Regulation of epithelial tissue homeostasis by active transepithelial transport
Huiqiong Wu,
Charlie Duclut,
Gregory Arkowitz,
Ranjith Chilupuri,
Tien Dang,
Jacques Prost,
Benoît Ladoux,
René-Marc Mège
Proceedings of the National Academy of Sciences of the United States of America
122
e2503156122
(2025)
| Journal
Epithelia are intricate tissues whose function is intimately linked to mechanics. While mechanobiology has primarily focused on factors such as cell-generated contractility and mechanical properties of extracellular matrix, an interesting mechanobiological paradigm highlights the role of osmotic and mechanical pressures in shaping epithelial tissues. In our study, we developed an in vitro model of cell-coated microsized hydrogel spheres (MHSs) which allows us to decipher the interplay between cellular activities and tissue mechanics. Drastic, isotropic MHS compressions were observed once the epithelia reached confluence. Further studies revealed that the compression was a process independent of cell contractility but rather regulated by active transepithelial fluid flow. Compressive stresses of about 7 kPa are generated by such an active hydraulic mechanism. Tissue homeostasis is then maintained by a fine balance between cell proliferation and extrusion. Our findings demonstrate the critical role of fluid transport in generating mechanical forces within epithelial tissues. Supported by a theoretical mechanohydraulic model, a mechanistic framework for understanding the intricate interplay between cellular processes and tissue mechanics was established. These results challenge traditional views of epithelial tissue mechanics, emphasizing the pivotal influence of osmotic and mechanical pressures in shaping tissues. We anticipate that this study will advance the understanding of epithelial tissue development, the maintenance of homeostasis, and the mechanisms underlying pathological conditions.
Capturing nematic order on tissue surfaces of arbitrary geometry
Julia Eckert,
Toby G. R. Andrews,
Joseph Pollard,
Yuan Shen,
Patricia Essebier,
Benoît Ladoux,
Anne K. Lagendijk,
Rashmi Priya,
Alpha S. Yap, et al.
Nature Communications
16
7596
(2025)
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A leading paradigm for understanding the large-scale behavior of tissues is via generalizations of liquid crystal physics; much like liquid crystals, tissues combine fluid-like, viscoelastic behaviors with local orientational order, such as nematic symmetry. Whilst aspects of quantitative agreement have been achieved for flat monolayers, the most striking features of tissue morphogenesis—including symmetry breaking, folding, and invagination—concern surfaces with complex curved geometries in three dimensions. As yet, however, characterizing such behaviors has been frustrated due to the absence of proper image analysis methods; current state-of-the-art methods almost exclusively rely on two-dimensional intensity projections of multiple image planes, which superimpose data and lose geometric information that can be crucial. Here, we describe an analysis pipeline that properly captures the nematic order and topological defects associated with tissue surfaces of arbitrary geometry, which we demonstrate in the context of in vitro multicellular aggregates and in vivo zebrafish hearts.
Flocking and giant fluctuations in epithelial active solids
Proceedings of the National Academy of Sciences of the United States of America
122
e2421327122
(2025)
| Journal
The collective motion of epithelial cells is a fundamental biological process which plays a significant role in embryogenesis, wound healing, and tumor metastasis. While it has been broadly investigated for over a decade both in vivo and in vitro, large-scale coherent flocking phases remain underexplored and have so far been mostly described as fluid. In this work, we report an additional mode of large-scale collective motion for different epithelial cell types in vitro with distinctive features. By tracking individual cells, we show that cells move over long time scales coherently not as a fluid, but as a polar elastic solid with negligible cell rearrangements. Our analysis reveals that this solid flocking phase exhibits signatures of long-range polar order, accompanying with scale-free correlations of the transverse component of velocity fluctuations, anomalously large density fluctuations, and shear waves. Based on a general theory of active polar solids, we argue that these features result from massless orientational Goldstone mode, which, in contrast to polar fluids where they are generic, require the decoupling of global rotations of the polarity and in-plane elastic deformations in polar solids. We theoretically show and consistently observe in experiments that the fluctuations of elastic deformations diverge for large system sizes in such polar active solid phases, leading eventually to rupture and thus potentially loss of tissue integrity at large scales.
Force transmission is a master regulator of mechanical cell competition
Andreas Schoenit,
Siavash Monfared,
Lucas Anger,
Carine Rosse,
Varun Venkatesh,
Lakshmi Balasubramaniam,
Elisabetta Marangoni,
Philippe Chavrier,
René-Marc Mège, et al.
Nature Materials
24
966-976
(2025)
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Cell competition is a tissue surveillance mechanism for eliminating unwanted cells, being indispensable in development, infection and tumourigenesis. Although studies have established the role of biochemical mechanisms in this process, due to challenges in measuring forces in these systems, how mechanical forces determine the competition outcome remains unclear. Here we report a form of cell competition that is regulated by differences in force transmission capabilities, selecting for cell types with stronger intercellular adhesion. Direct force measurements in ex vivo tissues and different cell lines reveal that there is an increased mechanical activity at the interface between two competing cell types, which can lead to large stress fluctuations resulting in upward forces and cell elimination. We show how a winning cell type endowed with a stronger intercellular adhesion exhibits higher resistance to elimination and benefiting from efficient force transmission to the neighbouring cells. This cell elimination mechanism could have broad implications for keeping the strong force transmission ability for maintaining tissue boundaries and cell invasion pathology.
Dynamic forces shape the survival fate of eliminated cells
Lakshmi Balasubramaniam,
Siavash Monfared,
Aleksandra Ardaševa,
Carine Rosse,
Andreas Schoenit,
Tien Dang,
Chrystelle Maric,
Mathieu Hautefeuille,
Leyla Kocgozlu, et al.
Tissues eliminate unfit, unwanted or unnecessary cells through cell extrusion, and this can lead to the elimination of both apoptotic and live cells. However, the mechanical signatures that influence the fate of extruding cells remain unknown. Here we show that modified force transmission across adherens junctions inhibits apoptotic cell eliminations. By combining cell experiments with varying levels of E-cadherin junctions and three-dimensional modelling of cell monolayers, we find that these changes not only affect the fate of the extruded cells but also shift extrusion from the apical to the basal side, leading to cell invasion into soft collagen gels. We generalize our findings using xenografts and cysts cultured in matrigel, derived from patients with breast cancer. Our results link intercellular force transmission regulated by cell–cell communication to cell extrusion mechanisms, with potential implications during morphogenesis and invasion of cancer cells.
How intercellular forces regulate cell competition
Andreas Schoenit,
Siavash Monfared,
Lucas Anger,
Carine Rosse,
Varun Venkatesh,
Lakshmi Balasubramaniam,
Elisabetta Marangoni,
Philippe Chavrier,
René‐Marc Mège, et al.
