Biology subjects

McEvoy, E.

Publications and source records attributed to McEvoy, E..

8 recordsLinked to original sources

bioRxiv2026

Cellular hydraulics ensures robust endothelial-to-haematopoietic transition

Haematopoietic stem and progenitor cells (HSPCs) emerge from specialised haemogenic endothelial cells (HECs) in the ventral wall of the dorsal aorta (VDA) through a process known as endothelial-to-haematopoietic transition (EHT). During EHT, elongated HECs undergo actomyosin-driven rounding and extrusion, a mechanically demanding transformation that requires cell integrity to be maintained. Here, we identify an osmo-hydraulic volume-regulation mechanism that enables HECs to adapt to and withstand this mechanical challenge. Haemodynamic forces increase Piezo-dependent calcium ion activity in ventral endothelial cells, while Piezo activation promotes HEC swelling. Combined genetic and pharmacological analyses support a pathway in which Piezo-mediated swelling triggers VRAC-dependent osmolyte efflux and Aqp1a.1-mediated water efflux to reduce HEC volume. Disrupting either osmolyte or water efflux causes excessive HEC swelling, compromises HEC integrity and reduces HSPC production. Together, our findings establish osmo-hydraulic volume regulation as a mechanism that preserves cellular robustness during EHT and support a model in which aquaporins act as pressure-relief valves, dissipating intracellular hydrostatic pressure to sustain HEC survival and definitive haematopoiesis.

cell biology↗

bioRxiv2025

Stress-dependent growth of breast cancer models emerges from a cellular volume checkpoint

Mechanoresponsive cell proliferation is a feature of growing tumours, despite the suppression of many other regulatory checkpoints in cancer, but the underlying cell-scale mechanisms driving this behaviour have not yet been established. In this study we propose a biophysical model for cell growth as governed by actively controlled osmolarity, which we integrate with a discrete particle framework to simulate growth and remodelling of breast cancer spheroids. Confinement and biomechanical feedback from the extracellular environment are analysed through a neuralnetwork-accelerated finite element solver. Combining the framework with experiments, our model reveals that stress-dependent spheroid growth can arise from a sizing checkpoint for mitosis. Under sufficient extracellular loading, cell growth is restricted by high hydrostatic forces in competition with osmotic pressure from biomolecule synthesis, which prevents cells from surpassing a critical volume. Our model provides new insight into mechanosensitive growth arrest in breast cancer, potentially serving as a computational tool for analysing growth in a wider range of normal and malignant biological tissues.

cancer biology↗

bioRxiv2024

4D bioprinting shape-morphing tissues in granular support hydrogels: Sculpting structure and guiding maturation

During embryogenesis, organs undergo dynamic shape transformations that sculpt their final shape, composition, and function. Despite this, current organ bioprinting approaches typically employ bioinks that restrict cell-generated morphogenetic behaviours resulting in structurally static tissues. Here, we introduce a novel platform that enables the bioprinting of tissues that undergo programmable and predictable 4D shape-morphing driven by cell-generated forces. Our method utilises embedded bioprinting to deposit collagen-hyaluronic acid bioinks within yield-stress granular support hydrogels that can accommodate and regulate 4D shape-morphing through their viscoelastic properties. Importantly, we demonstrate precise control over 4D shape-morphing by modulating factors such as the initial print geometry, cell phenotype, bioink composition, and support hydrogel viscoelasticity. Further, we observed that shape-morphing actively sculpts cell and extracellular matrix alignment along the principal tissue axis through a stress-avoidance mechanism. To enable predictive design of 4D shape-morphing patterns, we developed a finite element model that accurately captures shape evolution at both the cellular and tissue levels. Finally, we show that programmed 4D shape-morphing enhances the structural and functional properties of iPSC-derived heart tissues. This ability to design, predict, and program 4D shape-morphing holds great potential for engineering organ rudiments that recapitulate morphogenetic processes to sculpt their final shape, composition, and function.

bioengineering↗

bioRxiv2022

A novel mechanobiological model of bone metastasis reveals that mechanical stimulation inhibits the pro-osteoclastogenic effects of breast cancer cells

Bone is highly susceptible to cancer metastasis, and both tumour and bone cells enable tumour invasion through a "vicious cycle" of biochemical signalling. Tumor metastasis into bone also alters biophysical cues to both tumour and bone cells, which are highly sensitive to their mechanical environment. However, the mechanobiological feedback between these cells that perpetuates this cycle has not been studied. Here, we develop highly novel in vitro and computational models to provide an advanced understanding of how tumor growth is regulated by the synergistic influence of tumour-bone cell signaling and mechanobiological cues. In particular, we develop the first multicellular healthy and metastatic bone models, which can account for physiological mechanical signals within a custom bioreactor. These models successfully recapitulated mineralization, mechanobiological responses, osteolysis and metastatic activity. Ultimately we demonstrate that mechanical stimulus provided protective effects against tumor-induced osteolysis, confirming the importance of mechanobiological factors in bone metastasis development.

bioengineering↗

bioRxiv2021

Modeling the three-way feedback between cellular contractility, actin polymerization, and adhesion turnover resolves the contradictory effects of RhoA and Rac1 on endothelial junction dynamics

The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to atherosclerosis and tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the maintenance of endothelial junctions as dependent on the crosstalk between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Our theoretical model reveals that active cell tension can stabilize cadherin bonds within an adhesion, but excessive RhoA signaling can drive bond dissociation and junction failure. While Rac1-mediated actin polymerization aids gap closure, high levels of Rac1 may also facilitate junction weakening. Combining the modeling framework with novel experiments, we identify how dynamic rupture and heal cycles emerge and, further, describe why gaps tend to localize at multi-cell contacts. Beyond, our analysis also indicates that a critical balance between RhoA and Rac1 expression is required to maintain junction stability and limit endothelial dysfunction. The model predicts how pharmacological modulation of actin polymerization and cell contractility impacts junction stability, with predictions subsequently validated experimentally. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes.

biophysics↗

bioRxiv2020

Influence of multi-axial dynamic constraint on cell alignment and contractility in engineered tissues

In this study an experimental rig is developed to investigate the influence of tissue constraint and cyclic loading on cell alignment and active cell force generation in uniaxial and biaxial engineered tissues constructs. Addition of contractile cells to collagen hydrogels dramatically increases the measured forces in uniaxial and biaxial constructs under dynamic loading. This increase in measured force is due to active cell contractility, as is evident from the decreased force after treatment with cytochalasin-D. Prior to dynamic loading, cells are highly aligned in uniaxially constrained tissues but are uniformly distributed in biaxially constrained tissues, demonstrating the importance of tissue constraints on cell alignment. Dynamic uniaxial stretching resulted in a slight increase in cell alignment in the centre of the tissue, whereas dynamic biaxial stretching had no significant effect on cell alignment. Our active modelling framework accurately predicts our experimental trends and suggests that a slightly higher (3%) total SF formation occurs at the centre of a biaxial tissue compared to the uniaxial tissue. However, high alignment of SFs and lateral compaction in the case of the uniaxially constrained tissue results in a significantly higher (75%) actively generated cell contractile stress, compared to the biaxially constrained tissue. These findings have significant implications for engineering of contractile tissue constructs.

cell biology↗

bioRxiv2020

Gap Junctions Amplify Spatial Variations in Cell Volume in Proliferating Solid Tumors

Cancer progression is driven by cell proliferation, apoptosis, and matrix invasion, which in turn depend on a myriad of factors including microenvironment stiffness, nutrient supply, and intercellular communication. Cell proliferation is regulated by volume, but in 3D clusters it remains unclear how multiple cells interact to control their size. In this study, we propose a mechano-osmotic model to investigate the evolution of volume dynamics within multicellular systems. Volume control depends on an interplay between multiple cellular constituents, including gap junctions, mechanosensitive ion channels, energy consuming ion transporters, and the actomyosin cortex, that coordinate to manipulate cellular osmolarity. In connected cells, mechanical loading is shown to significantly affect how these components cooperate to transport ions, and precise volume control is impacted by the emergence of osmotic pressure gradients between cells. Consequent increases in cellular ion concentrations drive swelling, while a loss of ions impedes the compression resistance of cells. Combining the modeling framework with novel experiments, we identify how gap junctions can amplify spatial variations in cell volume within multicellular spheroids and, further, describe how the process depends on proliferation-induced solid stress. Our model provides new insight into the role of gap junctions in cancer progression and can help guide the development of therapeutics that target inter- and extra-cellular ion transport.

biophysics↗

bioRxiv2020

An Active Chemo-mechanical Model to Predict Adhesion and Microenvironmental Regulation of 3D Cell Shapes

Cell shapes are known to regulate cytoskeletal organization, stiffness and the ability of cells to migrate and proliferate. Yet a quantitative understanding of the fundamental biochemical and biophysical mechanisms that determine the cell shapes is currently not available. In this study, we developed a chemo-mechanical feedback model to predict how adhesions and the properties of the 3D microenvironment regulate cell shapes. We find that the cells in 3D collagen matrices remain round or adopt an elongated shape depending on the density of active integrins, the level of contractility regulated by mechanosensitive signaling pathways and the density and mechanics of the matrix. While the formation of actin fibers that run along the cell body mediated by integrins and matrix stiffness drive elongation of cells, the cortical and membrane tension resist elongation. Based on the competition between these mechanisms, we derive phase diagrams for cell shape in the space spanned by the density of active adhesions and the level of biochemical signaling that controls contractility. Our predictions are validated by studying the shapes of HT1080 cells cultured in collagen gels of varying densities and using pharmacological treatments to regulate adhesions and contractility. The predictions of the model are found to be in excellent agreement with our experiments and data reported on a number of cell types in the literature.

biophysics↗