Amin Doostmohammadi

Topological defects in epithelia govern cell death and extrusion

Epithelial tissues (epithelia) remove excess cells through extrusion, preventing the accumulation of unnecessary or pathological cells. The extrusion process can be triggered by apoptotic signalling, oncogenic transformation and overcrowding of cells. Despite the important linkage of cell extrusion to developmental, homeostatic and pathological processes such as cancer metastasis, its underlying mechanism and connections to the intrinsic mechanics of the epithelium are largely unexplored. We approach this problem by modelling the epithelium as an active nematic liquid crystal (that has a long range directional order), and comparing numerical simulations to strain rate and stress measurements within monolayers of MDCK (Madin Darby canine kidney) cells. Here we show that apoptotic cell extrusion is provoked by singularities in cell alignments in the form of comet-shaped topological defects. We find a universal correlation between extrusion sites and positions of nematic defects in the cell orientation field in different epithelium types. The results confirm the active nematic nature of epithelia, and demonstrate that defect-induced isotropic stresses are the primary precursors of mechanotransductive responses in cells, including YAP (Yes-associated protein) transcription factor activity, caspase-3-mediated cell death, and extrusions. Importantly, the defect-driven extrusion mechanism depends on intercellular junctions, because the weakening of cell–cell interactions in an α-catenin knockdown monolayer reduces the defect size and increases both the number of defects and extrusion rates, as is also predicted by our model. We further demonstrate the ability to control extrusion hotspots by geometrically inducing defects through microcontact printing of patterned monolayers. On the basis of these results, we propose a mechanism for apoptotic cell extrusion: spontaneously formed topological defects in epithelia govern cell fate. This will be important in predicting extrusion hotspots and dynamics in vivo, with potential applications to tissue regeneration and the suppression of metastasis. Moreover, we anticipate that the analogy between the epithelium and active nematic liquid crystals will trigger further investigations of the link between cellular processes and the material properties of epithelia.

Low-Reynolds-number swimming at pycnoclines

Microorganisms play pivotal functions in the trophic dynamics and biogeochemistry of aquatic ecosystems. Their concentrations and activities often peak at localized hotspots, an important example of which are pycnoclines, where water density increases sharply with depth due to gradients in temperature or salinity. At pycnoclines organisms are exposed to different environmental conditions compared to the bulk water column, including reduced turbulence, slow mass transfer, and high particle and predator concentrations. Here we show that, at an even more fundamental level, the density stratification itself can affect microbial ecology at pycnoclines, by quenching the flow signature, increasing the energetic expenditure, and stifling the nutrient uptake of motile organisms. We demonstrate this through numerical simulations of an archetypal low-Reynolds-number swimmer, the “squirmer.” We identify the Richardson number—the ratio of buoyancy forces to viscous forces—as the fundamental parameter that quantifies the effects of stratification. These results demonstrate an unexpected effect of buoyancy on low-Reynolds-number swimming, potentially affecting a broad range of abundant organisms living at pycnoclines in oceans and lakes.

Stabilization of active matter by flow-vortex lattices and defect ordering.

Active systems, from bacterial suspensions to cellular monolayers, are continuously driven out of equilibrium by local injection of energy from their constituent elements and exhibit turbulent-like and chaotic patterns. Here we demonstrate both theoretically and through numerical simulations, that the crossover between wet active systems, whose behaviour is dominated by hydrodynamics, and dry active matter where any flow is screened, can be achieved by using friction as a control parameter. Moreover, we discover unexpected vortex ordering at this wet–dry crossover. We show that the self organization of vortices into lattices is accompanied by the spatial ordering of topological defects leading to active crystal-like structures. The emergence of vortex lattices, which leads to the positional ordering of topological defects, suggests potential applications in the design and control of active materials.

Defect-Mediated Morphologies in Growing Cell Colonies.

Morphological trends in growing colonies of living cells are at the core of physiological and evolutionary processes. Using active gel equations, which include cell division, we show that shape changes during the growth can be regulated by the dynamics of topological defects in the orientation of cells. The friction between the dividing cells and underlying substrate drives anisotropic colony shapes toward more isotropic morphologies, by mediating the number density and velocity of topological defects. We show that the defects interact with the interface at a specific interaction range, set by the vorticity length scale of flows within the colony, and that the cells predominantly reorient parallel to the interface due to division-induced active stresses.

Upstream Swimming in Microbiological Flows

Interactions between microorganisms and their complex flowing environments are essential in many biological systems. We develop a model for microswimmer dynamics in non-Newtonian Poiseuille flows. We predict that swimmers in shear-thickening (-thinning) fluids migrate upstream more (less) quickly than in Newtonian fluids and demonstrate that viscoelastic normal stress differences reorient swimmers causing them to migrate upstream at the centerline, in contrast to well-known boundary accumulation in quiescent Newtonian fluids. Based on these observations, we suggest a sorting mechanism to select microbes by swimming speed.

Celebrating Soft Matter's 10th Anniversary: Cell division: a source of active stress in cellular monolayers.

We introduce the notion of cell division-induced activity and show that the cell division generates extensile forces and drives dynamical patterns in cell assemblies. Extending the hydrodynamic models of lyotropic active nematics we describe turbulent-like velocity fields that are generated by the cell division in a confluent monolayer of cells. We show that the experimentally measured flow field of dividing Madin-Darby Canine Kidney (MDCK) cells is reproduced by our modeling approach. Division-induced activity acts together with intrinsic activity of the cells in extensile and contractile cell assemblies to change the flow and director patterns and the density of topological defects. Finally we model the evolution of the boundary of a cellular colony and compare the fingering instabilities induced by cell division to experimental observations on the expansion of MDCK cell cultures.

Onset of meso-scale turbulence in active nematics

Meso-scale turbulence is an innate phenomenon, distinct from inertial turbulence, that spontaneously occurs at low Reynolds number in fluidized biological systems. This spatiotemporal disordered flow radically changes nutrient and molecular transport in living fluids and can strongly affect the collective behaviour in prominent biological processes, including biofilm formation, morphogenesis and cancer invasion. Despite its crucial role in such physiological processes, understanding meso-scale turbulence and any relation to classical inertial turbulence remains obscure. Here we show how the motion of active matter along a micro-channel transitions to meso-scale turbulence through the evolution of locally disordered patches (active puffs) from an ordered vortex-lattice flow state. We demonstrate that the stationary critical exponents of this transition to meso-scale turbulence in a channel coincide with the directed percolation universality class. This finding bridges our understanding of the onset of low-Reynolds-number meso-scale turbulence and traditional scale-invariant turbulence in confinement.

Active micromachines: Microfluidics powered by mesoscale turbulence

An ordered array of symmetric rotors immersed in active turbulence can turn persistently. Dense active matter, from bacterial suspensions and microtubule bundles driven by motor proteins to cellular monolayers and synthetic Janus particles, is characterized by mesoscale turbulence, which is the emergence of chaotic flow structures. By immersing an ordered array of symmetric rotors in an active fluid, we introduce a microfluidic system that exploits spontaneous symmetry breaking in mesoscale turbulence to generate work. The lattice of rotors self-organizes into a spin state where neighboring discs continuously rotate in permanent alternating directions due to combined hydrodynamic and elastic effects. Our virtual prototype demonstrates a new research direction for the design of micromachines powered by the nematohydrodynamic properties of active turbulence.

Hotspots of boundary accumulation: dynamics and statistics of micro-swimmers in flowing films

Biological flows over surfaces and interfaces can result in accumulation hotspots or depleted voids of microorganisms in natural environments. Apprehending the mechanisms that lead to such distributions is essential for understanding biofilm initiation. Using a systematic framework, we resolve the dynamics and statistics of swimming microbes within flowing films, considering the impact of confinement through steric and hydrodynamic interactions, flow and motility, along with Brownian and run–tumble fluctuations. Micro-swimmers can be peeled off the solid wall above a critical flow strength. However, the interplay of flow and fluctuations causes organisms to migrate back towards the wall above a secondary critical value. Hence, faster flows may not always be the most efficacious strategy to discourage biofilm initiation. Moreover, we find run–tumble dynamics commonly used by flagellated microbes to be an intrinsically more successful strategy to escape from boundaries than equivalent levels of enhanced Brownian noise in ciliated organisms.

Hydrodynamics of Micro-swimmers in Films

One of the principal mechanisms by which surfaces and interfaces affect microbial life is by perturbing the hydrodynamic flows generated by swimming. By summing a recursive series of image systems we derive a numerically tractable approximation to the three-dimensional flow fields of a Stokeslet (point force) within a viscous film between a parallel no-slip surface and no-shear interface and, from this Greens function, we compute the flows produced by a force- and torque-free micro-swimmer. We also extend the exact solution of Liron & Mochon (1976) to the film geometry, which demonstrates that the image series gives a satisfactory approximation to the swimmer flow fields if the film is sufficiently thick compared to the swimmer size, and we derive the swimmer flows in the thin-film limit. Concentrating on the thick film case, we find that the dipole moment induces a bias towards swimmer accumulation at the no-slip wall rather than the water-air interface, but that higher-order multipole moments can oppose this. Based on the analytic predictions we propose an experimental method to find the multipole coefficient that induces circular swimming trajectories, allowing one to analytically determine the swimmers three-dimensional position under a microscope.