Universität Stuttgart
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Item Open Access Collective cell migration on collagen-I networks: the impact of matrix viscoelasticity(2022) Pajic-Lijakovic, Ivana; Milivojevic, Milan; Clark, Andrew G.Collective cell migration on extracellular matrix (ECM) networks is a key biological process involved in development, tissue homeostasis and diseases such as metastatic cancer. During invasion of epithelial cancers, cell clusters migrate through the surrounding stroma, which is comprised primarily of networks of collagen-I fibers. There is growing evidence that the rheological and topological properties of collagen networks can impact cell behavior and cell migration dynamics. During migration, cells exert mechanical forces on their substrate, resulting in an active remodeling of ECM networks that depends not only on the forces produced, but also on the molecular mechanisms that dictate network rheology. One aspect of collagen network rheology whose role is emerging as a crucial parameter in dictating cell behavior is network viscoelasticity. Dynamic reorganization of ECM networks can induce local changes in network organization and mechanics, which can further feed back on cell migration dynamics and cell-cell rearrangement. A number of studies, including many recent publications, have investigated the mechanisms underlying structural changes to collagen networks in response to mechanical force as well as the role of collagen rheology and topology in regulating cell behavior. In this mini-review, we explore the cause-consequence relationship between collagen network viscoelasticity and cell rearrangements at various spatiotemporal scales. We focus on structural alterations of collagen-I networks during collective cell migration and discuss the main rheological parameters, and in particular the role of viscoelasticity, which can contribute to local matrix stiffening during cell movement and can elicit changes in cell dynamics.Item Open Access Mechanosensory feedback loops during chronic inflammation(2023) Saha, Sarbari; Müller, Dafne; Clark, Andrew G.Epithelial tissues are crucial to maintaining healthy organization and compartmentalization in various organs and act as a first line of defense against infection in barrier organs such as the skin, lungs and intestine. Disruption or injury to these barriers can lead to infiltration of resident or foreign microbes, initiating local inflammation. One often overlooked aspect of this response is local changes in tissue mechanics during inflammation. In this mini-review, we summarize known molecular mechanisms linking disruption of epithelial barrier function to mechanical changes in epithelial tissues. We consider direct mechanisms, such as changes in the secretion of extracellular matrix (ECM)-modulating enzymes by immune cells as well as indirect mechanisms including local activation of fibroblasts. We discuss how these mechanical changes can modulate local immune cell activity and inflammation and perturb epithelial homeostasis, further dysregulating epithelial barrier function. We propose that this two-way relationship between loss of barrier function and altered tissue mechanics can lead to a positive feedback loop that further perpetuates inflammation. We discuss this cycle in the context of several chronic inflammatory diseases, including inflammatory bowel disease (IBD), liver disease and cancer, and we present the modulation of tissue mechanics as a new framework for combating chronic inflammation.Item Open Access A stiff extracellular matrix favors the mechanical cell competition that leads to extrusion of bacterially-infected epithelial cells(2022) Aparicio-Yuste, Raúl; Muenkel, Marie; Clark, Andrew G.; Gómez-Benito, María J.; Bastounis, Effie E.Cell competition refers to the mechanism whereby less fit cells (“losers”) are sensed and eliminated by more fit neighboring cells (“winners”) and arises during many processes including intracellular bacterial infection. Extracellular matrix (ECM) stiffness can regulate important cellular functions, such as motility, by modulating the physical forces that cells transduce and could thus modulate the output of cellular competitions. Herein, we employ a computational model to investigate the previously overlooked role of ECM stiffness in modulating the forceful extrusion of infected “loser” cells by uninfected “winner” cells. We find that increasing ECM stiffness promotes the collective squeezing and subsequent extrusion of infected cells due to differential cell displacements and cellular force generation. Moreover, we discover that an increase in the ratio of uninfected to infected cell stiffness as well as a smaller infection focus size, independently promote squeezing of infected cells, and this phenomenon is more prominent on stiffer compared to softer matrices. Our experimental findings validate the computational predictions by demonstrating increased collective cell extrusion on stiff matrices and glass as opposed to softer matrices, which is associated with decreased bacterial spread in the basal cell monolayer in vitro. Collectively, our results suggest that ECM stiffness plays a major role in modulating the competition between infected and uninfected cells, with stiffer matrices promoting this battle through differential modulation of cell mechanics between the two cell populations.Item Open Access Self-generated gradients steer collective migration on viscoelastic collagen networks(2022) Clark, Andrew G.; Maitra, Ananyo; Jacques, Cécile; Bergert, Martin; Pérez-González, Carlos; Simon, Anthony; Lederer, Luc; Diz-Muñoz, Alba; Trepat, Xavier; Voituriez, Raphaël; Matic Vignjevic, DanijelaGrowing evidence suggests that the physical properties of the cellular microenvironment influence cell migration. However, it is not currently understood how active physical remodelling by cells affects migration dynamics. Here we report that cell clusters seeded on deformable collagen-I networks display persistent collective migration despite not showing any apparent intrinsic polarity. Clusters generate transient gradients in collagen density and alignment due to viscoelastic relaxation of the collagen networks. Combining theory and experiments, we show that crosslinking collagen networks or reducing cell cluster size results in reduced network deformation, shorter viscoelastic relaxation time and smaller gradients, leading to lower migration persistence. Traction force and Brillouin microscopy reveal asymmetries in force distributions and collagen stiffness during migration, providing evidence of mechanical cross-talk between cells and their substrate during migration. This physical model provides a mechanism for self-generated directional migration on viscoelastic substrates in the absence of internal biochemical polarity cues.