Abstract
The study of organoids, artificially grown cell aggregates with the functionality and small-scale anatomy of real organs, is one of the most active areas of research in biology and ...biophysics, yet the basic physical origins of their different morphologies remain poorly understood. Here, we propose a mechanistic theory of epithelial shells which resemble small-organoid morphologies. Using a 3D surface tension-based vertex model, we reproduce the characteristic shapes from branched and budded to invaginated structures. We find that the formation of branched morphologies relies strongly on junctional activity, enabling temporary aggregations of topological defects in cell packing. To elucidate our numerical results, we develop an effective elasticity theory, which allows one to estimate the apico-basal polarity from the tissue-scale modulation of cell height. Our work provides a generic interpretation of the observed epithelial shell morphologies, highlighting the role of physical factors such as differential surface tension, cell rearrangements, and tissue growth.
Cell rearrangements are fundamental mechanisms driving large-scale deformations of living tissues. In three-dimensional (3D) space-filling cell aggregates, cells rearrange through local topological ...transitions of the network of cell-cell interfaces, which is most conveniently described by the vertex model. Since these transitions are not yet mathematically properly formulated, the 3D vertex model is generally difficult to implement. The few existing implementations rely on highly customized and complex software-engineering solutions, which cannot be transparently delineated and are thus mostly non-reproducible. To solve this outstanding problem, we propose a reformulation of the vertex model. Our approach, called Graph Vertex Model (GVM), is based on storing the topology of the cell network into a knowledge graph with a particular data structure that allows performing cell-rearrangement events by simple graph transformations. Importantly, when these same transformations are applied to a two-dimensional (2D) polygonal cell aggregate, they reduce to a well-known T1 transition, thereby generalizing cell-rearrangements in 2D and 3D space-filling packings. This result suggests that the GVM's graph data structure may be the most natural representation of cell aggregates and tissues. We also develop a Python package that implements GVM, relying on a graph-database-management framework Neo4j. We use this package to characterize an order-disorder transition in 3D cell aggregates, driven by active noise and we find aggregates undergoing efficient ordering close to the transition point. In all, our work showcases knowledge graphs as particularly suitable data models for structured storage, analysis, and manipulation of tissue data.
Morphogenesis of an organism requires the development of its parts to be coordinated in time and space. While past studies concentrated on defined cell populations, a synthetic view of the ...coordination of these events in a whole organism is needed for a full understanding. Drosophila gastrulation begins with the embryo forming a ventral furrow, which is eventually internalized. It is not understood how the rest of the embryo participates in this process. Here we use multiview selective plane illumination microscopy coupled with infrared laser manipulation and mutant analysis to dissect embryo-scale cell interactions during early gastrulation. Lateral cells have a denser medial-apical actomyosin network and shift ventrally as a compact cohort, whereas dorsal cells become stretched. We show that the behaviour of these cells affects furrow internalization. A computational model predicts different mechanical properties associated with tissue behaviour: lateral cells are stiff, whereas dorsal cells are soft. Experimental analysis confirms these properties in vivo.
Using a three-dimensional active vertex model, we numerically study the shapes of strained unsupported epithelial monolayers subject to active junctional noise due to stochastic binding and unbinding ...of myosin. We find that while uniaxial, biaxial, and isotropic in-plane compressive strains do lead to the formation of longitudinal, herringbone pattern, and labyrinthine folds, respectively, the villus morphology characteristic of, e.g., the small intestine appears only if junctional tension fluctuations are strong enough to fluidize the tissue. Moreover, the fluidized epithelium features villi even in the absence of compressive strain provided that the apico-basal differential surface tension is large enough. We analyze several details of the different epithelial forms including the role of strain rate and the modulation of tissue thickness across folds. Our results show that even unsupported, non-patterned epithelia can form nontrivial morphologies.
Graphic abstract
As epithelial tissues develop, groups of cells related by descent tend to associate in clonal populations rather than dispersing within the cell layer. While this is frequently assumed to be a result ...of differential adhesion, precise mechanisms controlling clonal cohesiveness remain unknown. Here we employ computational simulations to modulate epithelial cell size in silico and show that junctions between small cells frequently collapse, resulting in clone-cell dispersal among larger neighbors. Consistent with similar dynamics in vivo, we further demonstrate that mosaic disruption of Drosophila Tor generates small cells and results in aberrant clone dispersal in developing wing disc epithelia. We propose a geometric basis for this phenomenon, supported in part by the observation that soap-foam cells exhibit similar size-dependent junctional rearrangements. Combined, these results establish a link between cell-size pleomorphism and the control of epithelial cell packing, with potential implications for understanding tumor cell dispersal in human disease.
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•Growth heterogeneity induces dispersal of small cells within mosaic epithelial tissue•Dispersal of small cells is not due to differential activity of junctional proteins•Geometric effects of growth discrepancies are sufficient to disperse aberrant cells
Although abnormal cell size variation is one of the defining characteristics of several cancers, the possible role of differential cell size on disease progression is unclear. Ramanathan et al. discover that the geometric effects of growth heterogeneity can disperse aberrant cells within mosaic epithelial tissue.
The shape of spatially modulated epithelial morphologies such as villi and crypts is usually associated with the epithelium-stroma area mismatch leading to buckling. We propose an alternative ...mechanical model based on intraepithelial stresses generated by differential tensions of apical, lateral, and basal sides of cells as well as on the elasticity of the basement membrane. We use it to theoretically study longitudinal folds in simple epithelia and we identify four types of corrugated morphologies: compact, invaginated, evaginated, and wavy. The obtained tissue contours and thickness profiles are compared to epithelial folds observed in invertebrates and vertebrates, and for most samples, the agreement is within the estimated experimental error. Our model establishes the groove-crest modulation of tissue thickness as a morphometric parameter that can, together with the curvature profile, be used to estimate the relative differential apicobasal tension in the epithelium.
We theoretically explore fluidization of epithelial tissues by active T1 neighbor exchanges. We show that the geometry of cell-cell junctions encodes important information about the local features of ...the energy landscape, which we support by an elastic theory of T1 transformations. Using a 3D vertex model, we show that the degree of active noise driving forced cell rearrangements governs the stress-relaxation timescale of the tissue. We study tissue response to in-plane shear at different timescales. At short time, the tissue behaves as a solid, whereas its long-time fluid behavior can be associated with an effective viscosity which scales with the rate of active T1 transformations. Furthermore, we develop a coarse-grained theory, where we treat the tissue as an active fluid and confirm the results of the vertex model. The impact of cell rearrangements on tissue shape is illustrated by studying axial compression of an epithelial tube.
Syncytial architecture is an evolutionarily-conserved feature of the germline of many species and plays a crucial role in their fertility. However, the mechanism supporting syncytial organization is ...largely unknown. Here, we identify a corset-like actomyosin structure within the syncytial germline of Caenorhabditis elegans, surrounding the common rachis. Using laser microsurgery, we demonstrate that actomyosin contractility within this structure generates tension both in the plane of the rachis surface and perpendicular to it, opposing membrane tension. Genetic and pharmacological perturbations, as well as mathematical modeling, reveal a balance of forces within the gonad and show how changing the tension within the actomyosin corset impinges on syncytial germline structure, leading, in extreme cases, to sterility. Thus, our work highlights a unique tissue-level cytoskeletal structure, and explains the critical role of actomyosin contractility in the preservation of a functional germline.
Cell rearrangements are fundamental mechanisms driving large-scale deformations of living tissues. In three-dimensional (3D) space-filling cell aggregates, cells rearrange through local topological ...transitions of the network of cell-cell interfaces, which is most conveniently described by the vertex model. Since these transitions are not yet mathematically properly formulated, the 3D vertex model is generally difficult to implement. The few existing implementations rely on highly customized and complex software-engineering solutions, which cannot be transparently delineated and are thus mostly non-reproducible. To solve this outstanding problem, we propose a reformulation of the vertex model. Our approach, called Graph Vertex Model (GVM), is based on storing the topology of the cell network into a knowledge graph with a particular data structure that allows performing cell-rearrangement events by simple graph transformations. Importantly, when these same transformations are applied to a two-dimensional (2D) polygonal cell aggregate, they reduce to a well-known T1 transition, thereby generalizing cell-rearrangements in 2D and 3D space-filling packings. This result suggests that the GVM's graph data structure may be the most natural representation of cell aggregates and tissues. We also develop a Python package that implements GVM, relying on a graph-database-management framework Neo4j. We use this package to characterize an order-disorder transition in 3D cell aggregates, driven by active noise and we find aggregates undergoing efficient ordering close to the transition point. In all, our work showcases knowledge graphs as particularly suitable data models for structured storage, analysis, and manipulation of tissue data.
Macroscopic properties and shapes of biological tissues depend on the remodeling of cell-cell junctions at the microscopic scale. We propose a theoretical framework that couples a vertex model of ...solid confluent tissues with the dynamics describing generation of local force dipoles in the junctional actomyosin. Depending on the myosin turnover rate, junctions either preserve stable length or collapse to initiate cell rearrangements. We find that noise can amplify and sustain transient oscillations to the fixed point, giving rise to quasiperiodic junctional dynamics. We also discover that junctional stability is affected by cell arrangements and junctional rest tensions, which may explain junctional collapse during convergence and extension in embryos.
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