Ming Guo

BACKGROUND Songling Xuemaikang Capsule (SXC), a Chinese herbal medicine, has shown promise in decreasing blood pressure (BP), but its efficacy in grade 1 hypertension patients at low-to-moderate cardiovascular (CV) risk remains uncertain. PURPOSE This study investigated the efficacy of SXC in grade 1 hypertension patients at low-to-moderate CV risk. STUDY DESIGN This study was designed as a multicenter, randomized, double-blind, placebo-controlled clinical trial. METHODS Eligible patients from 9 centers were randomized to receive SXC or placebo for consecutive 8 weeks. The primary outcome was the changes of 24-h ambulatory BP. The secondary outcomes were the changes of daytime/nighttime BP, office BP, and control rate of hypertension. The adverse events were reported. RESULTS Of 508 patients who underwent screening, 393 were randomized after a 2-week run-in phase, and 356 were included in final analysis. Intention-to-treat analysis revealed a greater reduction in 24-h systolic/diastolic blood pressure (SBP/DBP) in SXC group compared to placebo group (-5.91±11.32/-4.66±9.33 mm Hg vs -2.26±10.47/-2.56±8.76 mm Hg, p < 0.001/p < 0.001). The patients in SXC group also showed a greater reduction in daytime SBP/DBP, nighttime SBP/DBP and office SBP/DBP than placebo group (p = 0.002/p = 0.004, p = 0.005/p = 0.046 and p < 0.001/p = 0.001, respectively). The control rate of 24-h BP (defined as SBP/DBP <130/80 mm Hg) was higher in SXC group than in placebo group (38.04 % vs 24.42 %, p = 0.002). There was no statistical difference in adverse events between two groups. CONCLUSION Treatment with SXC for 8-week demonstrated a superiority in reducing 24-h average SBP/DBP over placebo, without increasing adverse events. The confirmed net efficacy suggested that SXC may provide an alternative therapy for grade 1 hypertension patients at low-to-moderate CV risk.

During a variety of physiological and pathological processes, such as development, wound healing, and tumor progression, epithelial cells collectively invade into their surroundings. Vimentin intermediate filaments (VIFs) are often observed to play a role in the epithelial cells located at the margins of 2D cultures. However, their role in 3D collective cell behavior remains underexplored. Here, we investigate how induced vimentin expression affects 3D multicellular architecture and mechanics in luminal breast cancer cells (MCF-7) that ordinarily express keratin intermediate filaments only. We find that vimentin expression significantly alters 3D cell cluster morphology, inducing protrusions and increasing boundary fluctuations. Furthermore, cells in vimentin-expressing clusters show enhanced, more stochastic migration. In addition, these clusters exert stronger and localized traction forces on the surrounding matrix, indicating increased cell-matrix interactions. Transcriptomic analysis corroborates these biophysical findings, revealing upregulated gene expression for cell migration and matrix adhesion, and downregulated cell-cell adhesion genes. Our results demonstrate that VIFs are critical in modulating 3D multicellular collective morphology and dynamics, promoting invasive-like behavior by enhancing cell migration and cell-matrix interactions. These results provide fundamental insights into understanding tissue morphogenesis and disease progression.

Uranium contamination in water and soil poses serious risks to human health and ecosystems. Adsorption is a promising method for uranium removal due to its efficiency and simplicity. This review highlights recent advancements in uranium (VI) adsorption using Metal-Organic Frameworks (MOFs), Covalent Organic Frameworks (COFs), Graphene Oxide (GO), and MXenes. MOFs and COFs offer high adsorption capacities and tunable structures, while GO and MXenes exhibit excellent performance due to their large surface areas and unique chemical properties. However, challenges such as regeneration costs, material stability, and large-scale production remain significant barriers. This review discusses these challenges, compares material advantages and limitations, and outlines future directions to develop efficient adsorbents for radioactive waste management and environmental remediation.

systems of cells and extra-cellular matrix (ECM) systems are well known to form ordered patterns of orientationally aligned fibers. Here, we interpret them as active analogs of the (disordered) isotropic to the (ordered) nematic phase transition seen in passive liquid crystalline elastomers. A minimal theoretical framework that couples cellular activity (embodied as mechanical stress) and the finite deformation elasticity of liquid crystal elastomers sets the stage to explain these patterns. Linear stability analysis of the governing equations about simple homogeneous isotropic base states shows how the onset of periodic morphologies depends on the activity, elasticity, and applied strain, provides an expression for the wavelength of the instability, and is qualitatively consistent with observations of cell-ECM experiments. Finite element simulations of the nonlinear problem corroborate the results of linear analysis. These results provide quantitative insights into the onset and evolution of nematic order in cell-matrix composites.

Within multicellular living systems, cells coordinate their positions with spatiotemporal accuracy to form various tissue structures and control development. These arrangements can be regulated by tissue geometry, biochemical cues, as well as mechanical perturbations. However, how cells pack during dynamic three-dimensional multicellular architectures formation remains unclear. Here, examining a growing spherical multicellular system, human lung alveolospheres, we observe an emergence of hexagonal packing order and a structural transition of cells that comprise the spherical epithelium. Surprisingly, the cell packing behavior on the spherical surface of lung alveolospheres resembles hard-disks packing on spheres, where the less deformable cell nuclei act as effective "hard disks" and prevent cells from getting too close. Nucleus-to-cell size ratio increases during lung spheroids growth; as a result, we find more hexagon-concentrated cellular packing with increasing bond orientational order. Furthermore, by osmotically changing the compactness of cells on alveolospheres, we observe a more ordered packing when nucleus-to-cell size ratio increases, and vice versa. These more ordered cell packing characteristics are consistent with reduced cell dynamics, together suggesting that better cellular packing stabilizes local cell neighborhoods and may regulate more complex biological functions such as cellular maturation and tissue morphogenesis.

Coordinated cell rotation along a curved matrix interface can sculpt epithelial tissues into spherical morphologies. Subsequently, radially-oriented invasion of multicellular strands or branches can occur by local remodeling of the confining matrix. These symmetry-breaking transitions emerge from the dynamic reciprocity between cells and matrix, but remain poorly understood. Here, we show that epithelial cell spheroids collectively transition from circumferential orbiting to radial invasion via bi-directional interactions with the surrounding matrix curvature. Initially, spheroids exhibit an ellipsoidal shape but become rounded as orbiting occurs. However, cells gradually reorient from coordinated rotation towards outward strand invasion due to the accumulation of contractile tractions at discrete sites. Remarkably, the initial ellipsoid morphology predicts subsequent invasion of 2-4 strands roughly aligned with the major axis. We then perturb collective migration using osmotic pressure, showing that orbiting can be arrested and invasion can be reversed. We also investigate coordinated orbiting in "mosaic" spheroids, showing a small fraction of "leader" cells with weakened cell-cell adhesions can impede collective orbiting but still invade into the matrix. Finally, we establish a minimal self-propelled particle model to elucidate how collective orbiting is mediated by the crosstalk of cell-cell and cell-matrix adhesion along a curved boundary. Altogether, this work elucidates how tissue morphogenesis is governed by the interplay of collective behaviors and the local curvature of the cell-matrix, with relevance for embryonic development and tumor progression.

While tumor organoids have revolutionized cancer research by recapitulating the cellular architecture and behaviors of real tumors in vitro, their lack of functional vasculature hinders their attainment of full physiological capabilities. Current efforts to vascularize organoids are struggling to achieve well-defined vascular networks, mimicking the intricate hierarchy observed in vivo, which restricts the physiological relevance particularly for studying tumor progression and response to therapies targeting the tumor vasculature. An innovative vascularized patient-derived tumor organoids (PDTOs)-on-a-chip with hierarchical, tumor-specific microvasculature is presented, providing a versatile platform to explore tumor-vascular dynamics and antivascular drug efficacy. It is found that highly metastatic tumor cells induced vessel angiogenesis and simultaneously migrated toward blood vessels via the Notch pathway. The evident association between the angiogenic and migratory capacities of PDTOs and their clinical metastatic outcomes underscores the potential of the innovative platform for evaluating tumor metastasis, thus offering valuable insights for clinical decision-making. Ultimately, the system represents a promising avenue for advancing the understanding of tumor metastasis and developing personalized treatment strategies based on patient-specific tumor characteristics.

Multicellular self-assembly into functional structures is a dynamic process that is critical in the development of biological structures and diseases, including embryo development, organ formation, tumor invasion, and other processes. Being able to infer collective cell migratory dynamics from their static configuration is valuable for both understanding and predicting these complex behaviors. However, the identification of structural features that can indicate multicellular motion has been difficult, and existing metrics largely rely on physical instincts. Here we show that, through the use of a graph neural network, the motion of multicellular collectives can be inferred from a static snapshot of cell positions, in both experimental and synthetic datasets. Published by the American Physical Society 2024

Eukaryotic cell rheology has important consequences for vital processes such as adhesion, migration, and differentiation. Experiments indicate that cell cytoplasm can exhibit both elastic and viscous characteristics in different regimes, while the transport of fluid (cytosol) through the cross-linked filamentous scaffold (cytoskeleton) is reminiscent of mass transfer by diffusion through a porous medium. To gain insights into this complex rheological behaviour, we construct a computational model for the cell cytoplasm as a poroviscoelastic material formulated on the principles of nonlinear continuum mechanics, where we model the cytoplasm as a porous viscoelastic scaffold with an embedded viscous fluid flowing between the pores to model the cytosol. Baseline simulations (neglecting the viscosity of the cytosol) indicate that the system exhibits seven different regimes across the parameter space spanned by the viscoelastic relaxation timescale of the cytoskeleton and the poroelastic diffusion timescale; these regimes agree qualitatively with experimental measurements. Furthermore, the theoretical model also allows us to elucidate the additional role of pore fluid viscosity, which enters the system as a distinct viscous timescale. We show that increasing this viscous timescale hinders the passage of the pore fluid (reducing the poroelastic diffusion) and makes the cytoplasm rheology increasingly incompressible, shifting the phase boundaries between the regimes.

The cytoskeleton is a complex network of interconnected biopolymers consisting of actin filaments, microtubules, and intermediate filaments. These biopolymers work in concert to transmit cell-generated forces to the extracellular matrix required for cell motility, wound healing, and tissue maintenance. While we know cell-generated forces are driven by actomyosin contractility and balanced by microtubule network resistance, the effect of intermediate filaments on cellular forces is unclear. Using a combination of theoretical modeling and experiments, we show that vimentin intermediate filaments tune cell stress by assisting in both actomyosin-based force transmission and reinforcement of microtubule networks under compression. We show that the competition between these two opposing effects of vimentin is regulated by the microenvironment stiffness. These results reconcile seemingly contradictory results in the literature and provide a unified description of vimentin's effects on the transmission of cell contractile forces to the extracellular matrix.

Constant proportionalities between cells and their intracellular organelles have been widely observed in various types of cells, known as intracellular size scaling. However, the mechanism underlying the size scaling and its modulation by environmental factors in multicomponent systems remain poorly understood. Here, we study the size scaling of membrane-less condensates using microdroplet-encapsulated minimalistic condensates formed by droplet microfluidics and mean-field theory. We demonstrate that the size scaling of condensates is an inherent characteristic of liquid-liquid phase separation. This concept is supported by experiments showing the occurrence of size scaling phenomena in various condensate systems and a generic lever rule acquired from mean-field theory. Moreover, it is found that the condensate-to-microdroplet scaling ratio can be affected by the solute and salt concentrations, with good agreement between experiments and predictions by theory. Notably, we identify a noise buffering mechanism whereby condensates composed of large macromolecules effectively maintain constant volumes and counteract concentration fluctuations of small molecules. This mechanism is achieved through the dynamic rearrangement of small molecules in and out of membrane-free interfaces. Our work provides crucial insights into understanding mechanistic principles that govern the size of cells and intracellular organelles as well as associated biological functions.

In the extracellular matrix, eukaryotic cells exert forces that deform their surroundings. By doing so, they can perform mechanosensation: Cells measure the mechanics of their environment, and adapt their behavior accordingly. Extracellular matrices are, however, disordered nonlinear media: How can a mechanosensor at the cellular scale reliably measure the surroundings mechanics through local probing? Here, we develop a model for nonlinear mechanosensation in disordered fiber networks. At low forces, the linear response of the matrix combined with its extreme mechanical heterogeneity precludes reliable mechanosensation. In contrast, we find that this heterogeneity is strongly suppressed in the physiologically relevant nonlinear mechanical regime where fibers buckle. Conceptually, nonlinearity increases the range of mechanosensation, thereby enhancing disorder averaging and providing more accurate nonlinear mechanical measurements. We support our model using microrheology experiments and show theoretically that this nonlinear mechanosensation is generic to all fiber networks. This contrasts with the collagen-specific observation that nonlinear macroscopic elastic moduli are independent of network density, which we show to originate from the fiber's constitutive nonlinearity. Together, our theoretical study disentangles the micro- and macrorheological nonlinearities of fiber networks, and shows how mechanosensors such as cells can take advantage of these nonlinearities to robustly measure their mechanical environment despite heterogeneities. Published by the American Physical Society 2024

Through its involvement in gene transcription and heterochromatin formation, DNA methylation regulates how cells interact with their environment. Nevertheless, the extracellular signaling cues that modulate the distribution of this central chromatin modification are largely unclear. DNA methylation is highly abundant at repetitive elements, but its investigation in live cells has been complicated by methodological challenges. Utilizing a CRISPR/dCas9 biosensor that reads DNA methylation of human α-satellite repeats in live cells, we here uncover a signaling pathway linking the chromatin and transcriptional state of repetitive elements to epithelial adherens junction integrity. Specifically, we find that in confluent breast epithelial cell monolayers, α-satellite repeat methylation is reduced by comparison to low density cultures. This is coupled with increased transcriptional activity at repeats. Through comprehensive perturbation experiments, we identify the junctional protein E-cadherin, which links to the actin cytoskeleton, as a central molecular player for signal relay into the nucleus. Furthermore, we find that this pathway is impaired in cancer cells that lack E-cadherin and are not contact-inhibited. This suggests that the molecular connection between cell density and repetitive element methylation could play a role in the maintenance of epithelial tissue homeostasis.

Abstract Photocatalytic nitrogen reduction represents a viable technology for green ammonia synthesis under mild conditions. However, the performance of the photocatalysts is typically limited by high charge carrier recombination and low adsorption and activation of nitrogen molecules. Herein, Bi/Bi 2 Sn 2 O 7 (Bi/BSO) heterojunction nanocomposites are prepared via a one‐step hydrothermal method, where NaOH etching of oxygen vacancies in the Bi─O bonds of Bi 2 Sn 2 O 7 (BSO) is exploited for the in situ formation of metallic Bi and hence Schottky junctions with the semiconducting BSO. This leads to a high separation rate of photogenerated charge carriers. Consequently, compared to the pure‐phase BSO, the Bi/BSO heterostructures exhibit markedly enhanced ammonia production, reaching an optimum rate of 284.5 µmol g −1 h −1 , where the rectifying contact between the semiconducting BSO and metallic Bi facilitates directional BSO to Bi electron transfer, leading to enrichment of photogenerated electrons at the active sites of metallic Bi. First‐principles calculations confirm the alteration of active sites and the guided electron flow by the Schottky junctions and surface oxygen vacancies. Results from this study offer an effective paradigm of structural engineering in manipulating the photocatalytic activity of bismuth‐based pyrochlore materials toward nitrogen fixation to ammonia.

EDITORIAL article Front. Cell Dev. Biol., 30 January 2024Sec. Cell Adhesion and Migration Volume 12 - 2024 | https://doi.org/10.3389/fcell.2024.1369713

Multicellular self-assembly into functional structures is a dynamic process that is critical in the development and diseases, including embryo development, organ formation, tumor invasion, and others. Being able to infer collective cell migratory dynamics from their static configuration is valuable for both understanding and predicting these complex processes. However, the identification of structural features that can indicate multicellular motion has been difficult, and existing metrics largely rely on physical instincts. Here we show that using a graph neural network (GNN), the motion of multicellular collectives can be inferred from a static snapshot of cell positions, in both experimental and synthetic datasets.

We reveal the mechanism for the strong reinforcement of attractive nanofiller-hydrogel composites. Measuring the linear viscoelastic properties of hydrogels containing filler nanoparticles, we show that a significant increase of the modulus can be achieved at unexpectedly low volume fractions of nanofillers when the filler-hydrogel interactions are attractive. Using three-dimensional numerical simulations, we identify a general microscopic mechanism for the reinforcement, common to hydrogel matrices of different compositions and concentrations and containing nanofillers of varying sizes. The attractive interactions induce a local increase in the gel density around the nanofillers. The effective fillers, composed of the nanofillers and the densified regions around them, assemble into a percolated network, which constrains the gel displacement and enhances the stress coupling throughout the system. A global reinforcement of the composite is induced as the stresses become strongly coupled. This physical mechanism of reinforcement, which relies only on attractive filler-matrix interactions, provides design strategies for versatile composites that combine low nanofiller fractions with an enhanced mechanical strength.

Cell viability assessment is critical, yet existing assessments are not accurate enough. We report a cell viability evaluation method based on the metabolic ability of a single cell. Without culture medium, we measured the absorption of cells to terahertz laser beams, which could target a single cell. The cell viability was assessed with a convolution neural classification network based on cell morphology. We established a cell viability assessment model based on the THz-AS (terahertz-absorption spectrum) results as y = a = ( x – b ) c, where x is the terahertz absorbance and y is the cell viability, and a, b, and c are the fitting parameters of the model. Under water stress the changes in terahertz absorbance of cells corresponded one-to-one with the apoptosis process, and we propose a cell 0 viability definition as terahertz absorbance remains unchanged based on the cell metabolic mechanism. Compared with typical methods, our method is accurate, label-free, contact-free, and almost interference-free and could help visualize the cell apoptosis process for broad applications including drug screening.

본고는 <초승달>에 나타난 기녀 이미지에 대한 분석을 통해 하층 기녀의 곤경과 민국 정부의 ‘위선’을 밝혀냈다. 5·4운동과 신문화운동의 세례를 거쳐 중국에 서양민주사상이 도입되며 점차 ‘남녀평등’의 이념이 받아들여졌다. 이에 ‘성매매 폐지·금지’ 운동이 벌어졌으나 하층 사회에서는 매춘 행위가 오히려 기승을 부렸다. 1912년부터 1917년까지의 기녀 수가 증가한 것을 보면 민국정부의 정책은 실패한 것으로 보아야 한다. 민국 정부는 기녀의 생계는 고려하지 않고 서양 사상만을 도입했다. 기녀는 수입원을 잃고 가난한 남자와 결혼해 가난한 삶을 살아야 했다.<초승달>에서 어머니가 아버지를 잃고 재혼에 실패한 후, 기녀가 되었고, 자신의 몸으로 적은 수입을 벌어 ‘나’를 공부시켰다. 처음에 ‘나’는 어머니의 행동을 경멸했지만, 교장의 조카를 만나 사랑에 빠졌을 때, 자신도 남자의 노리개인 걸 깨닫자 기녀로 타락하였다. 소설은 ‘남성부족’이라는 특징을 통해 민국시기 남성에 대한 여성의 의존도를 보여준다. ‘나’와 어머니는 남성에 의존하지 않으면 기녀가 될 운명을 받아들일 수밖에 없다. 작가는 소설에서 삶을 열심히 살아보려는 어머니의 이미지를 보여줬으나 결말에 가서 ‘나’는 매춘을 할 수밖에 없는 비극적 운명을 벗어나지 못한다. ‘나’는 어머니가 재혼할 때부터 남자에 의존해야 하는 것을 깨달아야 했으나 당시에 아직 받아들이지 못했다. 교장의 조카와 연애했을 때 남자의 총애를 즐겼고 의식주도 해결되었기 때문에 생각이 바뀌었다. 이것은 ‘나’를 타락하게 한 원인 중 하나이다. 그러나 ‘나’는 교육을 받은 여성으로서 지식을 통해 운명을 바꿀 수 있다는 것은 깨닫지 못했다. 이는 민국 여성의 의식이 약하고 사회가 여성에게 불공평하다는 것을 보여주고 있다. 작품 속에서 지식은 남성에게만 유익하고 남성들만 이를 활용해 자신을 발전시킬 수 있다. ‘감화원’은 기녀의 삶을 실질적으로 바꾸는 것이 아니라 여성을 하층 남성에게 파는 또 다른 방식이라고 할 수가 있다.필자가 <초승달>에 대한 분석을 통해 민국시대 기녀 제도의 결함과 위선을 보여주고자 한다.

Cells migrate by adapting their leading-edge behaviors to heterogeneous extracellular microenvironments (ECMs) during cancer invasions and immune responses. Yet it remains poorly understood how such complicated dynamic behaviors emerge from millisecond-scale assembling activities of protein molecules, which are hard to probe experimentally. To address this gap, we establish a spatiotemporal "resistance-adaptive propulsion" theory based on the interactions between Arp2/3 complexes and polymerizing actin filaments and a multiscale dynamic modeling system spanning from molecular proteins to the cell. We quantitatively find that cells can accurately self-adapt propulsive forces to overcome heterogeneous ECMs via a resistance-triggered positive feedback mechanism, dominated by polymerization-induced actin filament bending and the bending-regulated actin-Arp2/3 binding. However, for high resistance regions, resistance triggers a negative feedback, hindering branched filament assembly, which adapts cellular morphologies to circumnavigate the obstacles. Strikingly, the synergy of the two opposite feedbacks not only empowers the cell with both powerful and flexible migratory capabilities to deal with complex ECMs but also enables efficient utilization of intracellular proteins by the cell. In addition, we identify that the nature of cell migration velocity depending on ECM history stems from the inherent temporal hysteresis of cytoskeleton remodeling. We also show that directional cell migration is dictated by the competition between the local stiffness of ECMs and the local polymerizing rate of actin network caused by chemotactic cues. Our results reveal that it is the polymerization force-regulated actin filament-Arp2/3 complex binding interaction that dominates self-adaptive cell migrations in complex ECMs, and we provide a predictive theory and a spatiotemporal multiscale modeling system at the protein level.

Cell migration plays important roles in many biological processes, but how migrating cells orchestrate intracellular molecules and subcellular structures to regulate their speed and direction is still not clear. Here, by characterizing the intracellular diffusion and the three-dimensional lamellipodium structures of fish keratocyte cells, we observe a strong positive correlation between the intracellular diffusion and cell migration speed and, more importantly, discover a switching of cell migration modes with reversible intracellular diffusion variation and lamellipodium structure deformation. Distinct from the normal fast mode, cells migrating in the newly-found slow mode have a deformed lamellipodium with swollen-up front and thinned-down rear, reduced intracellular diffusion and compartmentalized macromolecule distribution in the lamellipodium. Furthermore, in turning cells, both lamellipodium structure and intracellular diffusion dynamics are also changed, with left-right symmetry breaking. We propose a mechanism involving the front-localized actin polymerization and increased molecular crowding in the lamellipodium to explain how cells spatiotemporally coordinate the intracellular diffusion dynamics and the lamellipodium structure in regulating their migrations.

Sculpting of structure and function of three-dimensional multicellular tissues depend critically on the spatial and temporal coordination of cellular physical properties. Yet the organizational principles that govern these events, and their disruption in disease, remain poorly understood. My lab works on developing new tools to characterize and understand the role of mechanics in biology. In this talk, I will first introduce our recent progress in characterizing cell and ECM mechanics in 3D and in multicellular systems, such as a breast cancer model. Then I will discuss a recent work reporting the crucial role of interfacial curvature on collective cell migration. Finally, I would also like to discuss the impact of cell mechanics on a verity of critical cell biological functions.

Nonlinear stiffening is a ubiquitous property of major types of biopolymers that make up the extracellular matrices (ECM) including collagen, fibrin, and basement membrane. Within the ECM, many types of cells such as fibroblasts and cancer cells have a spindle-like shape that acts like two equal and opposite force monopoles, which anisotropically stretch their surroundings and locally stiffen the matrix. Here, we first use optical tweezers to study the nonlinear force–displacement response to localized monopole forces. We then propose an effective-probe scaling argument that a local point force application can induce a stiffened region in the matrix, which can be characterized by a nonlinear length scale R * that increases with the increasing force magnitude; the local nonlinear force–displacement response is a result of the nonlinear growth of this effective probe that linearly deforms an increasing portion of the surrounding matrix. Furthermore, we show that this emerging nonlinear length scale R * can be observed around living cells and can be perturbed by varying matrix concentration or inhibiting cell contractility.

Dataset corresponding to the underlying numerical and experimental data of the research article "Local response and emerging nonlinear elastic length scale in biopolymer matrices". This repository contains four categories of data, each contained in a folder: <br> - Fiber Network Simulations <br> - Finite Elements Simulations <br> - Optical Tweezer Experiments<br> - Traction Force Microscopy<br> In each folder, a README.txt document provides a detailed description of the content. We would like to acknowledge the support from the NIH (1R01GM140108), MathWorks, and the Jeptha H. and Emily V. Wade Award at the Massachusetts Institute of Technology. H.Y. acknowledges the MathWorks Mechanical Engineering Fellowship. M.G. acknowledges the Sloan Research Fellowship. This project received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 891217 and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Project-ID 201269156 - SFB 1032 (Project B12) (E.B. and C.P.B.). P.R. is supported by France 2030, the French National Research Agency (ANR-16-CONV-0001), and the Excellence Initiative of Aix- Marseille University—A*MIDEX.

Dataset corresponding to the underlying numerical and experimental data of the research article "Local response and emerging nonlinear elastic length scale in biopolymer matrices". This repository contains four categories of data, each contained in a folder: <br> - Fiber Network Simulations <br> - Finite Elements Simulations <br> - Optical Tweezer Experiments<br> - Traction Force Microscopy<br> In each folder, a README.txt document provides a detailed description of the content. We would like to acknowledge the support from the NIH (1R01GM140108), MathWorks, and the Jeptha H. and Emily V. Wade Award at the Massachusetts Institute of Technology. H.Y. acknowledges the MathWorks Mechanical Engineering Fellowship. M.G. acknowledges the Sloan Research Fellowship. This project received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement no. 891217 and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Project-ID 201269156 - SFB 1032 (Project B12) (E.B. and C.P.B.). P.R. is supported by France 2030, the French National Research Agency (ANR-16-CONV-0001), and the Excellence Initiative of Aix- Marseille University—A*MIDEX.

Abstract Cells migrate by adapting their leading-edge behaviours to heterogeneous extracellular microenvironments (ECMs) during cancer invasions and immune responses. Yet it remains poorly understood how such complicated dynamic behaviours emerge from millisecond-scale assembling activities of protein molecules, which are hard to probe experimentally. To address this gap, we established a spatiotemporal “resistance-adaptive propulsion” theory based on the protein interactions between Arp2/3 complexes and polymerizing actin filaments, and a multiscale dynamic modelling system spanning from molecular proteins to the cell. Combining spatiotemporal simulations with experiments, we quantitatively find that cells can accurately self-adapt propulsive forces to overcome heterogeneous ECMs via a resistance-triggered positive feedback mechanism, dominated by polymerization-induced actin filament bending and the bending-regulated actin-Arp2/3 binding. However, for high resistance regions, resistance triggered a negative feedback, hindering branched filament assembly, which adapts cellular morphologies to circumnavigate the obstacles. Strikingly, the synergy of the two opposite feedbacks not only empowers cells with both powerful and flexible migratory capabilities to deal with complex ECMs, but also endows cells to use their intracellular proteins efficiently. In addition, we identify that the nature of cell migration velocity depending on ECM history stems from the inherent temporal hysteresis of cytoskeleton remodelling. We also quantitatively show that directional cell migration is dictated by the competition between the local stiffness of ECMs and the local polymerizing rate of actin network caused by chemotactic cues. Our results reveal that it is the polymerization force-regulated actin filament-Arp2/3 complex binding interaction that dominates self-adaptive cell migrations in complex ECMs, and we provide a predictive theory and a spatiotemporal multiscale modelling system at the protein level.

The multicellular organization of diverse systems, including embryos, intestines, and tumors relies on coordinated cell migration in curved environments. In these settings, cells establish supracellular patterns of motion, including collective rotation and invasion. While such collective modes have been studied extensively in flat systems, the consequences of geometrical and topological constraints on collective migration in curved systems are largely unknown. Here, we discover a collective mode of cell migration in rotating spherical tissues manifesting as a propagating single-wavelength velocity wave. This wave is accompanied by an apparently incompressible supracellular flow pattern featuring topological defects as dictated by the spherical topology. Using a minimal active particle model, we reveal that this collective mode arises from the effect of curvature on the active flocking behavior of a cell layer confined to a spherical surface. Our results thus identify curvature-induced velocity waves as a mode of collective cell migration, impacting the dynamical organization of 3D curved tissues.