Biology subjects

Saez, P.

Publications and source records attributed to Saez, P..

11 recordsLinked to original sources

bioRxiv2026

Computational insights on the competition between electrotaxis and durotaxis

Understanding how cells migrate in response to external cues has important implications for biology, medicine, and bioengineering. Chemical, mechanical, and electrical signals are the primary drivers of directed cell migration, and each has been extensively studied over the past decades. Among them, chemical cues were the first to be investigated and remain the most widely studied due to their undeniable role in in vivo guidance. Mechanical signals--particularly substrate stiffness gradients--have gained prominence for their ubiquity across cell types and their potential to direct migration. More recently, growing evidence suggests that electrotaxis offers a highly precise and programmable means to guide cell movement. Despite this, these cues are often studied in isolation, whereas in vivo they typically coexist and interact. Using wellestablished biophysical models, we investigate how mechanical and electrical signals cooperate and how they can be engineered to compete for control over cell migration. We demonstrate that an electric field can override and even reverse durotaxis, with outcomes that depend strongly on the specific cell type. To address this large variability in controlling cell migration, we propose particular steps toward further exploration. To support such future research, we provide a freely available platform for predicting electro-mechanical interactions in cell migration, based on a given cells sensing and signaling characteristics, which could tailor the mechanical and electrical signals that arise naturally during organ development, cancer invasion, or tissue regeneration.

biophysics↗

bioRxiv2025

Competing signaling pathways controls electrotaxis

Understanding how cells migrate following exogenous cues is one of the most fundamental questions for biology, medicine, and bioengineering. Growing evidence shows that electrotaxis, the directed cell migration toward electric potential gradients, represents a precise and programmable method to control cell migration. Most data suggest that the polarization of membrane components and the following downstream signaling are central to electrotaxis. Unfortunately, how these multiple mechanisms coordinate with the motile machinery of the cell to respond to an electric field is still poorly understood. Here, we develop a mechanistic model that explains and recapitulate electrotaxis across different cell types. Using the zebrafish proteome, we identify membrane proteins directly related to migration signaling pathways that polarize anodally and cathodally. Further, we show that simultaneous and asymmetric distribution of charged membrane receptors towards the anode and the cathode establishes multiple cooperative and competing stimuli for downstream signaling pathways. The resulting polarization of signals controls the actomyosin network dynamics, directing the anodal and cathodal migration of the cell. Our theoretical framework rationalizes the physical processes that determine electrotaxis across cell types and provides a physical framework to test multiple electrotactic pathways. These results together show us how to control cell migration to, e.g., enhance, cancel, or switch directed cell migration, which opens up new avenues not only to promote tissue regeneration or arrest tumor progression but also to design better biomimetic-engineered tissue constructs.

biophysics↗

bioRxiv2023

A multi-scale clutch model for adhesion complex mechanics

Cell-matrix adhesion is a central mechanical function to a large number of phenomena in physiology and disease, including morphogenesis, wound healing and tumor cell invasion. Today, how single cells responds to different extracellular cues has been comprehensibly studied. However, how the mechanical behavior of the main individual molecules that form an adhesion complex cooperatively respond to force within the adhesion complex has not been addressed. This is a key aspect in cell adhesion because how these cell adhesion molecules respond to force determines not only cell-matrix behavior but, ultimately, cell function. To answer this question, we develop a multi-scale computational model for adhesion complexes mechanics. Based on the classical clutch hypothesis, we model individual adhesion chains made of a contractile actin network, a talin rod and an integrin molecule that binds at individual adhesion sites on the extracellular matrix. We explore several scenarios of integrins dynamics and analyze the effects of diverse extracellular matrices on the behavior of the adhesion molecules and on the whole adhesion complex. Our results explains how every single component of the adhesion chain mechanically responds to the contractile actomyosin force and show how they control the tractions forces exerted by the cell on the extracellular space. Importantly, our computational results are in agreement with previous experimental data both at the molecular and cell level. Our multi-scale clutch model presents a step forward not only to further understand adhesion complexes mechanics but also to, e.g., engineer better biomimetic materials, repair biological tissues or arrest invasive tumor migration. Author summaryCell-matrix adhesions are directly implicated in key biological processes such as tissue development, regeneration and tumor cell invasion. These cell functions are determined by how adhesion complexes feel and respond to mechanical forces. Still, how forces are transmitted through the individual cell adhesion molecules that integrate the adhesion complex is poorly understood. To address this issue, we develop a multi-scale clutch model for adhesion complexes where individual adhesion chains, made of integrin and talin molecules, are considered within classical clutch models. This approach provides a rich mechanosensivity insight of how the mechanics of cell adhesion works. It allows to integrate accurate biophysical models of individual adhesion molecules into whole adhesion complex models. Our multi-scale clutch approach allows to extend our current knowledge of adhesion complexes for physiology and disease, e.g., the regeneration of biological tissues or arrest invasive tumor migration, and for engineering better biomimetic materials.

biophysics↗

bioRxiv2022

Cell response to extracellular matrix energy dissipation outweighs rigidity sensing

The mechanical properties of the extracellular matrix (ECM) determine cell differentiation, proliferation and migration through mechanoresponsive proteins including YAP. However, how different mechanical signals cooperate, synergize or compete to steer cell behavior remains poorly understood. Here, we have examined competition between the two major ECM mechanical cues, i.e. rigidity, which activates cell mechanosensing, and viscous energy dissipation, which reduces stiffness blunting cell mechanotransduction. To trigger competition, we have engineered protein hydrogels allowing concomitant modulation of stiffness and viscosity by mechanisms characteristic of native ECM. Culturing cells on these hydrogels, we have found that substrate energy dissipation attenuates YAP mechanosensing prevailing over stiffness cues. Hampered YAP activation on more dissipative substrates correlates with faster actin flow and smaller focal adhesions. Mechanistically, inhibition of actomyosin contractility reverses the outcome of the competition between rigidity and energy dissipation. Our results highlight the dominating contribution of substrate viscosity to the biology of the cell.

bioengineering↗

bioRxiv2022

Brain tissue mechanics is governed by microscale relations of the tissue constituents

Local mechanical tissue properties are a critical regulator of cell function in the central nervous system (CNS) during development and disorder. However, we still dont fully understand how the mechanical properties of individual tissue constituents, such as cell nuclei or myelin, determine tissue mechanics. Here we developed a model predicting local tissue mechanics, which induces non-affine deformations of the tissue components. Using the mouse hippocampus and cerebellum as model systems, we show that considering individual tissue components alone, as identified by immunohistochemistry, is not sufficient to reproduce the local mechanical properties of CNS tissue. Our results suggest that brain tissue shows a universal response to applied forces that depends not only on the amount and stiffness of the individual tissue constituents but also on the way how they assemble. Our model may unify current incongruences between the mechanics of soft biological tissues and the underlying constituents and facilitate the design of better biomedical materials and engineered tissues. To this end, we provide a freely-available platform to predict local tissue elasticity upon providing immunohistochemistry images and stiffness values for the constituents of the tissue.

biophysics↗

bioRxiv2022

A full computational model of cell motility: Early spreading, cell migration and competing taxis

Cell motility represents one of the most fundamental function in mechanobiology. Cell motility is directly implicated in development, cancer or tissue regeneration, but it also plays a key role in the future of tissue and biomedical engineering. Here, we derived a computational model of cell motility that incorporates the most important mechanisms toward cell motility: cell protrusion, polarization and retrograde flow. We first validate our model to explain two important types of cell migration, i.e. confined and ameboid cell migration, as well as all phases of the latter cell migration type, i.e. symmetric cell spreading, cell polarization and latter migration. Then, we use our model to investigate durotaxis and chemotaxis. The model predicts that chemotaxis alone induces larger migration velocities than durotaxis and that durotaxis is activated in soft matrices but not in stiff ones. More importantly, we analyze the competition between chemical and mechanical signals. We show that chemotaxis rules over durotaxis in most situations although durotaxis diminishes chemotaxis. Moreover, we show that inhibiting the effect of GTPases in actin polymerization at the cell front may allow durotaxis to take control over chemotaxis in soft substrates. Understanding how the main forces in cell motility cooperate, and how a precise manipulation of external cues may control directed cell migration is not only key for a fundamental comprehension of cell biology but also to engineer better biomimetic tissues. To this end, we provide a freely-available platform to predict all phases and modes of cell motility analyzed in this work.

biophysics↗

bioRxiv2022

Positive, negative and engineered durotaxis

Cell migration is a physical process central to life. Among others, it regulates embryogenesis, tissue regeneration and tumor growth. Therefore, understanding and controlling cell migration represent fundamental challenges in science. Specifically, the ability of cells to follow stiffness gradients, known as durotaxis, is ubiquitous across most cell types. Even so, certain cells follow positive stiffness gradients while others move along negative gradients. How the physical mechanisms involved in cell migration works to enable a wide range of durotactic responses is still poorly understood. Here, we provide a mechanistic rationale of durotaxis by integrating stochastic clutch models for cell adhesion with an active gel theory of cell migration. We show that positive and negative durotaxis found across cell types are explained by asymmetries in the cell adhesion dynamics. We rationalize durotaxis by an asymmetric mechanotransduction in the cell adhesion behavior that further polarizes the intracellular retrograde flow and the protruding velocity at the cell membrane. Our theoretical framework confirms previous experimental observations and explains positive and negative durotaxis. Moreover, we show how durotaxis can be engineer to manipulate cell migration, which has important implications in biology, medicine and bioengineering.

biophysics↗

bioRxiv2022

Mechanical Stimulation Shapes the Immunoregulatory Properties of Dendritic Cells

Motile cells such as immune and cancer cells experience large deformation events that result from the physical constraints they encounter while migrating within tissues or circulating between organs. It has become increasingly clear that these cells can survive and adapt to these changes in cell shape using dedicated shape sensing pathways. However, how shape sensing impacts their function and fate remains largely unknown. Here we identify a shape sensing mechanism that couples cell motility to expression of CCR7, the chemokine receptor that guides immune cells to lymph nodes. We found that this mechanism is controlled by the lipid metabolism enzyme cPLA2, requires an intact nuclear envelop and exhibits an exquisitely sensitive activation threshold tuned by ARP2/3 and its inhibitor Arpin. We further show that shape sensing through the ARP2/3-cPLA2 axis controls Ikk{beta}-NF{kappa}B-dependent transcriptional reprogramming of dendritic cells, which instructs them to migrate to lymph nodes in an immunoregulatory state compatible with their homeostatic tolerogenic function. These results highlight that the cell shape changes experienced by motile cells evolving within the complex environment of tissues can dictate their behavior and fate.

cell biology↗

bioRxiv2022

The laminin-keratin link shields the nucleus from mechanical deformation and signalling

The mechanical properties of the extracellular matrix (ECM) dictate tissue behaviour. In epithelial tissues, laminin is both a very abundant ECM component, and a key supporting element. Here we show that laminin hinders the mechanoresponses of breast epithelial cells by shielding the nucleus from mechanical deformation. Coating substrates with laminin-111, unlike fibronectin or collagen I, impairs cell response to substrate rigidity, and YAP nuclear localization. Blocking the laminin-specific integrin {beta}4 increases nuclear YAP ratios in a rigidity dependent manner, without affecting cell forces or focal adhesions. By combining mechanical perturbations and mathematical modelling, we show that {beta}4 integrins establish a mechanical linkage between the substrate and the keratin cytoskeleton, which stiffens the network and shields the nucleus from actomyosin-mediated mechanical deformation. In turn, this affects nuclear YAP mechanoresponses and chromatin methylation. Our results demonstrate a mechanism by which tissues can regulate their sensitivity to mechanical signals.

cell biology↗

bioRxiv2020

HIF2α is a Direct Regulator of Neutrophil Motility

Orchestrated recruitment of neutrophils to inflamed tissue is essential during initiation of inflammation. Inflamed areas are usually hypoxic, and adaptation to reduced oxygen pressure is typically mediated by hypoxia pathway proteins. However, it is still unclear how these factors influence the migration of neutrophils to and at the site of inflammation either during their transmigration through the blood-endothelial cell barrier, or their motility in the interstitial space. Here, we reveal that activation of the Hypoxia Inducible Factor-2 (HIF2) due to deficiency of HIF-prolyl hydroxylase domain protein-2 (PHD2) boosts neutrophil migration specifically through highly confined microenvironments. In vivo, the increased migratory capacity of PHD2-deficient neutrophils resulted in massive tissue accumulation in models of acute local inflammation. Using systematic RNAseq analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2-dependent neutrophil motility. Thus, we propose that the here identified novel PHD2-HIF2-RhoA axis is vital to the initial stages of inflammation as it promotes neutrophil movement through highly confined tissue landscapes.

immunology↗

bioRxiv2020

Evaluating features of scientific conferences: A call for improvements

Scientific conferences provide valuable opportunities for researchers across career stages and disciplines to present their latest work, and to network with their peers. These meetings have largely been held in-person with rapid proliferation in the number of meetings and attendees. Yet the format and quality of their organization lag behind what is possible and as a result, the current experience of attending conferences in many disciplines remains unchanged in many respects. We created a database of 270 national and international academic conferences held in-person during 2018-2019 in various disciplines and examined them for their features, costs and impact on the community. We found that many meetings could still be improved significantly in terms of diversity, inclusivity, promoting early career researcher (ECR) networking and career development, venue accessibility, and importantly, reducing the meetings carbon footprint. It is important to accelerate and mandate efforts to improve conferences so that researchers in all disciplines, in particular ECRs, consistently benefit from scientific gatherings, for years to come. We discuss a combination of approaches and recommendations to make conferences more modern, effective, equitable and intellectually productive for the research community and environmentally sustainable for our planet. "They always say time changes things, but you actually have to change them yourself." -- Andy Warhol

scientific communication and education↗