Cisternae house integral membrane enzymes that catalyse glycosylation, the addition of polymeric sugars to protein cargo, which is important for the trafficking and function of the products. The unusual and specific shape of Golgi cisternae is highly conserved across eukaryotic cells, suggesting significant influence in the correct functioning of the Golgi. Motivated by experimental evidence that disruption to Golgi morphology can lead to observable changes in secreted cargo mass distribution, we develop and analyse a mathematical model of polymerisation in a cisterna that combines chemical kinetics, spatial diffusion and adsorption and desorption between lumen and membrane. Exploiting the slender geometry, we derive a non-local nonlinear advection-diffusion equation that predicts secreted cargo mass distribution as a function of cisternal shape. The model predicts a maximum cisternal thickness for which successful glycosylation is possible, demonstrates the existence of an optimal thickness for most efficient glycosylation, and suggests how kinetic and geometric factors may combine to promote or disrupt polymer production. Author SummaryThe Golgi apparatus is a universal feature of eukaryotic cells, playing a critical role in post-translational modification of secreted proteins. Its importance is demonstrated by the variety of disorders caused by errors in its function. A major post-translational modification is glycosylation: the addition of sugar chains to protein cargo. The Golgi has a distinctive structure, being comprised of stacks of thin, hollow, flattened, cisternae. We develop a mathematical model of glycosylation, combining enzyme-mediated membrane-bound reactions with intra-cisternal diffusion, to quantify the effect of cisternal morphology on processing rate. The model identifies optimal and maximal cisternal thicknesses for glycosylation to proceed, in terms of biochemical parameters. The model offers a quantitative connection between the Golgis cisternal morphology and its function.

biophysics↗

bioRxiv2025

Travelling Waves in Gene Expression: A Mathematical Model of Cell-State Dynamics in Melanoma

Melanoma is a cancer of the melanocyte, known to have an ability to readily switch between different transcriptional cell states that convey different phenotypic properties (e.g. hyper-differentiated, neural crest-like). This ability is believed to underpin intratumour heterogeneity and plastic adaptation, which contributes to resistance to therapy and immune evasion of the tumour. Therefore, understanding the mechanisms underlying acquisition of transcriptional cell states and cell-state switching is crucial for the development of therapies. We model a minimal gene regulatory network comprising three key transcription factors, whose varying gene expression encodes different melanoma cell states, and use deterministic spatiotemporal differential-equation models to study gene-expression dynamics. We exploit an approximation, based on cooperative binding of transcription factors, in which the models are piecewise-linear. We classify stable states of the local model in a biologically relevant manner and, using a naive model of intercellular communication, we explore how a population of cells can take on a shared characteristic through travelling waves of gene expression. We derive a condition determining which characteristic will become dominant, under sufficiently strong cell-cell signalling, which creates a partition of parameter space.

cancer biology↗

bioRxiv2024

Mitotic spindle orientation and dynamics are fine-tuned by anisotropic tissue stretch via NuMA localisation

Cell division orientation, which is key to cell fate and tissue morphogenesis, is influenced by mechanical forces. However, uncoupling whether divisions orient in direct response to force or indirectly via interphase cell shape remains challenging. By applying an external stretch to epithelial tissue and monitoring mitotic spindle dynamics, we show that the spindle orientation protein, NuMA, is recruited to the cell cortex earlier during mitosis in stretched tissue. This stretch-induced recruitment of NuMA coincides with the onset and subsequent amplification of dynamic spindle oscillations. We show by mathematical modelling that increased spindle oscillation indicates increased cortical force generation to orient the spindle. Additionally, we show that knockdown of NuMA reduces spindle oscillations and disrupts division orientation according to stretch and cell shape. Our results indicate that a mechanosensitive re-localisation of NuMA provides a direct response to mechanical force, fine-tuning spindle dynamics and orientation during mitosis and ensuring the accurate alignment of divisions with cell shape and anisotropic tension.

cell biology↗

bioRxiv2024

Apical Size Reduction by Macropinocytosis Alleviates Tissue Crowding

Tissue crowding represents a critical challenge to epithelial tissues, which often respond via the irreversible process of live cell extrusion. We report cell size reduction via macropinocytosis as an alternative mechanism. Macropinocytosis is triggered by tissue crowding via mechanosensory signaling, leading to substantial internalization of apical membrane and driving a reduction in apical cell size that remodels the epithelium to alleviate crowding. We report that this mechanism regulates the long-term organization of developing epithelium in response to proliferation-induced crowding but also serves as an immediate response to acute external compression. In both cases, inhibiting macropinocytosis induces a dramatic increase in cell extrusion suggesting cooperation between cell extrusion and macropinocytosis in response to compression. Our findings implicate macropinocytosis as an important regulator of dynamic epithelial remodeling.

cell biology↗

bioRxiv2023

Modelling collagen fibril self-assembly from extracellular medium in embryonic tendon

Collagen is a key structural component of multicellular organisms and is arranged in a highly organised manner. In structural tissues such as tendons, collagen forms bundles of parallel fibres between cells, which appear within a 24 hour window between E13.5 and E14.5 during mouse embryonic development. Current models assume that the organised structure of collagen requires direct cellular control, whereby cells actively lay down collagen fibrils from cell surfaces. However, such models appear incompatible with the time- and length-scales of fibril formation. We propose a phase-transition model to account for the rapid development of ordered fibrils in embryonic tendon, reducing reliance on active cellular processes. We develop phase-field crystal simulations of collagen fibrillogenesis in domains derived from electron micrographs of inter-cellular spaces in embryonic tendon and compare results qualitatively and quantitatively to observed patterns of fibril formation. To test the prediction of this phase-transition model that free protomeric collagen should exist in the intercellular spaces prior to the formation of observable fibrils, we use laser-capture microdissection, coupled with mass spectrometry, which demonstrates steadily increasing free collagen in intercellular spaces up to E13.5, followed by a rapid reduction of free collagen that coincides with the appearance of less soluble collagen fibrils. The model and measurements together provide evidence for extracellular self-assembly of collagen fibrils in embryonic mouse tendon, supporting an additional mechanism for rapid collagen fibril formation during embryonic development.

biophysics↗

bioRxiv2022

Red blood cell dynamics in extravascular biological tissues modelled as canonical disordered porous media

The dynamics of blood flow in the smallest vessels and passages of the human body, where the cellular character of blood becomes prominent, plays a dominant role in the transport and exchange of solutes. Recent studies have revealed that the micro-haemodynamics of a vascular network is underpinned by its interconnected structure, and certain structural alterations such as capillary dilation and blockage can substantially change blood flow patterns. However, for extravascular media with disordered microstructure (e.g., the porous intervillous space in the placenta), it remains unclear how the mediums structure affects the haemodynamics. Here, we simulate cellular blood flow in simple models of canonical porous media representative of extravascular biological tissue, with corroborative microfluidic experiments performed for validation purposes. For the media considered here, we observe three main effects: first, the relative apparent viscosity of blood increases with the structural disorder of the medium; second, the presence of red blood cells (RBCs) dynamically alters the flow distribution in the medium; third, increased structural disorder of the medium can promote a more homogeneous distribution of RBCs. Our findings contribute to a better understanding of the cellscale haemodynamics that mediates the relationship linking the function of certain biological tissues to their microstructure.

biophysics↗

bioRxiv2020

Spectral graph theory efficiently characterises ventilation heterogeneity in lung airway networks.

This paper introduces a linear operator for the purposes of quantifying the spectral properties of transport within resistive trees, such as airflow in lung airway networks. The operator, which we call the Maury matrix, acts only on the terminal nodes of the tree and is equivalent to the adjacency matrix of a complete graph summarising the relationships between all pairs of terminal nodes. We show that the eigenmodes of the Maury operator have a direct physical interpretation as the relaxation, or resistive, modes of the network. We apply these findings to both idealised and image-based models of ventilation in lung airway trees and show that the spectral properties of the Maury matrix characterise the flow asymmetry in these networks more concisely than the Laplacian modes, and that eigenvector centrality in the Maury spectrum is closely related to the phenomenon of ventilation heterogeneity caused by airway narrowing or obstruction. This method has applications in dimensionality reduction in simulations of lung mechanics, as well as for characterisation of models of the airway tree derived from medical images.Competing Interest StatementThe authors have declared no competing interest.View Full Text

biophysics↗

bioRxiv2018

Modelling structural determinants of ventilation heterogeneity: a perturbative approach.

We have developed a computational model of gas mixing and ventilation in the human lung represented as a bifurcating network. We have simulated multiple-breath washout (MBW), a clinical test for measuring ventilation heterogeneity (VH) in patients with obstructive lung conditions. By applying airway constrictions inter-regionally, we have predicted the response of MBW indices to obstructions and found that they detect a narrow range of severe constrictions that reduce airway radius to 10%-30% of healthy values. These results help to explain the success of the MBW test to distinguish obstructive lung conditions from healthy controls. Further, we have used a perturbative approach to account for intra-regional airway heterogeneity that avoids modelling each airway individually. We have found, for random airway heterogeneity, that the variance in MBW indices is greater when indices are already elevated due to constrictions. By quantifying this effect, we have shown that variability in lung structure and mechanical properties alone can lead to clinically significant variability in LCI and Scond, but only in cases simulating obstructive lung conditions. This method is a computationally efficient way to probe the lungs sensitivity to structural changes, and to quantify uncertainty in predictions due to random variations in lung mechanical and structural properties.

biophysics↗

bioRxiv2018

A mechanosensitive RhoA pathway that protects epithelia against acute tensile stress.

Adherens junctions are tensile structures that couple epithelial cells together. Junctional tension can arise from cell-intrinsic application of contractility or from the cell-extrinsic forces of tissue movement. In all these circumstances, it is essential that epithelial integrity be preserved despite the application of tensile stress. In this study, we identify junctional RhoA as a mechanosensitive signaling pathway that responds to epithelial stress. The junctional specificity of this response is mediated by the heterotrimeric protein G12, which is recruited by E-cadherin and, in turn, recruits p114 RhoGEF to activate RhoA. Further, we identify Myosin VI as a key mechanosensor, based on its intrinsic capacity to anchor E-cadherin to F-actin when exposed to tensile load. Tension-activated RhoA signaling was necessary to preserve epithelial integrity, which otherwise undergoes fracture when monolayer stress is acutely increased by calyculin. Paradoxically, this homeostatic RhoA signaling pathway increases junctional actomyosin, a contractile response that might be expected to itself promote fracture. Simulations of a vertex-based model revealed that the protective effect of RhoA signaling can be explained through increased yield limit at multicellular vertices, where experiments showed p114 RhoGEF was necessary to increase E-cadherin and promote actin assembly and organization.

cell biology↗

bioRxiv2017

Whole-tissue stretching reveals a shape-dependent mechanism of orienting the mitotic spindle and a role for mechanical stress in cueing mitosis

Distinct mechanisms involving cell shape and mechanical force are known to influence the rate and orientation of division in cultured cells. However, uncoupling the impact of shape and force in tissues remains challenging. Combining stretching of Xenopus laevis tissue with a novel method of inferring relative mechanical stress, we find separate roles for cell shape in orientating division and mechanical stress in cueing division. We demonstrate that division orientation is best predicted by an axis of cell shape defined by the position of tricellular junctions (TCJs), which aligns exactly with the principal axis of local cell stress rather than the tissue-level stress. The alignment of division to cell shape requires functional cadherin and the localisation of the spindle orientation protein, LGN, to TCJs, but is not sensitive to relative cell stress magnitude. In contrast, cell proliferation rate is more directly regulated by mechanical stress, being correlated with relative isotropic stress, and can be decoupled from cell shape when myosin II is depleted.

cell biology↗

bioRxiv2017

Three-dimensional plant architecture and sunlit-shaded dynamics: A stochastic model to enable high-throughput physiological analysis

Background and AimsDiurnal changes in solar position and intensity combined with the structural complexity of plant architecture result in highly variable and dynamic light patterns within the plant canopy. This affects productivity through the complex ways that photosynthesis responds to changes in light intensity. Current methods to characterise light dynamics, such as ray-tracing, are able to produce data with excellent spatio-temporal resolution but are computationally intensive and the resultant data are complex and high dimensional. This necessitates development of more economical models for summarising the data and for simulating realistic light patterns over the course of a day.\n\nMethodsHigh-resolution reconstructions of field-grown plants are assembled in various configurations to form canopies, and a forward ray-tracing algorithm is applied to the canopies to compute light dynamics at high (1 minute) temporal resolution. From the ray-tracer output, the sunlit or shaded state for each patch on the plants is determined, and these data are used to develop a novel stochastic model for the sunlit-shaded patterns. The model is designed to be straightforward to fit to data using maximum likelihood estimation, and fast to simulate from.\n\nKey ResultsFor a wide range of contrasting 3D canopies, the stochastic model is able to summarise, and replicate in simulations, key features of the light dynamics. When light patterns simulated from the stochastic model are used as input to a model of photoinhibition, the predicted reduction in carbon gain is similar to that from calculations based on the (extremely costly) ray-tracer data.\n\nConclusionsThe model provides a way to summarise highly complex data in a small number of parameters, and a cost-effective way to simulate realistic light patterns. Simulations from the model will be particularly useful for feeding into larger-scale photosynthesis models for calculating how light dynamics affects the photosynthetic productivity of canopies.

plant biology↗