Biology subjects

Torres-Sanchez, A.

Publications and source records attributed to Torres-Sanchez, A..

8 recordsLinked to original sources

bioRxiv2025

Theory of multiscale epithelial mechanics under stretch: from active gels to vertex models

Epithelial monolayers perform a variety of mechanical functions, which include maintaining a cohesive barrier or developing 3D shapes, while undergoing stretches over a wide range of magnitudes and loading rates. To perform these functions, they rely on a hierarchical organization, which spans molecules, cytoskeletal networks, adhesion complexes and junctional networks up to the tissue scale. While the molecular understanding and ability to manipulate cytoskeletal components within cells is rapidly increasing, how these components integrate to control tissue mechanics is far less understood, partly due to the disconnect between theoretical models of sub-cellular dynamics and those at a tissue scale. To fill this gap, here we propose a formalism bridging active-gel models of the actomyosin cortex and 3D vertex-like models at a tissue scale. We show that this unified framework recapitulates a number of seemingly disconnected epithelial time-dependent phenomenologies, including stress relaxation following stretch/unstretch maneuvers, active flattening after buckling, or nonreciprocal and non-affine pulsatile contractions. We further analyze tissue dynamics probed by a novel experimental setup operating in a pressure-controlled ensemble. Overall, the proposed framework systematically connects sub-cellular cortical dynamics and tissue mechanics, and ties a variety of epithelial phenomenologies to a common sub-cellular origin.

biophysics↗

bioRxiv2025

Mechanical fracturing of the extracellular matrix patterns the vertebrate heart

Pattern formation is fundamental to embryonic morphogenesis. In the zebrafish heart, spatially confined single-cell delamination in the ventricle outer curvature initiates trabeculation, a conserved morphogenetic process critical for heart function and embryonic life. Yet, what confines delamination in the ventricle outer curvature remains ill-understood. Contrary to the prevailing notion of patterning through biochemical signals, we now show that mechanical fracturing of the cardiac extracellular matrix (cECM) patterns delamination in the outer curvature. cECM fractures emerge preferentially in the outer curvature, cells delaminate into these fractures and experimental blocking of fractures blocks delamination. These fractures display characteristic signature of mechanical defects and myocardial tissue contractility is sufficient to fracture the cECM, independent of molecular signals, enzymatic activity, or delamination events. Notably, the anisotropic geometry of myocardial tissue generates higher mechanical strain in the outer curvature, thereby locally patterning cECM fractures and delamination. Consequently, cECM fractures evolve in response to dynamic changes in tissue geometry, and experimental manipulation of tissue geometry is sufficient to alter the fracture pattern. Together, our findings underscore mechanical fractures as a morphogenetic strategy, and more generally, corroborate the long-standing but understudied paradigm that tissue form-function can feed back to steer its own patterning.

developmental biology↗

bioRxiv2023

Patterning of membrane adhesion under hydraulic stress

Hydraulic fracturing plays a major role in the formation of biological lumens during embryonic development, when the accumulation of pressurized fluid leads to the formation of microlumens that fracture cell-cell contacts and later evolve to form a single large lumen. However, the physical principles underpinning the formation of a pattern of microlumens from a pristine adhesion and their subsequent coarsening are poorly understood. Here, we use giant unilamellar vesicles adhered to a supported lipid bilayer and subjected to osmotic stress to generate and follow the dynamics of hydraulic fracturing akin to those in cells. Using this simplified system together with theoretical modelling and numerical simulations, we provide a mechanistic understanding of the nucleation of hydraulic cracks, their spatial patterns and their coarsening dynamics. Besides coarsening, we show that microlumens can irreversibly bud out of the membrane, reminiscent of endocytic vesicles in cell-cell adhesion. By establishing the physics of patterning and dynamics of hydraulic cracks, our work unveils the mechanical constraints for the biological regulation of hydraulically-driven adhesion remodeling.

biophysics↗

bioRxiv2022

Polarity-driven three-dimensional spontaneous rotation of a cell doublet

Cell mechanical interactions play a fundamental role in the self-organisation of organisms. How these interactions drive coordinated cell movement in three-dimensions remains unclear. Here we report that cell doublets embedded in a 3D extracellular matrix undergo spontaneous rotations and we investigate the rotation mechanism using live cell imaging, quantitative measurements, mechanical perturbations, and theory. We find that rotation is driven by a polarized distribution of myosin within cell cortices. The mismatched orientation of this polarized distribution breaks the doublet mirror symmetry. In addition, cells adhere at their interface through adherens junctions and with the extracellular matrix through focal contacts near myosin clusters. Using a physical theory describing the doublet as two interacting active surfaces, we find that rotation is driven by myosin-generated gradients of active tension, whose profiles are dictated by interacting cell polarity axes. We show that interface three-dimensional shapes can be understood from the Curie principle: shapes symmetries are related to broken symmetries of myosin distribution in cortices. To test for the rotation mechanism, we suppress myosin clusters using laser ablation and we generate new myosin clusters by optogenetics. Our work clarifies how polarity-oriented active mechanical forces drive collective cell motion in three dimensions.

biophysics↗

bioRxiv2022

Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I

Oocytes form before birth and remain viable for several decades before fertilisation. Although poor oocyte quality accounts for the majority of female fertility problems, little is known about how oocytes maintain cellular fitness, nor why they eventually decline with age. Reactive oxygen species (ROS) produced as by-products of mitochondrial activity are associated with lower rates of fertilisation and embryo survival. Yet, how healthy oocytes balance essential mitochondrial activity with the production of ROS is unknown. Here, we show that oocytes evade ROS by remodelling the mitochondrial electron transport chain (ETC) through elimination of complex I. Combining live-cell imaging and proteomics in human and Xenopus oocytes, we find that early oocytes exhibit greatly reduced levels of complex I. This is accompanied by a highly active mitochondrial unfolded protein response, which is indicative of an imbalanced ETC. Biochemical and functional assays confirm that complex I is neither assembled nor active in early oocytes. Thus, we report the first physiological cell type without complex I in animals. Our findings clarify why patients suffering from complex I related hereditary mitochondrial diseases do not experience subfertility, in contrast to diseases involving other mitochondrial complexes. Complex I suppression represents an evolutionary-conserved strategy that allows longevity while maintaining biological activity in long-lived oocytes.

cell biology↗

bioRxiv2022

Mapping mechanical stress in curved epithelia of designed size and shape

The function of organs such as lungs, kidneys and mammary glands relies on the three-dimensional geometry of their epithelium. To adopt shapes such as spheres, tubes and ellipsoids, epithelia generate mechanical stresses that are generally unknown. Here we engineered curved epithelial monolayers of controlled size and shape and mapped their state of stress. We designed pressurized epithelia with circular, rectangular and ellipsoidal footprints. We developed a computational method to map the stress tensor in these epithelia. This method establishes a direct correspondence between epithelial shape and mechanical stress without assumptions of material properties. In epithelia with spherical geometry spanning more than one order of magnitude in radius, we show that stress weakly increases with areal strain in a size-independent manner. In epithelia with rectangular and ellipsoidal cross-section we found pronounced stress anisotropies consistent with the asymmetric distribution of tractions measured at the cell-substrate contact line. In these anisotropic profiles, cell shape tended to align with the direction of maximum principal stress but this alignment was non-universal and depended on epithelial geometry. Besides interrogating the fundamental mechanics of epithelia over a broad range of sizes and shapes, our approach will enable a systematic study of how geometry and stress influence epithelial fate and function in three-dimensions.

biophysics↗

bioRxiv2022

Interacting active surfaces: a model for three-dimensional cell aggregates

We introduce a modelling and simulation framework for cell aggregates in three dimensions based on interacting active surfaces. Cell mechanics is captured by a physical description of the acto-myosin cortex that includes cortical flows, viscous forces, active tensions, and bending moments. Cells interact with each other via short-range forces capturing the effect of adhesion molecules. We discretise the model constitutive equations using a finite element method, and provide a parallel implementation in C++. We discuss examples of application of this framework to simulations involving small and medium-sized aggregates: we consider the shape and dynamics of a cell doublet, a planar cell sheet, and a growing cell aggregate. This framework opens the door to the systematic exploration of the cell to tissue-scale mechanics of cell aggregates, which plays a key role in the morphogenesis of embryos and organoids. Author summaryUnderstanding how tissue-scale morphogenesis arises from cell mechanics and cell-cell interactions is a fundamental question in developmental biology. Here we propose a mathematical and numerical framework to address this question. In this framework, each cell is described as an active surface representing the cell acto-myosin cortex, subjected to flows and shape changes according to active tensions, and to interaction with neighbouring cells in the tissue. Our method describes cellular processes such as cortical flows, cell adhesion, and cell shape changes in a deforming three-dimensional cellular aggregate. To solve the equations numerically, we employ a finite element discretisation, which allows us to solve for flows and cell shape changes with arbitrary resolution. We discuss applications of our framework to describe cell-cell adhesion in doublets, three-dimensional cell shape in a simple epithelium, and three-dimensional growth of a cell aggregate.

biophysics↗

bioRxiv2020

ECM remodeling and spatial cell cycle coordination determine tissue growth kinetics

During development, multicellular organisms undergo stereotypical patterns of tissue growth to yield organs of highly reproducible sizes and shapes. How this process is orchestrated remains unclear. Analysis of the temporal dynamics of tissue growth in the Drosophila abdomen reveals that cell cycle times are spatially correlated and that growth termination occurs through the rapid emergence of a population of arrested cells rather than a gradual slowing down of cell cycle time. Reduction in apical tension associated with tissue crowding has been proposed as a developmental growth termination mechanism. Surprisingly, we find that growth arrest in the abdomen occurs while apical tension increases, showing that in this tissue a reduction in tension does not underlie the mechanism of growth arrest. However, remodeling of the extracellular matrix is necessary for tissue expansion. Thus, changes in the tissue microenvironment, and a rapid exit from proliferation, control the formation of the adult Drosophila abdomen.

developmental biology↗