Emad Moeendarbary

University College London | UCL · Department of Mechanical Engineering

To learn more about cancer-associated fibroblasts (CAFs), we have isolated fibroblasts from different stages of breast cancer progression and analysed their function and gene expression. These analyses reveal that activation of the YAP transcription factor is a signature feature of CAFs. YAP function is required for CAFs to promote matrix stiffenin...

Understanding the physical basis of cellular shape change in response to both internal and external mechanical stresses requires understanding cytoplasmic rheology. At subsecond time-scales and micron length-scales, cells behave as fluid-filled sponges in which shape changes necessitate intracellular fluid redistribution. However, whether these cyt...

The evaluation of nanoparticle dispersion within viscoelastic fluids upon impact on hydrophobic and hydrophilic surfaces is conducted using the Euler-Lagrangian technique. The volume-of-fluid approach is employed in conjunction with the Lagrangian method to model the transport of nanoparticles in a three-phase system (particles-air-viscoelastic flu...

The small-molecule drug, FTY720 (fingolimod), is a synthetic sphingosine 1-phosphate (S1P) analogue currently used to treat relapsing-remitting multiple sclerosis in both adults and children. FTY720 can cross the blood-brain barrier (BBB) and, over time, accumulate in lipid-rich areas of the central nervous system (CNS) by incorporating into phosph...

The knowledge of the blood microvasculature and its functional role in health and disease has grown significantly attributable to decades of research and numerous advances in cell biology and tissue engineering; however, the lymphatics (the secondary vascular system) has not garnered similar attention, in part due to a lack of relevant in vitro mod...

Background Cancer cells remodel their local physical environment through processes of matrix reorganisation, deposition, stiffening and degradation. Urokinase-type plasminogen activator (uPA), which is encoded by the PLAU gene, is an extracellular proteolytic enzyme known to be involved in cancer progression and tumour microenvironment (TME) remode...

The interplay between genetic transformations, biochemical communications, and physical interactions is crucial in cancer progression. Metastasis, a leading cause of cancer-related deaths, involves a series of steps, including invasion, intravasation, circulation survival, and extravasation. Mechanical alterations, such as changes in stiffness and...

The remarkable contractility and force generation ability exhibited by cancer cells empower them to overcome the resistance and steric hindrance presented by a three-dimensional, interconnected matrix. Cancer cells disseminate by actively remodelling and deforming their extracellular matrix (ECM). The process of tumour growth and its ECM remodellin...

Vascularization is driven by morphogen signals and mechanical cues that coordinately regulate cellular force generation, migration, and shape change to sculpt the developing vascular network. However, it remains unclear whether developing vasculature actively regulates its own mechanical properties to achieve effective vascularization. We engineere...

Widespread neurodegeneration, enlargement of cerebral ventricles, and atrophy of cortical and hippocampal brain structures are classic hallmarks of Alzheimer’s disease (AD). Prominent macroscopic disturbances to the cytoarchitecture of the AD brain occur alongside changes in the mechanical properties of brain tissue, as reported in recent magnetic...

Endochondral ossification (EO) is an essential biological process than underpins how human bones develop, grow, and heal in the event of a fracture. So much is unknown about this process, thus clinical manifestations of dysregulated EO cannot be adequately treated. This can be partially attributed to the absence of predictive in vitro models of mus...

Cancer cell extravasation, a key step in the metastatic cascade, involves cancer cell arrest on the endothelium, transendothelial migration (TEM), followed by the invasion into the subendothelial extracellular matrix (ECM) of distant tissues. While cancer research has mostly focused on the biomechanical interactions between tumor cells (TCs) and EC...

Epithelial to mesenchymal transition (EMT) in cancer is the process described where cancer epithelial cells acquire mesenchymal properties which can lead to enhanced invasiveness. Three-dimensional cancer models often lack the relevant and biomimetic microenvironment parameters appropriate to the native tumour microenvironment thought to drive EMT....

The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to 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 prop...

The human thymus is the site of T‐cell maturation and induction of central tolerance. Hematopoietic stem cell (HSC)‐derived progenitors are recruited to the thymus from the fetal liver during early prenatal development and from bone marrow at later stages and postnatal life. The mechanism by which HSCs are recruited to the thymus is poorly understo...

The stiffness of tumors and their host tissues is much higher than most hydrogels, which are conventionally used to study in vitro cancer progression. The tumoroid assay is an engineered 3D in vitro tumor model that allows investigation of cancer cell invasion in an environment that is biomimetic in terms of extracellular matrix (ECM) composition a...

Development of three dimensional (3D) in vitro models to realistically recapitulate tumor microenvironment has the potential to improve translatability of anti-cancer drugs at the preclinical stage. To capture the in vivo complexity, these in vitro models should minimally incorporate the 3D interactions between multiple cell types, cellular structu...

Objective Engineering bone in 3D is important for both regenerative medicine purposes and for the development of accurate in vitro models of bone tissue. The changing material stiffness of bone tissue had not yet been monitored throughout the process of mineralisation and bone nodule formation by osteoblasts either during in vitro engineering or in...

Pump dynamic operational conditions result in extreme transient events that enhance the response of piping networks. Generally, the predominant transients during rapid startup and shutdown are mainly studied for centrifugal pumps and are scarce for reciprocating pumps. Our study extends the conventional steady-state analysis to include the effect o...

Blood vessels form vast networks in all vertebrate organs to sustain tissue growth, repair and homeostatic metabolism, but they also contribute to a range of diseases with neovascularisation. It is, therefore, important to define the molecular mechanisms that underpin blood vessel growth. The receptor tyrosine kinase KIT is required for the normal...

The interactions between multiple pulsatile sources and the acoustic eigenmodes are analysed to elucidate the influence of source characteristics and contrasting phase differences on the acoustic response in a liquid-filled complex piping network with multiple branches. For illustration, the interactions between two reciprocating pumps operating in...

Quantifying mechanical forces generated by cellular systems has led to key insights into a broad range of biological phenomena from cell adhesion to immune cell activation. Traction force microscopy (TFM), the most widely employed force measurement methodology, fundamentally relies on knowledge of the force-displacement relationship and mechanical...

Cells maintain their volume through fine intracellular osmolarity regulation. Osmotic challenges drive fluid into or out of cells causing swelling or shrinkage respectively. The dynamics of cell volume changes depend on the rheology of the cellular constituents and on how fast the fluid permeates through membrane and cytoplasm. We investigated whet...

Medical procedures can disperse infectious agents and spread disease. Particularly, dental procedures may pose a high risk of disease transmission as they use high-powered instruments operating within the oral cavity that may contain infectious microbiota or viruses. Here we assess the ability of powered dental devices in removing the biofluid film...

The high-Strouhal-number pulsatile flow in a curved pipe is studied numerically. A general force analysis is developed for the bend force, where the new contribution from flow acceleration is identified and analysed. The mechanisms of secondary flow production are studied by extending Hawthorne's (Proc. R. Soc. Lond. A, vol. 206, issue 1086, 1951,...

Bone contains a dense network of blood vessels that are essential to its homoeostasis, endocrine function, mineral metabolism and regenerative functions. In addition, bone vasculature is implicated in a number of prominent skeletal diseases, and bone has high affinity for metastatic cancers. Despite vasculature being an integral part of bone physio...

Background: Tumorigenesis is attributed to the interactions of cancer cells with the tumor microenvironment through both biochemical cues and physical stimuli. Increased matrix deposition and realignment of the collagen fibers are detected by cancer cells, inducing epithelial-to-mesenchymal transition, which in turn stimulates cell motility and in...

Quantifying small, rapidly progressing three-dimensional forces generated by cells remains a major challenge towards a more complete understanding of mechanobiology. Traction force microscopy is one of the most broadly applied force probing technologies but ascertaining three-dimensional information typically necessitates slow, multi-frame z-stack...

During cancer metastasis, tumor cells undergo significant deformation in order to traverse through endothelial cell junctions in the walls of blood vessels. As cells pass through narrow gaps, smaller than the nuclear diameter, the spatial configuration of chromatin must change along with the distribution of nuclear enzymes. Nuclear stiffness is an...

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...

In the brain, REST (Repressor Element‐1 Silencing Transcription factor) is a key regulator of neuron cell‐specific gene expression. Nuclear translocation of neuronal REST has been shown to be neuroprotective in a healthy ageing context. In contrast, inability to upregulate nuclear REST is thought to leave ageing neurons vulnerable to neurodegenerat...

Just as the epigenome, the proteome and the electrophysiological properties of a cell influence its function, so too do its intrinsic mechanical properties and its extrinsic mechanical environment. This is especially true for neurons of the central nervous system (CNS) since long‐term maintenance of synaptic connections relies on efficient axonal t...

Osteoderms are hard tissues embedded in the dermis of vertebrates and have been suggested to be formed from several different mineralized regions. However, their nano architecture and micro mechanical properties had not been fully characterized. Here, using electron microscopy, µ-CT, atomic force microscopy and finite element simulation, an in-dept...

Understanding the influence of the mechanical environment on neurite behavior is crucial in the development of peripheral nerve repair solutions, and could help tissue engineers to direct and guide regeneration. In this study, a new protocol to fabricate physiologically relevant hydrogel substrates with controlled mechanical cues is proposed. These...

To characterize a poroelastic material, typically an indenter is pressed onto the surface of the material with a ramp of a finite approach velocity followed by a hold where the indenter displacement is kept constant This leads to deformation of the porous matrix, pressurization of the interstitial fluid and relaxation due to redistribution of fluid...

Quantification of mechanical forces is a major challenge across biomedical sciences. Yet, such measurements are essential to understanding the role of biomechanics in cell regulation and function. Traction force microscopy remains the most broadly applied force probing technology but typically restricts itself to single plane two-dimensional quanti...

The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model of an endothelial cell monolaye...

Cytoskeletal actin dynamics is essential for T cell activation. Here, we show evidence that the binding kinetics of the antigen engaging the T cell receptor influences the nanoscale actin organization and mechanics of the immune synapse. Using an engineered T cell system expressing a specific T cell receptor and stimulated by a range of antigens, w...

Bleach region tracking of actin (gray, SNAP-cell-505) during the activation of a 1G4 TCR Jurkat T cell interacting with a coverslip functionalised with HLA-9V pMHC. Scale bar: 1 μm. The time between frames is 0.22 s and the total duration is 14.2 s.

Confocal time-lapse of actin (green, SNAP-cell-505) and 40 nm red fluorescent beads (red) during the activation of a 1G4 TCR Jurkat T cell interacting with a 1 kPa PAA gel functionalised with OKT3 and PLL. Scale bar: 5 μm. The time between frames is 10 s and the total duration is 603 s.

Video S6. Fluorescence Recovery after Photobleaching of Actin and Membrane Dynamics, Related to Figure 3 FRAP time-lapse of actin (Left, green, SNAP-cell-505) and plasma membrane (Right, red, CellMask DR) during the activation of a 1G4 TCR Jurkat T cell interacting with a coverslip functionalised with HLA-9V pMHC. Scale bar: 5 μm. The time between...

Video S1. TFM Shows Load-Fail Dynamics during T Cell Activation, Related to Figure 1 Confocal time-lapse of actin (green, SNAP-cell-505) and 40 nm red fluorescent beads (red) during the activation of a 1G4 TCR Jurkat T cell interacting with a 3 kPa PAA gel functionalised with HLA-9V pMHC. Scale bar: 2 μm. The time between frames is 0.5 s and the t...

Video S3. Actin Dynamics Imaged by Extended Total Internal Reflection Fluorescence-Structured Illumination Microscopy (eTIRF-SIM), Related to Figure 2 eTIRF-SIM time-lapse of actin (green, Lifeact-citrine) the activation of a 1G4 TCR Jurkat T cell interacting with a coverslip functionalised with HLA-9V pMHC. Scale bar: 5 μm. The time between frame...

Video S4. Load-Fail Dynamics during Actin Filament Stabilization, Related to Figure 2 Confocal time-lapse of actin (green, SNAP-cell-505) and 40 nm red fluorescent beads (red) during the activation of a 1G4 TCR Jurkat T cell interacting with a 3 kPa PAA gel functionalised with HLA-9V pMHC and treated with 500 μM Jasplakinolide. Scale bar: 5 μm. Th...

Confocal time-lapse of actin (green, SNAP-cell-505) and 40 nm red fluorescent beads (red) during the activation of a 1G4 TCR Jurkat T cell interacting with a 3 kPa PAA gel functionalised with HLA-9V pMHC and treated with 100 μM Y27632. Scale bar: 5 μm. The time between frames is 2 s and the total duration is 337 s.

Aggressive behaviours of solid tumours are highly influenced by the tumour microenviron-ment. Multiple signalling pathways can affect the normal function of stromal fibroblasts in tumours, but how these events are coordinated to generate tumour-promoting cancer-associated fibroblasts (CAFs) is not well understood. Here we show that stromal expressi...

Three-dimensional complex biomechanical interactions occur from the initial steps of tumor formation to the later phases of cancer metastasis. Conventional monolayer cultures cannot recapitulate the complex microenvironment and chemical and mechanical cues that tumor cells experience during their metastatic journey, nor the complexity of their inte...

A defining pathophysiological hallmark of Alzheimer’s disease (AD) is the amyloid plaque; an extracellular deposit of aggregated fibrillar Aβ1-42 peptides. Amyloid plaques are hard, brittle structures scattered throughout the hippocampus and cerebral cortex and are thought to cause hyperphosphorylation of tau, neurofibrillary tangles, and progressi...

The formation of gaps in the endothelium is a crucial process underlying both cancer and immune cell extravasation, contributing to the functioning of the immune system during infection, the unfavorable development of chronic inflammation and tumor metastasis. Here, we present a stochastic-mechanical multiscale model of an endothelial cell monolaye...

Physical gradients play a major role in the regeneration of peripheral nerves [1, 2]. Collagen, the predominant structural protein in nerve extracellular matrix, is commonly used as a physical support for cells to make repair scaffolds [1]. To improve nerve repair approaches, it is useful to understand the mechanosensitivity of neurons and quantify...

Local tissue stiffness provides an important signal to which cells respond in vivo. However, assessing tissue mechanics is currently challenging and requires sophisticated technology. We here developed a model quantitatively predicting nervous tissue stiffness heterogeneities at cellular resolution based on cell density, myelin and GFAP fluorescenc...

The extracellular matrix (ECM) performs many critical functions, one of which is to provide structural and mechanical integrity, and many of the constituent proteins have clear mechanical roles. The composition and structural characteristics of the ECM are widely variable among different tissues, suiting diverse functional needs. In diseased tissue...

Basement membranes (BMs) are specialized extracellular matrices required for tissue organization and organ formation. We study the role of laminin and its integrin receptor in the regulation of tissue migration during Drosophila oogenesis. Egg production in Drosophila involves the collective migration of follicle cells (FCs) over the BM to shape th...

In addition to a multitude of genetic and biochemical alterations, abnormal morphological, structural and mechanical changes in cells and their extracellular environment are key features of tumour invasion and metastasis. Furthermore, it is now evident that mechanical cues alongside biochemical signals contribute to critical steps of cancer initiat...

Injury to the central nervous system (CNS) alters the molecular and cellular composition of neural tissue and leads to glial scarring, which inhibits the regrowth of damaged axons. Mammalian glial scars supposedly form a chemical and mechanical barrier to neuronal regeneration. While tremendous effort has been devoted to identifying molecular chara...

Supplementary Figures and Supplementary Tables

Injury to the central nervous system (CNS) alters the molecular and cellular composition of neural tissue and leads to glial scarring, which inhibits the regrowth of damaged axons. Mammalian glial scars supposedly form a chemical and mechanical barrier to neuronal regeneration. While tremendous effort has been devoted to identifying molecular chara...

Cell-free studies have demonstrated how collective action of actin-associated proteins can organize actin filaments into dynamic patterns, such as vortices, asters and stars. Using complementary microscopic techniques, we here show evidence of such self-organization of the actin cortex in living HeLa cells. During cell adhesion, an active multistag...

Transition from an actin star to asters. eTIRF-SIM movie of actin (green, Lifeact-citrine) at the basal plane of a live HeLa cell at >4 hours incubation. The movie shows an actin star dividing into two actin asters within the cortical actin network. Scale bar (in first frame): 1 μm. The time between frames is 1 s and the total duration 41s.

Transition from actin asters to an actin star. eTIRF-SIM movie of actin (green, Lifeact-citrine) at the basal plane of a live HeLa cell at >4 hours incubation. The movie shows three actin asters fusing into one actin star within the cortical actin network. Scale bar (in first frame): 1 μm. The time between frames is 1 s and the total duration 118s.

Dynamics of the Arp2/3 complex around actin stars. eTIRF-SIM movie of actin (green, Lifeact-citrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells after 4 hours incubation. Scale bar (in first frame): 5 μm. The time between frames is 5 s and the total duration 80s.

Dynamics of the Arp2/3 complex around an individual actin star after short CK666 treatment. eTIRF-SIM movie of actin (green, Lifeact-citrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells after 4 hours incubation and 30s CK666 treatment (100μM). Arp2/3 complexes were immobile at the peripheral F-actin of the...

Dynamics of F-actin and the Arp2/3 complex. eTIRF-SIM movie of actin (green, Lifeact-citrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells at early stages of adherence. Scale bar (in first frame): 5 μm. The time between frames is 5 s and the total duration 45s.

Dynamics of F-actin and the Arp2/3 complex. eTIRF-SIM movie of actin (green, Lifeact-citrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells at early stages of adherence. Scale bar (in first frame): 5 μm. The time between frames is 5 s and the total duration 95s.

Zoom-in on one of the ring-like actin structures in Supplementary Movie 3, indicating continuous emergence of new actin filaments from the outer ring. eTIRF-SIM movie of actin (grey, Lifeact-citrine) at the basal plane of a live HeLa cell after 2-3 hours incubation. Scale bar (in first frame): 5 μm. The time between frames is 5 s and the total dura...

Zoom-in on one of the ring-like actin structures, indicating its rotation, and simultaneous dynamics of Arp2/3 complexes. eTIRF-SIM movie of actin (green, Lifeactcitrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells after 2-3 hours incubation. The movie shows a ring-like actin structure and the dynamics of t...

Dynamics of several actin asters and Arp2/3 complexes after 12h incubation. eTIRF-SIM movie of actin (green, Lifeact-citrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells after 12 hours incubation. Arp2/3 complexes and F-actin are highly mobile. Scale bar (in first frame): 5 μm. The time between frames is 5...

Dynamics of an individual actin aster and Arp2/3 complexes after 12h incubation. eTIRF-SIM movie of actin (green, Lifeact-citrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells after 12 hours incubation. Arp2/3 complexes and F-actin are highly mobile. Scale bar (in first frame): 1 μm. The time between frames...

Supplementary Notes, Supplementary Figures, Supplementary Table 1, Supplementary Discussion and Supplementary References

Emergence of asterisk-like patterns out of vortices. eTIRF-SIM movie of actin (green, Lifeact-citrine) at the basal plane of a live HeLa cell at ~3 hours incubation. The movie shows actin vortices generating actin strands at their periphery within the cortical actin network. Scale bar (in first frame): 1 μm. The time between frames is 1 s and the t...

Dynamics of the Arp2/3 complex around actin stars after short CK666 treatment. eTIRF-SIM movie (larger overview than supplementary movie 10) of actin (green, Lifeact-citrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells after 4 hours incubation and 30s CK666 treatment (100μM). Arp2/3 complexes were immobile...

Dynamics of the Arp2/3 complex around an individual actin aster after long CK666 treatment. eTIRF-SIM movie of actin (green, Lifeact-citrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells after 4 hours incubation and 30min CK666 treatment (100μM). Arp2/3 complexes are immobile in the periphery of the aster co...

Ring-like actin structures polymerizing F-actin at their periphery. eTIRFSIM movie of actin (grey, Lifeact-citrine) at the basal plane of a live HeLa cell after 2-3 hours incubation. Scale bar (in first frame): 5 μm. The time between frames is 5 s and the total duration 470s.

Dynamics of an individual actin aster and Arp2/3 complexes after 12h incubation. eTIRF-SIM movie of actin (green, Lifeact-citrine) and Arp2/3 complexes (red to yellow, JF542-p16) at the basal plane of live HeLa cells after 12 hours incubation. Arp2/3 complexes and F-actin are highly mobile. Scale bar (in first frame): 1 μm. The time between frames...

For all types of cancer, the survival rate while the tumor is still localized is significantly higher than when cancer has metastasized. Though different therapeutic methods can be applied to successfully treat primary tumors, treatment of metastasised cancer is a great challenge due to its complex and systemic nature. A deeper understanding of how...

Nature presents to us a plethora of materials composed by mixtures of finely assembled phases, the most abundant in biology being the fluid phase that mainly comprises of water. Physical interactions of water with other phases are fundamental to describe many systems, including living materials. The theory of poroelasticity provides a way to descri...

It is now evident that the cell nucleus undergoes dramatic shape changes during important cellular processes such as cell transmigration through extracellular matrix and endothelium. Recent experimental data suggest that during cell transmigration the deformability of the nucleus could be a limiting factor, and the morphological and structural alte...