Biology subjects

GABRIELE, S.

Publications and source records attributed to GABRIELE, S..

4 recordsLinked to original sources

bioRxiv2023

A minimal physical model for curvotaxis driven by curved protein complexes at the cell's leading edge

Cells often migrate on curved surfaces inside the body, such as curved tissues, blood vessels or highly curved protrusions of other cells. Recent in-vitro experiments provide clear evidence that motile cells are affected by the curvature of the substrate on which they migrate, preferring certain curvatures to others, termed "curvotaxis". The origin and underlying mechanism that gives rise to this curvature sensitivity are not well understood. Here, we employ a "minimal cell" model which is composed of a vesicle that contains curved membrane protein complexes, that exert protrusive forces on the membrane (representing the pressure due to actin polymerization). This minimal-cell model gives rise to spontaneous emergence of a motile phenotype, driven by a lamellipodia-like leading edge. By systematically screening the behaviour of this model on different types of curved substrates (sinusoidal, cylinder and tube), we show that minimal ingredients and energy terms capture the experimental data. The model recovers the observed migration on the sinusoidal substrate, where cells move along the grooves (minima), while avoiding motion along the ridges. In addition, the model predicts the tendency of cells to migrate circumferentially on convex substrates and axially on concave ones. Both of these predictions are verified experimentally, on several cell types. Altogether, our results identify the minimization of membrane-substrate adhesion energy and binding energy between the membrane protein complexes as key players of curvotaxis in cell migration.

biophysics↗

bioRxiv2023

Stretch-injury promotes activation of microglia with enhanced phagocytic and synaptic stripping activities

Microglial cells must act as the first line of defense of the central nervous system, but they can be exposed to various mechanical signals that may trigger their activation. While the impact of chemical signaling on brain cells has been studied in detail, our current understanding of the mechanical signaling in microglia is still limited. To address this challenge, we exposed microglial cells to a single mechanical stretch and compared their behavior to chemical activation by lipopolysaccharide treatment. Here we show that stretching microglial cells results in their activation, demonstrating a strong mechanosensitivity. Stretched microglial cells exhibited higher Iba1 protein levels, a denser actin cytoskeleton and migrated more persistently. In contrary to LPS-treated cells, stretched microglia maintain a robust secretory profile of chemokines and cytokines, except for TNF-, highlighting the relevance of this model. Interestingly, a single stretch injury results in more compacted chromatin and DNA damage, suggesting possible long-term genomic instabilities in stretched microglia. Using neuronal networks in compartmentalized microfluidic chambers, we found that stretched microglial cells exhibit enhanced phagocytic and synaptic stripping activities. Altogether, our results propose that the immune potential of microglial cells can be unlocked by stretching events to maintain brain tissue homeostasis after mechanical injury.

biophysics↗

bioRxiv2022

Mechanoresponse of epithelial monolayers to in-plane and out-of-plane curvatures imposed by 3D microwells

The organization of epithelial tissues with precise spatial definition is essential to various biological processes and to generate curved epithelial structures. However, the regulation of the architecture and dynamics of collective epithelial assemblies by the matrix curvature remains understudied. Here, we photopolymerize microwells of various diameters in hydrogels to form curved epithelial structures such as breast epithelial lobules, and study how in-plane and out-of-plane curvatures modulate the mechanoresponse of epithelial tissues. In-plane curvature governed by the microwell radius drives the centripetal orientation of cells and nuclei close to the edge of the microwell, resulting from contractile forces exerted by a supracellular actomyosin purse-string. Convex out-of-plane curvature imposed at the microwell entrance leads to a vertical orientation of the nuclei towards the microwell axis. We demonstrated that increasing the out-of-plane curvature leads to more flatten and elongated nuclear morphologies with high levels of compacted chromatin. Epithelial cells exhibit higher directionality and speed around the microwell edge, demonstrating that the out-of-plane curvature significantly enhances the cellular trafficking. These findings demonstrate the importance of in-plane and out-of-plane curvatures in epithelial organization and how both can be leveraged to facilitate the engineering of curved structures to study curvature-dependent mechanotransduction pathways.

biophysics↗

bioRxiv2022

Geometry-driven migration efficiency of minimal cell clusters

The directed migration of epithelial cell collectives through coordinated movements plays a crucial role in various physiological and pathological processes and is increasingly understood at the level of large confluent monolayers. However, numerous processes rely on the migration of small groups of polarized epithelial clusters in complex environments, and their responses to external geometries remain poorly understood. To address this, we cultivated primary epithelial keratocyte tissues on adhesive microstripes, creating autonomous epithelial clusters with well-defined geometries. We showed that their migration efficiency is strongly influenced by the contact geometry, and the orientation of cell-cell contacts with respect to the direction of migration. To elucidate the underlying mechanisms, we systematically explored possible cell-cell interactions using a minimal active matter model. Our investigations revealed that a combination of velocity and polarity alignment with contact regulation of locomotion captures the experimental data, which we then validated via force and intracellular stress measurements. Furthermore, we predict that this combination of rules enables efficient navigation in complex geometries, which we confirm experimentally. Altogether, our findings provide a conceptual framework for extracting interaction rules governing the behavior of active systems interacting with physical boundaries, as well as designing principles for collective navigation in complex microenvironments.

biophysics↗