Dynamic cytoskeletal regulation of cell shape supports resilience of lymphatic endothelium

Hans Schoofs, Nina Daubel, Sarah Schnabellehner, Max L. B. Grönloh, Sebastián Palacios Martínez, Aleksi Halme, Amanda M. Marks, Marie Jeansson, Sara Barcos, Cord Brakebusch, Rui Benedito, Britta Engelhardt, Dietmar Vestweber, Konstantin Gaengel, Fabian Linsenmeier, Sebastian Schürmann, Pipsa Saharinen, Jaap D. Buul, Oliver Friedrich, Richard S. Smith, Mateusz Majda and Taija Mäkinen ()
Additional contact information
Hans Schoofs: Uppsala University
Nina Daubel: Uppsala University
Sarah Schnabellehner: Uppsala University
Max L. B. Grönloh: location AMC
Sebastián Palacios Martínez: Leeuwenhoek Centre for Advanced Microscopy at Swammerdam Institute for Life Sciences at the University of Amsterdam
Aleksi Halme: University of Helsinki
Amanda M. Marks: Uppsala University
Marie Jeansson: Uppsala University
Sara Barcos: University of Bern
Cord Brakebusch: University of Copenhagen
Rui Benedito: Centro Nacional de Investigaciones Cardiovasculares
Britta Engelhardt: University of Bern
Dietmar Vestweber: Max Planck Institute for Molecular Biomedicine
Konstantin Gaengel: Uppsala University
Fabian Linsenmeier: Friedrich-Alexander University Erlangen-Nürnberg
Sebastian Schürmann: Friedrich-Alexander University Erlangen-Nürnberg
Pipsa Saharinen: University of Helsinki
Jaap D. Buul: location AMC
Oliver Friedrich: Friedrich-Alexander University Erlangen-Nürnberg
Richard S. Smith: Norwich Research Park
Mateusz Majda: University of Lausanne
Taija Mäkinen: Uppsala University

Nature, 2025, vol. 641, issue 8062, 465-475

Abstract: Abstract Lymphatic capillaries continuously take up interstitial fluid and adapt to resulting changes in vessel calibre1–3. The mechanisms by which the permeable monolayer of loosely connected lymphatic endothelial cells (LECs)4 maintains mechanical stability remain elusive. Here we identify dynamic cytoskeletal regulation of LEC shape, induced by isotropic stretch, as crucial for the integrity and function of dermal lymphatic capillaries. We found that the oak leaf-shaped LECs showed a spectrum of VE-cadherin-based junctional configurations at the lobular intercellular interface and a unique cytoskeletal organization, with microtubules at concave regions and F-actin at convex lobes. Multispectral and longitudinal intravital imaging of capillary LEC shape and actin revealed dynamic remodelling of cellular overlaps in vivo during homeostasis and in response to interstitial fluid volume increase. Akin to puzzle cells of the plant epidermis5,6, LEC shape was controlled by Rho GTPase CDC42-regulated cytoskeletal dynamics, enhancing monolayer stability. Moreover, cyclic isotropic stretch increased cellular overlaps and junction curvature in primary LECs. Our findings indicate that capillary LEC shape results from continuous remodelling of cellular overlaps that maintain vessel integrity while preserving permeable cell–cell contacts compatible with vessel expansion and fluid uptake. We propose a bellows-like fluid propulsion mechanism, in which fluid-induced lumen expansion and shrinkage of LEC overlaps are countered by actin-based lamellipodia-like overlap extension to aid vessel constriction.

Date: 2025
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DOI: 10.1038/s41586-025-08724-6

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