Biology subjects

Francis, E. A.

Publications and source records attributed to Francis, E. A..

8 recordsLinked to original sources

bioRxiv2026

Mechanochemical Feedback between Cell Shape and Intracellular Mechanics Revealed by a Finite-Element Framework

Cell shape and mechanics are intricately connected and tightly regulated by mechanochemical events including biochemical signaling, cytoskeletal remodeling, and plasma membrane mechanics. While experimental advances in microscopy have shed light on the intricate coordination involved in cell shape change in response to different cues, the ability to conduct three-dimensional simulations in realistic geometries remains an open computational challenge. In this work, we develop a finite-element framework that incorporates advection-diffusion-reaction equations coupled with equations governing the kinematics of a deformable interface representing the cell membrane. We applied this framework to three distinct coupled mechanochemical systems, each governed by geometric partial differential equations, resulting in large deformations of the interface. In all three examples, our simulations revealed the emergence of feedback between cellular signaling, cytoskeletal organization, and cell shape. In our first two sets of simulations, we observed that cell migration and neutrophil protrusion were regulated by membrane tension-mediated feedback. In our final application, we predicted shape changes of a dendritic spine starting from a realistic geometry, and found that the complex shape of the spine gives rise to localized regimes of actin cytoskeleton remodeling not previously observed with idealized geometries. Thus, our finite-element framework allows us to generate new mechanistic insights for biophysical problems.

cell biology↗

bioRxiv2026

A predictive mechanochemical modeling framework for the deformation and remodeling of the nuclear lamina

1Nuclear envelope stretch and rupture are common to cell spreading and migration in a variety of microenvironments, leading to marked changes in nucleocytoplasmic transport. Predicting cell response to different mechanochemical cues that are transmitted to the nucleus remains an open problem in the field of mechanomedicine. We developed a predictive modeling framework to examine how nuclear deformation on substrates with different nanotopographies influences nucleocytoplasmic transport and rearrangement of the nuclear lamina. Using the finite element method, we simulated nuclear compression by the perinuclear actin cap on substrates with arrays of nanopillars, modeling the nuclear envelope as a nonlinear elastic structure and coupling deformations to a biochemical model of lamin remodeling and nucleocytoplasmic transport. These simulations predicted regions of high nuclear envelope stretch adjacent to cell-nanopillar contacts, leading to maximized nuclear envelope tension on small nanopillars spaced by 4-5 microns. We then considered the effects on nuclear transport of YAP and TAZ and found that increased nuclear compression led to YAP/TAZ nuclear localization in agreement with previous experiments. Furthermore, the simulated force load per lamin was maximized on nanopillar substrates with high nuclear stretch. The magnitude of this load was modulated by the rate of actin cap assembly and the overall expression level of lamin A/C - decreasing lamin content in the nuclear envelope led to a higher likelihood of rupture. We validated this prediction in subsequent experiments with lamin-depleted U2OS cells, establishing the central importance of lamin transport and microenvironment nanotopography to nuclear mechanotransduction. 2 SignificanceCell nuclei commonly experience large strains, but existing computational models do not explain the coupling between such deformations and molecular transport. Here, we present a modeling framework that includes the mechanics of nuclear deformations and the reaction-transport of molecules within the cytoplasm, nuclear envelope, and nuclear interior. As a well-controlled setup for comparing experiments and simulations, we consider nuclear indentations exhibited by cells on nanopillar substrates. Our simulations recapitulate measurements of nuclear YAP/TAZ localization from the literature and predict that low-lamin cells experience higher force loads at the nuclear envelope. We validate this prediction experimentally, showing that lamin-depleted cells are more likely to exhibit nuclear rupture. Overall, our framework presents opportunities to predict nuclear mechanoadaptation to different microenvironments.

biophysics↗

bioRxiv2025

Systems modeling reveals that store-operated calcium entry modulates force and fatigue during exercise

The dynamics of calcium ions (Ca2+) in skeletal muscles link electrochemical activation and contractile force generation. Recent experimental data suggest that store-operated Ca2+ entry (SOCE), the process of extracellular Ca2+ influx upon depletion of Ca2+ from the sarcoplasmic reticulum (SR), helps delay the onset of muscle fatigue during exercise. We hypothesize that SOCE regulates force generation during prolonged muscle activity by allowing for sustained Ca2+ release from the SR. We test this hypothesis with a quantitative biophysical model that simulates the biochemical events of muscle contraction, from depolarization at the T-tubules to Ca2+ release from the SR to Ca2+ binding and force generation throughout the myoplasm. We also consider the balance between Ca2+ removal from the myoplasm and SOCE through the T-tubule membrane, along with mitochondrial uptake of free Ca2+ and phosphate. We use the model to test the effects of SOCE inhibition on force production. The magnitude of myoplasmic Ca2+ and force are lower in SOCE knockout cells, especially when SOCE reduction is combined with impaired uptake of phosphate by mitochondria. We then test the effects of SOCE during resistance exercise or high-intensity interval training. These simulations predict a context-dependent relationship between force generation and SOCE - increased SOCE is associated with greater force production during resistance exercise, but worsens the effects of fatigue in certain cases of high-intensity training. Such SOCE-induced fatigue is attributed to phosphate accumulation in the myoplasm and can be mitigated by increased rates of mitochondrial phosphate uptake. Key pointsO_LIStore-operated calcium entry (SOCE) provides a mechanism for calcium ion (Ca2+) influx following depletion of Ca2+ from intracellular stores such as the sarcoplasmic reticulum (SR). C_LIO_LIRecent experiments suggest that SOCE is an important modulator of contractile force generation in skeletal muscle. C_LIO_LIHere, we develop a computational model of Ca2+ handling in the myoplasm, SR, and mitochondria and the resulting effects on force generation in skeletal muscle fibers to examine the role of SOCE during extended periods of activity. C_LIO_LIOur model predicts that increasing SOCE leads to enhanced force over periods of repeated stimuli during resistance exercise due to sustained Ca2+ release. C_LIO_LIOur simulations show a complex relationship between SOCE and force production during high-intensity interval training, with exacerbated phosphate accumulation in the myoplasm leading to force reduction for very high levels of SOCE. This effect can be mitigated by enhanced mitochondrial phosphate uptake. C_LI First author profileEmmet Francis is a K99/R00 awardee in the Rangamani Lab at UC San Diego whose research explores the intersection between cell signaling and mechanics. His doctoral research in the Heinrich Lab at UC Davis examined the role of calcium bursts in neutrophil chemotaxis and phagocytosis. More recently, he has used spatial modeling approaches to shed light on the role of nanoscale membrane curvature and nuclear deformation in YAP/TAZ mechanotransduction. In his own research lab, he plans to use both experiments and computational models to probe the mechanisms of bidirectional mechanotransduction in neutrophils. Abstract figureThis study uses systems modeling to demonstrate a role for SOCE in sustained force generation during exercise. SOCE leads to two competing effects on contractile force in myofibers - increased crossbridge cycling due to elevated myoplasmic Ca2+ enhances force, whereas increased accumulation of myoplasmic phosphate (due to increased ATP hydrolysis) can lead to force reduction (fatigue). The tradeoff between these two effects is modulated by phosphate uptake into mitochondria via the phosphate carrier PiC. Figure created in BioRender. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/655415v3_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@5c9dc9org.highwire.dtl.DTLVardef@7b06b1org.highwire.dtl.DTLVardef@f478c5org.highwire.dtl.DTLVardef@24d321_HPS_FORMAT_FIGEXP M_FIG C_FIG

systems biology↗

bioRxiv2024

Nanoscale curvature of the plasma membrane regulates mechanoadaptation through nuclear deformation and rupture

Nuclear translocation of the transcription regulatory proteins YAP and TAZ is a critical readout of cellular mechanotransduction. Recent experiments have demonstrated that cells on substrates with well-defined nanotopographies demonstrate mechanoadaptation through a multitude of effects - increased integrin endocytosis as a function of nanopillar curvature, increased local actin assembly on nanopillars but decreased global cytoskeletal stiffness, and enhanced nuclear deformation. How do cells respond to local nanotopo-graphical cues and integrate their responses across multiple length scales? This question is addressed using a biophysical model that incorporates plasma membrane (PM) curvature-dependent endocytosis, PM curvature-sensitive actin assembly, and stretch-induced opening of nuclear pore complexes (NPCs) in the nuclear envelope (NE). This model recapitulates lower levels of global cytoskeletal assembly on nanopillar substrates, which can be partially compensated for by local actin assembly and NE indentation, leading to enhanced YAP/TAZ transport through stretched NPCs. Using cell shapes informed by electron micrographs and fluorescence images, the model predicts lamin A and F-actin localization around nanopillars, in good agreement with experimental measurements. Finally, simulations predict nuclear accumulation of YAP/TAZ following rupture of the NE and this is validated by experiments. Overall, this study indicates that nanotopography tunes mechanoadaptation through both positive and negative feedback on mechanotransduction. Table of Contents O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/619165v2_ufig1.gif" ALT="Figure 1"> View larger version (84K): org.highwire.dtl.DTLVardef@ec6d5aorg.highwire.dtl.DTLVardef@1ff6ec2org.highwire.dtl.DTLVardef@c09f46org.highwire.dtl.DTLVardef@18df50_HPS_FORMAT_FIGEXP M_FIG C_FIG This study uses experiments and biophysical modeling to examine the response and adaptation of cells to nanoscale topography of surfaces. It is shown that cytoskeletal assembly and nuclear localization of transcription regulatory factors such as YAP/TAZ can be tuned by nanoscale membrane curvature and nuclear deformation and rupture due to substrate nanotopography.

biophysics↗

bioRxiv2024

Spatial Modeling Algorithms for Reactions and Transport (SMART) in Biological Cells

Biological cells rely on precise spatiotemporal coordination of biochemical reactions to control their many functions. Such cell signaling networks have been a common focus for mathematical models, but they remain challenging to simulate, particularly in realistic cell geometries. Herein, we present our software, Spatial Modeling Algorithms for Reaction and Transport (SMART), a package that takes in high-level user specifications about cell signaling networks and molecular transport, and then assembles and solves the associated mathematical and computational systems. SMART uses state-of-the-art finite element analysis, via the FEniCS Project software, to efficiently and accurately resolve cell signaling events over discretized cellular and subcellular geometries. We demonstrate its application to several different biological systems, including YAP/TAZ mechanotransduction, calcium signaling in neurons and cardiomyocytes, and ATP generation in mitochondria. Throughout, we utilize experimentally-derived realistic cellular geometries represented by well-conditioned tetrahedral meshes. These scenarios demonstrate the applicability, flexibility, accuracy and efficiency of SMART across a range of temporal and spatial scales.

systems biology↗

bioRxiv2023

Computational modeling establishes mechanotransduction as a potent entrainment cue for the mammalian circadian clock

Mechanotransduction, which is the integration of mechanical signals from the cells external environment to changes in intracellular signaling, governs many cellular functions. Recent studies have shown that the mechanical state of the cell is also coupled to the cellular circadian clock. To investigate possible interactions between circadian rhythms and cellular mechanotransduction, we have developed a computational model that integrates the two pathways. We postulated that the translocation of the transcriptional regulators YAP/TAZ and MRTF into the nucleus leads to altered expression of circadian proteins. Simulations from our model predict that lower levels of cytoskeletal activity are associated with longer circadian oscillation periods and higher oscillation amplitudes, consistent with recent experimental observations. Furthermore, accumulation of YAP/TAZ and MRTF in the nucleus causes circadian oscillations to decay. These effects hold both at the single-cell level and within a population-level framework. Finally, we investigated the effects of mutations in YAP or lamin A, the latter of which lead to a class of diseases known as laminopathies. Oscillations in circadian proteins are substantially weaker in populations of cells with in silico mutations in YAP or lamin A, suggesting that defects in mechanotransduction can disrupt the circadian clock in certain disease states. However, by reducing substrate stiffness, we were able to restore normal oscillatory behavior, suggesting a possible compensatory mechanism. Thus our study identifies that mechanotransduction could be a potent modulatory cue for cellular clocks and this crosstalk can be leveraged to rescue the circadian clock in disease states.

systems biology↗

bioRxiv2022

Integrative experimental/computational approach establishes active cellular protrusion as the primary driving force of phagocytic spreading by immune cells

The dynamic interplay between cell adhesion and protrusion is a critical determinant of many forms of cell motility. When modeling cell spreading on adhesive surfaces, traditional mathematical treatments often consider passive cell adhesion as the primary, if not exclusive, mechanistic driving force of this cellular motion. To better assess the contribution of active cytoskeletal protrusion to immune-cell spreading during phagocytosis, we here develop a computational framework that allows us to optionally investigate both purely adhesive spreading ("Brownian zipper hypothesis") as well as protrusion-dominated spreading ("protrusive zipper hypothesis"). We model the cell as an axisymmetric body of highly viscous fluid surrounded by a cortex with uniform surface tension and incorporate as potential driving forces of cell spreading an attractive stress due to receptor-ligand binding and an outward normal stress representing cytoskeletal protrusion, both acting on the cell boundary. We leverage various model predictions against the results of a directly related experimental companion study of human neutrophil phagocytic spreading on substrates coated with different densities of antibodies. We find that the concept of adhesion-driven spreading is incompatible with experimental results such as the independence of the cell-spreading speed on the density of immobilized antibodies. In contrast, the protrusive zipper model agrees well with experimental findings and, when adapted to simulate cell spreading on discrete adhesion sites, it also reproduces the observed positive correlation between antibody density and maximum cell-substrate contact area. Together, our integrative experimental/computational approach shows that phagocytic spreading is driven by cellular protrusion, and that the extent of spreading is limited by the density of adhesion sites. Author SummaryTo accomplish many routine biological tasks, cells must rapidly spread over different types of surfaces. Here, we examine the biophysical underpinnings of immune cell spreading during phagocytosis, the process by which white blood cells such as neutrophils engulf pathogens or other foreign objects. Our computational framework models the case in which a human neutrophil spreads over a flat surface coated with antibodies, which we also test experimentally in a companion paper. Our primary purpose is to assess whether phagocytic spreading is actively driven by protrusive forces exerted by the cell, or passively by adhesive forces acting between receptors in the cell membrane and antibodies on the surface. By directly comparing our model predictions to experimental results, we demonstrate that phagocytic spreading is primarily driven by protrusion, but the extent of spreading is still limited by the availability of binding sites. Our findings improve the fundamental understanding of phagocytosis and may also pave the way for future investigations of the balance between adhesion and protrusion in other forms of cell spreading, such as wound healing or cancer cell migration.

biophysics↗

bioRxiv2022

Mechanisms of frustrated phagocytic spreading of human neutrophils on antibody-coated surfaces

Complex motions of immune cells are an integral part of diapedesis, chemotaxis, phagocytosis, and other vital processes. To better understand how immune cells execute such motions, we present a detailed analysis of phagocytic spreading of human neutrophils on flat surfaces functionalized with different densities of immunoglobulin G (IgG) antibodies. We visualize the cell-substrate contact region at high resolution and without labels using reflection interference contrast microscopy (RICM) and quantify how the area, shape, and position of the contact region evolves over time. We find that the likelihood of the cell commitment to spreading strongly depends on the surface density of IgG, but the rate at which the substrate-contact area of spreading cells increases does not. Validated by a theoretical companion study, our results resolve controversial notions about the mechanisms controlling cell spreading, establishing that active forces generated by the cytoskeleton rather than cell-substrate adhesion primarily drive cellular protrusion. Adhesion, on the other hand, aids phagocytic spreading by regulating the cell commitment to spreading, the maximum cell-substrate contact area, and the directional movement of the contact region. SummaryThe detailed analysis of immune-cell spreading on antibody-coated surfaces establishes that active cytoskeletal protrusion rather than passive substrate adhesion drives phagocytic spreading.

biophysics↗