Publications gallery Team Piel
2022
Atypical CXCL12 signaling enhances neutrophil migration by modulating nuclear deformability
Bianca Calì, Mathieu Deygas, Fabio Munari, Elisabetta Marcuzzi, Antonino Cassará, Lara Toffali, Massimo Vetralla, Mathilde Bernard, Matthieu Piel, Onelia Gagliano, Marta Mastrogiovanni, Carlo Laudanna, Nicola Elvassore, Barbara Molon, Pablo Vargas and Antonella Viola.
We showed that chemokines, the extracellular signals that guide cell migration in vivo, modulated nuclear plasticity to support neutrophil migration in restricted microenvironments. We propose that chemical cues regulate the nuclear plasticity of migrating leukocytes to optimize their motility in restricted microenvironments.
Actin Stress Fibers Response and Adaptation under Stretch
Roberto Bernal, Milenka Van Hemelryck, Basile Gurchenkov, and Damien Cuvelier.
We study the response of peripheral stress fibers (SFs) to external stretch in mammalian cells, plated onto deformable micropatterned substrates. A local fluorescence analysis reveals that an adaptation response is observed at the vicinity of the focal adhesion sites (FAs) due to its mechanosensor function. A model is proposed to take into account the effect of the applied stretch on the mechanics of the SF, from which relevant parameters of the healing process are obtained. As a result, the SFs display strain-softening features due to the incorporation of new actin material into the bundle. In contrast, the response under compression shows a reorganization with a constant actin material suggesting a gliding process of the SFs by the myosin II motors.
A mechano-osmotic feedback couples cell volume to the rate of cell deformation
Larisa Venkova, Amit Singh Vishen, Sergio Lembo, Nishit Srivastava, Baptiste Duchamp, Artur Ruppel, Alice Williart, Stéphane Vassilopoulos, Alexandre Deslys, Juan Manuel Garcia Arcos, Alba Diz-Muñoz, Martial Balland, Jean-François Joanny, Damien Cuvelier, Pierre Sens, and Matthieu Piel.
We show that a parameter central to both the physics and the physiology of the cell, its volume, depends on a mechano-osmotic coupling. We found that cells change their volume depending on the rate at which they change shape, when they spontaneously spread or when they are externally deformed. We propose a mechanosensitive pump and leak model to explain this phenomenon. Our model and experiments suggest that volume modulation depends on the state of the actin cortex and the coupling of ion fluxes to membrane tension.
T-cell-derived Hodgkin lymphoma has motility characteristics intermediate between Hodgkin and anaplastic large cell lymphoma. (Journal of Cellular and Molecular Medicine)
Julia Bein, Nadine Flinner, Björn Häupl, Aastha Mathur, Olga Schneider, Marwa Abu-Ayyad, Martin-Leo Hansmann, Matthieu Piel, Thomas Oellerich, and Sylvia Hartmann.
Based on proteomics and migration behaviour, T-cell-derived Classic Hodgkin lymphoma (cHL) is a neoplasm that shares features with both cHL and Anaplastic Large T-Cell Lymphoma (ALCL) and is not an ALCL with low tumour cell content. Complementary clinical studies on this lymphoma are warranted.
Genetic instability from a single S phase after whole-genome duplication
Simon Gemble, René Wardenaar, Kristina Keuper, Nishit Srivastava, Maddalena Nano, Anne-Sophie Macé, Andréa E. Tijhuis, Sara Vanessa Bernhard, Diana C. J. Spierings, Anthony Simon, Oumou Goundiam, Helfrid Hochegger, Matthieu Piel, Floris Foijer, Zuzana Storchová, and Renata Basto.
Human cells undergo high rates of DNA damage during DNA replication in the first S phase following induction of tetraploidy. Using DNA combing and single-cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we find that these defects result from a shortage of proteins during the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the genetic instability landscape that favours tumorigenesis after tetraploidization.
2021
Compromised nuclear envelope integrity drives TREX1-dependent DNA damage and tumor cell invasion. (CellPress)
Guilherme Pedreira de Freitas Nader, Sonia Agüera-Gonzalez, Fiona Routet, Matthieu Gratia, Mathieu Maurin, Valeria Cancila, Clotilde Cadart, Andrea Palamidessi, Rodrigo Nalio Ramos, Mabel San Roman, Matteo Gentili, Ayako Yamada, Alice Williart, Catalina Lodillinsky, Emilie Lagoutte, Catherine Villard, Jean-Louis Viovy, Claudio Tripodo, Jérôme Galon, Giorgio Scita, Nicolas Manel, Philippe Chavrier, Matthieu Piel.
Nuclear envelope ruptures induce DNA damage and the endoplasmic reticulum (ER)-associated exonuclease TREX1 translocates into the nucleus after nuclear envelope rupture and is required to induce DNA damage. Inside the mammary duct, cellular crowding leads to nuclear envelope ruptures that generate TREX1-dependent DNA damage, thereby driving the progression of in situ carcinoma to the invasive stage. DNA damage and nuclear envelope rupture markers were also enriched at the invasive edge of human tumors. DNA damage in mechanically challenged nuclei could affect the pathophysiology of crowded tissues by modulating proliferation and extracellular matrix degradation of normal and transformed cells.
Keywords: TREX1, nuclear envelope rupture, DNA damage, mammary duct carcinoma, tumor invasion, senescence, breast cancer, cGAS, confinement, epithelial to mesenchymal transition.
HIF2α is a direct regulator of neutrophil motility. (Blood)
Sundary Sormendi, Mathieu Deygas, Anupam Sinha, Mathilde Bernard, Anja Krüger, Ioannis Kourtzelis, Gregoire Le Lay, Pablo J Sáez, Michael Gerlach, Kristin Franke, Ana Meneses, Martin Kräter, Alessandra Palladini, Jochen Guck, Ünal Coskun, Triantafyllos Chavakis, Pablo Vargas, Ben Wielockx
We reveal that activation of hypoxia-inducible factor 2 (HIF2α) as a result of a deficiency in HIF prolyl hydroxylase domain protein 2 (PHD2) boosts neutrophil migration specifically through highly confined microenvironments. Using systematic RNA sequencing analyses and mechanistic approaches, we identified RhoA, a cytoskeleton organizer, as the central downstream factor that mediates HIF2α-dependent neutrophil motility. Thus, we propose that the novel PHD2-HIF2α-RhoA axis is vital to the initial stages of inflammation because it promotes neutrophil movement through highly confined tissue landscapes.
Pinching the cortex of live cells reveals thickness instabilities caused by myosin II motors. (Sciences Advances)
Valentin Laplaud, Nicolas Levernier, Judith Pineau, Mabel San Roman, Lucie Barbier, Pablo J Sáez, Ana-Maria Lennon-Duménil, Pablo Vargas, Karsten Kruse, Olivia du Roure, Matthieu Piel and Julien Heuvingh
Using two mutually attracted magnetic beads, one inside the cell and the other in the extracellular medium, we pinch the cortex of dendritic cells and provide an accurate and time-resolved measure of its thickness. Our observations draw a new picture of the cell cortex as a highly dynamic layer, harboring large fluctuations in its third dimension because of actomyosin contractility. We propose that the cortex dynamics might be responsible for the fast shape-changing capacity of highly contractile cells that use amoeboid-like migration.
2020
The nucleus acts as a ruler tailoring cell responses to spatial constraints (Science)
Vol. 370, Issue 6514
A. J. Lomakin, C. J. Cattin, D. Cuvelier, Z. Alraies, M. Molina, G. P. F. Nader, N. Srivastava,P. J. Saez, J. M. Garcia-Arcos, I. Y. Zhitnyak, A. Bhargava, M. K. Driscoll, E. S. Welf, R. Fiolka, R. J. Petrie,N. S. De Silva, J. M. González-Granado, N. Manel, A. M. Lennon-Duménil, D. J. Müller, M. Piel.
Cells rely on the nuclear ruler to modulate the motive force that enables their passage through restrictive pores in complex three-dimensional environments, a process relevant to cancer cell invasion, immune responses, and embryonic development.
2019
Myosin II Activity Is Selectively Needed for Migration in Highly Confined Microenvironments in Mature Dendritic Cells (Frontiers in Immunology)
Lucie Barbier, Pablo J Sáez, Rafaele Attia, Ana-Maria Lennon-Duménil, Ido Lavi, Matthieu Piel, Pablo Vargas
We identified a specific role of MyoII activity in the regulation of mDCs migration in highly confined microenvironments. Using microfluidic systems, we observed that during mDCs chemotaxis in 3D collagen gels under defined CCL21 gradients, MyoII activity was required to sustain their fast speed but not to orientate them toward the chemokine.
Macropinocytosis Overcomes Directional Bias in Dendritic Cells Due to Hydraulic Resistance and Facilitates Space Exploration (Developmental cell)
Hélène D Moreau, Carles Blanch-Mercader, Rafaele Attia, Mathieu Maurin, Zahraa Alraies, Doriane Sanséau, Odile Malbec, Maria-Graciela Delgado, Philippe Bousso, Jean-François Joanny, Raphaël Voituriez, Matthieu Piel, Ana-Maria Lennon-Duménil
The migration of immune cells can be guided by physical cues imposed by the environment, such as geometry, rigidity, or hydraulic resistance (HR). Neutrophils preferentially follow paths of least HR in vitro, a phenomenon known as barotaxis. The mechanisms and physiological relevance of barotaxis remain unclear. We show that barotaxis results from the amplification of a small force imbalance by the actomyosin cytoskeleton, resulting in biased directional choices.
Reconstitution of cell migration at a glance (Journal Of Cell Science)
Juan Manuel Garcia-Arcos, Renaud Chabrier, Mathieu Deygas, Guilherme Nader, Lucie Barbier, Pablo José Sáez, Aastha Mathur, Pablo Vargas, Matthieu Piel
In this Cell Science at a Glance article and accompanying poster, we present selected experimental setups that mimic different events that cells undergo during migration in vivo. These include polydimethylsiloxane (PDMS) devices to deform whole cells or organelles, micro patterning, nano-fabricated structures like grooves, and compartmentalized collagen chambers with chemical gradients. We also outline the main contribution of each technique to the understanding of different aspects of single-cell migration.
Polarization of Myosin II Refines Tissue Material Properties to Buffer Mechanical Stress. (Developmental Cell)
Ablation in Anchored
Tissue Expressing E-cad:GFP
Maria Duda, Natalie J Kirkland, Nargess Khalilgharibi, Melda Tozluoglu, Alice C Yuen, Nicolas Carpi, Anna Bove, Matthieu Piel, Guillaume Charras, Buzz Baum, Yanlan Mao
Through the development of a tissue-stretching device, we uncover a mechanosensitive pathway that regulates tissue responses to mechanical stress through the polarization of actomyosin across the tissue. We show that stretch induces the formation of linear multicellular actomyosin cables, which depend on Diaphanous for their nucleation.
2018
Spontaneous migration of cellular aggregates from giant keratocytes to running spheroids (PNAS)
of cellular aggregates from
giant keratocytes to running
spheroids
Grégory Beaune, Carles Blanch-Mercader, Stéphane Douezan, Julien Dumond, David Gonzalez-Rodriguez, Damien Cuvelier, Thierry Ondarçuhu, Pierre Sens, Sylvie Dufour, Michael P Murrell, Françoise Brochard-Wyart
This manuscript details modes of collective migration and the role of tissue dewetting in generating a symmetry breaking, which drives the spontaneous migration of cell aggregates en masse. This discovery, its corresponding assay, and the establishment of the underlying fundamental physical principles provide a powerful platform for further in-depth studies and insights into biological migration at the mesoscopic scale.
Size control in mammalian cells involves modulation of both growth rate and cell cycle duration. (Nature Communications)
Clotilde Cadart, Sylvain Monnier, Jacopo Grilli, Pablo J Sáez, Nishit Srivastava, Rafaele Attia, Emmanuel Terriac, Buzz Baum, Marco Cosentino-Lagomarsino, Matthieu Piel
Direct measurements of single-cell volumes over entire cell cycles on various mammalian cell lines and primary human cells.
Leukocyte Migration and Deformation in Collagen Gels and Microfabricated Constrictions (Methods in Molecular Biology)
Pablo J Sáez, Lucie Barbier, Rafaele Attia, Hawa-Racine Thiam, Matthieu Piel, Pablo Vargas
A multichamber device for the visualization of cell haptotaxis toward the collagen-binding chemokine CCL21. Microfabricated channels connected to small constrictions
2017
ATP promotes the fast migration of dendritic cells through the activity of pannexin 1 channels and P2X7 receptors (Science Signaling)
Pablo J. Sáez, Pablo Vargas, Kenji F. Shoji, Paloma A. Harcha, Ana-María Lennon-Duménil, Juan C. Sáez.
When dendritic cells (DCs) in peripheral tissues encounter danger-associated signals, such as microbial products or ATP released from damaged cells, they migrate to lymph nodes to activate T cells and initiate the adaptive immune response. Sáez et al. found that ATP stimulated P2X7 receptors in DCs, which resulted in the opening of pannexin 1 (Panx1) channels and the release of ATP as part of an autocrine loop that increased DC migration speed. DCs from Panx1-deficient mice migrated more slowly than did DCs from wild-type mice. When injected into the footpads of mice, ATP-treated Panx1-deficient DCs exhibited defective migration to draining lymph nodes. Together, these data suggest that P2X7 receptors and Panx1 channels facilitate the speedy migration of DCs to lymph nodes in response to danger signals.
2016
ESCRT III repairs nuclear envelope ruptures during cell migration to limit DNA damage and cell death. (Science)
M Raab, M Gentili, H de Belly, H R Thiam, P Vargas, A J Jimenez, F Lautenschlaeger, Raphaël Voituriez, A M Lennon-Duménil, N Manel, M Piel
We found that the nuclear envelope opened at high frequency in migrating mammalian cells during interphase, which allowed nuclear proteins to leak out and cytoplasmic proteins to leak in. This transient opening was caused by nuclear deformation and was rapidly repaired in an ESCRT (endosomal sorting complexes required for transport)–dependent manner.
Perinuclear Arp2/3-driven actin polymerization enables nuclear deformation to facilitate cell migration through complex environments. (Nature Communications)
Hawa-Racine Thiam, Pablo Vargas, Nicolas Carpi, Carolina Lage Crespo, Matthew Raab, Emmanuel Terriac, Megan C King, Jordan Jacobelli, Arthur S Alberts, Theresia Stradal, Ana-Maria Lennon-Dumenil, Matthieu Piel
We show that dendritic cells possess a mechanism to pass through micrometric constrictions. This mechanism is based on a rapid Arp2/3-dependent actin nucleation around the nucleus that disrupts the nuclear lamina, the main structure limiting nuclear deformability.
Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells. (Nature Cell Biology)
Pablo Vargas, Paolo Maiuri, Marine Bretou, Pablo J Sáez, Paolo Pierobon, Mathieu Maurin, Mélanie Chabaud, Danielle Lankar, Dorian Obino, Emmanuel Terriac, Matthew Raab, Hawa-Racine Thiam, Thomas Brocker, Susan M Kitchen-Goosen, Arthur S Alberts, Praveen Sunareni, Sheng Xia, Rong Li, Raphael Voituriez, Matthieu Piel, Ana-Maria Lennon-Duménil
We show that the migration of immature DCs depends on two main actin pools: a RhoA–mDia1-dependent actin pool located at their rear, which facilitates forward locomotion; and a Cdc42–Arp2/3-dependent actin pool present at their front, which limits migration but promotes antigen capture.
Deterministic patterns in cell motility.
Ido Lavi, Matthieu Piel, Ana-Maria Lennon-Duménil, Raphaël Voituriez and Nir S. Gov
We propose a physical model of such a competitive system, namely dendritic cells whose antigen capture function and migratory ability are coupled by myosin II. The model predicts that this coupling gives rise to a dynamic instability, whereby cells switch from persistent migration to unidirectional self-oscillation, through a Hopf bifurcation. Cells can then switch to periodic polarity reversals through a homoclinic bifurcation. These predicted dynamic regimes are characterized by robust features that we identify through in vitro trajectories of dendritic cells over long timescales and distances. We expect that competition for limited resources in other migrating cell types can lead to similar deterministic migration modes.
Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation. (Science Immunology)
Friederike Ufer, Pablo Vargas, Jan Broder Engler, Joseph Tintelnot, Benjamin Schattling, Hana Winkler, Simone Bauer, Nina Kursawe, Anne Willing, Oliver Keminer, Ora Ohana,Gabriela Salinas-Riester, Ole Pless, Dietmar Kuhl, Manuel A. Friese.
Skin-migratory dendritic cells (migDCs) are pivotal antigen-presenting cells that continuously transport antigens to draining lymph nodes and regulate immune responses. However, identification of migDCs is complicated by the lack of distinguishing markers, and it remains unclear which molecules determine their migratory capacity during inflammation. We show that, in the skin, the neuronal plasticity molecule activity regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc/Arg3.1) was strictly confined to migDCs. Mechanistically, Arc/Arg3.1 was required for accelerated DC migration during inflammation because it regulated actin dynamics through nonmuscle myosin II. Accordingly, Arc/Arg3.1 dependent DC migration was critical for mounting T cell responses in experimental autoimmune encephalomyelitis and allergic contact dermatitis. Thus, Arc/Arg3.1 was restricted to migDCs in the skin and drove fast DC migration by exclusively coordinating cytoskeletal changes in response to inflammatory challenges. These findings commend Arc/Arg3.1 as a universal switch in migDCs that may be exploited to selectively modify immune responses.
2015
Actin flows mediate a universal coupling between cell speed and cell persistence. (Cell)
Fluorescence Time-Lapse Movie of mBMDCs in 2D Confinement
Movie of mBMDCs in 2D
Confinement
Paolo Maiuri, Jean-François Rupprecht, Stefan Wieser, Verena Ruprecht, Olivier Bénichou, Nicolas Carpi, Mathieu Coppey, Simon De Beco, Nir Gov, Carl-Philipp Heisenberg, Carolina Lage Crespo, Franziska Lautenschlaeger, Maël Le Berre, Ana-Maria Lennon-Dumenil, Matthew Raab, Hawa-Racine Thiam, Matthieu Piel, Michael Sixt, Raphaël Voituriez
We show on the basis of experimental data in vitro and in vivo that cell persistence, which quantifies the straightness of trajectories, is robustly coupled to cell migration speed. We suggest that this universal coupling constitutes a generic law of cell migration, which originates in the advection of polarity cues by an actin cytoskeleton undergoing flows at the cellular scale.
Confinement and Low Adhesion Induce Fast Amoeboid Migration of Slow Mesenchymal Cells (Cell).
Yan-Jun Liu, Maël Le Berre, Franziska Lautenschlaeger, Paolo Maiuri, Andrew Callan-Jones, Mélina Heuzé, Tohru Takaki, Raphaël Voituriez, Matthieu Piel
We investigated how confinement and adhesion affect mesenchymal-amoeboid transition. We report that, in the absence of focal adhesions and under conditions of confinement, mesenchymal cells can spontaneously switch to a fast amoeboid migration phenotype.
2014
ESCRT machinery is required for plasma membrane repair. (Science)
Jimenez AJ, Maiuri P, Lafaurie-Janvore J, Divoux S, Piel M, Perez F.
Plasma membrane damage can be triggered by numerous phenomena, and efficient repair is essential for cell survival. Endocytosis, membrane patching, or extracellular budding can be used for plasma membrane repair. We found that endosomal sorting complex required for transport (ESCRT), involved previously in membrane budding and fission, plays a critical role in plasma membrane repair. ESCRT proteins were recruited within seconds to plasma membrane wounds. Quantitative analysis of wound closure kinetics coupled to mathematical modeling suggested that ESCRTs are involved in the repair of small wounds. Real-time imaging and correlative scanning electron microscopy (SEM) identified extracellular buds and shedding at the site of ESCRT recruitment. Thus, the repair of certain wounds is ensured by ESCRT-mediated extracellular shedding of wounded portions.
2013
ESCRT-III Assembly and Cytokinetic Abscission Are Induced by Tension Release in the Intercellular Bridge (Science)
Julie Lafaurie-Janvore, Paolo Maiuri, Irène Wang, Mathieu Pinot, Jean-Baptiste Manneville, Timo Betz, Martial Balland, Matthieu Piel
We found that pulling forces exerted by daughter cells on the intercellular bridge appear to regulate abscission. Counterintuitively, these forces prolonged connection, whereas a release of tension induced abscission.