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How dividing cells stay in shape Studies of the mechanism of cytokinesis, the process by which a mother cell undergoes cleavage to form two separated daughter cells, often focus on the action of the contractile actomyosin ring at the cell equator. Ewa Paluch and colleagues instead investigate the mechanics of the actomyosin cortex found at the cell poles during cytokinesis. They find that the presence of a contractile polar cortex makes cytokinesis an inherently unstable process that can result in misalignment of the constriction ring. They propose that the membrane blebs forming at the poles of dividing cells stabilize the position by releasing cortical contractility. These findings reveal an inherent instability in the shape of a dividing cell and demonstrate a novel mechanism that helps to limit shape instability. Cytokinesis, the physical separation of daughter cells at the end of mitosis, requires precise regulation of the mechanical properties of the cell periphery 1 , 2 . Although studies of cytokinetic mechanics mostly focus on the equatorial constriction ring 3 , a contractile actomyosin cortex is also present at the poles of dividing cells 2 , 4 . Whether polar forces influence cytokinetic cell shape and furrow positioning remains an open question. Here we demonstrate that the polar cortex makes cytokinesis inherently unstable. We show that limited asymmetric polar contractions occur during cytokinesis, and that perturbing the polar cortex leads to cell shape oscillations, resulting in furrow displacement and aneuploidy. A theoretical model based on a competition between cortex turnover and contraction dynamics accurately accounts for the oscillations. We further propose that membrane blebs, which commonly form at the poles of dividing cells 5 and whose role in cytokinesis has long been enigmatic, stabilize cell shape by acting as valves releasing cortical contractility. Our findings reveal an inherent instability in the shape of the dividing cell and unveil a novel, spindle-independent mechanism ensuring the stability of cleavage furrow positioning.

Defects in nuclear morphology often correlate with the onset of disease, including cancer, progeria, cardiomyopathy, and muscular dystrophy. However, the mechanism by which a cell controls its nuclear shape is unknown. Here, we use adhesive micropatterned surfaces to control the overall shape of fibroblasts and find that the shape of the nucleus is tightly regulated by the underlying cell adhesion geometry. We found that this regulation occurs through a dome-like actin cap that covers the top of the nucleus. This cap is composed of contractile actin filament bundles containing phosphorylated myosin, which form a highly organized, dynamic, and oriented structure in a wide variety of cells. The perinuclear actin cap is specifically disorganized or eliminated by inhibition of actomyosin contractility and rupture of the LINC complexes, which connect the nucleus to the actin cap. The organization of this actin cap and its nuclear shape-determining function are disrupted in cells from mouse models of accelerated aging (progeria) and muscular dystrophy with distorted nuclei caused by alterations of A-type lamins. These results highlight the interplay between cell shape, nuclear shape, and cell adhesion mediated by the perinuclear actin cap.

Cells have evolved multiple mechanisms to apprehend and adapt finely to their environment. Here we report a new cellular ability, which we term “curvotaxis” that enables the cells to respond to cell-scale curvature variations, a ubiquitous trait of cellular biotopes. We develop ultra-smooth sinusoidal surfaces presenting modulations of curvature in all directions, and monitor cell behavior on these topographic landscapes. We show that adherent cells avoid convex regions during their migration and position themselves in concave valleys. Live imaging combined with functional analysis shows that curvotaxis relies on a dynamic interplay between the nucleus and the cytoskeleton—the nucleus acting as a mechanical sensor that leads the migrating cell toward concave curvatures. Further analyses show that substratum curvature affects focal adhesions organization and dynamics, nuclear shape, and gene expression. Altogether, this work identifies curvotaxis as a new cellular guiding mechanism and promotes cell-scale curvature as an essential physical cue. The effect that microscale surface curvature has on cell migration has not been evaluated. Here the authors fabricate sinusoidal 3D surfaces and show that the cell nucleus and cytoskeleton cooperate to guide cells to concave valleys in a process they coin curvotaxis.

Because differentiation of mesenchymal stem cells (MSCs) is enacted through the integration of soluble signaling factors and physical cues, including substrate architecture and exogenous mechanical stimulation, it is important to understand how micropatterned biomaterials may be optimized to enhance differentiation for the formation of functional soft tissues. In this work, macroscopic strain applied to MSCs in an aligned nanofibrous microenvironment elicited cellular and nuclear deformations that varied depending on scaffold orientation. Reorientation of aligned, oriented MSCs corresponded at the microscopic scale with the affine approximation of their deformation based on macroscopic strains. Moreover, deformations at the subcellular scale corresponded with scaffold orientation, with changes in nuclear shape depending on the direction of substrate alignment. Notably, these deformations induced changes in gene expression that were also dependent on scaffold and cell orientations. These findings demonstrate that directional biases in substrate microstructure convey direction-dependent mechanosensitivity to MSCs and provide an experimental framework in which to explore the mechanistic underpinnings of this response.

Collective cell migration is a highly regulated process involved in wound healing, cancer metastasis, and morphogenesis. Mechanical interactions among cells provide an important regulatory mechanism to coordinate such collective motion. Using a self-propelled Voronoi (SPV) model that links cell mechanics to cell shape and cell motility, we formulate a generalized mechanical inference method to obtain the spatiotemporal distribution of cellular stresses from measured traction forces in motile tissues and show that such traction-based stresses match those calculated from instantaneous cell shapes. We additionally use stress information to characterize the rheological properties of the tissue. We identify a motility-induced swim stress that adds to the interaction stress to determine the global contractility or extensibility of epithelia. We further show that the temporal correlation of the interaction shear stress determines an effective viscosity of the tissue that diverges at the liquid–solid transition, suggesting the possibility of extracting rheological information directly from traction data.

The cytoskeleton and its components — actin, microtubules and intermediate filaments — have been studied for decades, and multiple roles of the individual cytoskeletal substructures are now well established. However, in recent years it has become apparent that the three cytoskeletal elements also engage in extensive crosstalk that is important for core biological processes. Actin–microtubule crosstalk is particularly important for the regulation of cell shape and polarity during cell migration and division and the establishment of neuronal and epithelial cell shape and function. This crosstalk engages different cytoskeletal regulators and encompasses various physical interactions, such as crosslinking, anchoring and mechanical support. Thus, the cytoskeleton should be considered not as a collection of individual parts but rather as a unified system in which subcomponents co-regulate each other to exert their functions in a precise and highly adaptable manner.

Mammalian embryos initiate morphogenesis with compaction, which is essential for specifying the first lineages of the blastocyst. The 8-cell-stage mouse embryo compacts by enlarging its cell–cell contacts in a Cdh1-dependent manner. It was therefore proposed that Cdh1 adhesion molecules generate the forces driving compaction. Using micropipette aspiration to map all tensions in a developing embryo, we show that compaction is primarily driven by a twofold increase in tension at the cell–medium interface. We show that the principal force generator of compaction is the actomyosin cortex, which gives rise to pulsed contractions starting at the 8-cell stage. Remarkably, contractions emerge as periodic cortical waves when cells are disengaged from adhesive contacts. In line with this, tension mapping of mzCdh1 −/− embryos suggests that Cdh1 acts by redirecting contractility away from cell–cell contacts. Our study provides a framework to understand early mammalian embryogenesis and original perspectives on evolutionary conserved pulsed contractions. By measuring surface tensions in developing mouse embryos, Maître and colleagues show that compaction of the blastomere stage embryo is driven by downregulation of actomyosin at cell–cell contacts.

Cell migration is a pervasive process in many biology systems and involves protrusive forces generated by actin polymerization, myosin dependent contractile forces, and force transmission between the cell and the substrate through adhesion sites. Here we develop a computational model for cell motion that uses the phase-field method to solve for the moving boundary with physical membrane properties. It includes a reaction-diffusion model for the actin-myosin machinery and discrete adhesion sites which can be in a \"gripping\" or \"slipping\" mode and integrates the adhesion dynamics with the dynamics of the actin filaments, modeled as a viscous network. To test this model, we apply it to fish keratocytes, fast moving cells that maintain their morphology, and show that we are able to reproduce recent experimental results on actin flow and stress patterns. Furthermore, we explore the phase diagram of cell motility by varying myosin II activity and adhesion strength. Our model suggests that the pattern of the actin flow inside the cell, the cell velocity, and the cell morphology are determined by the integration of actin polymerization, myosin contraction, adhesion forces, and membrane forces.

Mesenchymal stem cell shape and fate are intrinsic manifestations of form and function at the cellular level. We hypothesize that cell seeding density and initial seeding protocol influence stem cell shape and fate. Nucleus shape and early (within days of seeding) expression of genes typical for pre-, peri-, and postcondensation events were compared between groups of cells after seeding at or proliferating to target density (low density [LD], 16,500 cells/cm 2 ; high density [HD], 35,000 cells/cm 2 ; very high density [VHD], 86,500 cells/cm 2 ). Significant differences in nuclear shape could be attributed to seeding protocol in the VHD group, where nuclei from cells that proliferated to VHD were significantly rounder than nuclei from cells seeded at target VHD. Furthermore, cells that proliferated to VHD exhibited significantly rounder nuclei than nuclei from all other cell density and seeding protocol groups. In contrast, nuclei from cells that were seeded at the VHD were flatter than nuclei from cells of all other groups. Furthermore, the significant rounding of nuclei in the cells that proliferated to VHD was accompanied by a two-, six-, and ninefold increase from baseline in Runx2 , Sox9 , and Aggrecan ( AGC ) expression, markers indicative of precondensation, peri-, and post-condensation events, respectively. None of the other groups showed significant changes in gene expression over baseline. Finally, seeding at target density results in greater overlap of cells compared to groups in which cells proliferate to target density, conferring increased thickness to multicellular culture aggregates seeded at target density. These data suggest that seeding protocols can be exploited to modulate mesenchymal stem cell shape and early gene expression typical for condensation events in development, which occur over an approximately 12-h period at E11.5 in the mouse limb bud. Follow-on studies will delineate longer-term effects of density and seeding protocol on modulation of stem cell fate and cell assembly to form tissues.

Motivated by the wealth of experimental data recently available, we present a cellular-automaton-based modeling framework focussing on high-level cell functions and their concerted effect on cellular migration patterns. Specifically, we formulate a coarse-grained description of cell polarity through self-regulated actin organization and its response to mechanical cues. Furthermore, we address the impact of cell adhesion on collective migration in cell cohorts. The model faithfully reproduces typical cell shapes and movements down to the level of single cells, yet allows for the efficient simulation of confluent tissues. In confined circular geometries, we find that specific properties of individual cells (polarizability; contractility) influence the emerging collective motion of small cell cohorts. Finally, we study the properties of expanding cellular monolayers (front morphology; stress and velocity distributions) at the level of extended tissues.