Abstract
Tissue deformations are a central feature of development, from early embryogenesis, growth and building the body plan to the establishment of functional organs. These deformations often result from active contractile forces generated by cells and cell collectives, and are mediated by changes in their mechanical properties. Mechanical forces drive the formation of functional organ architectures, but they also coordinate cell behaviour and fate transitions, ensuring robustness of development. Advances in microscopy, genetics and chemistry have enabled increasingly powerful tools for measuring, generating and perturbing mechanical forces. Here we discuss approaches to measure and manipulate mechanical forces with a focus on developmental processes, ranging from quantification of molecular interactions to mapping the mechanical properties of tissues. We focus on contemporary methods, and discuss the biological discoveries that these approaches have enabled. We conclude with an outlook to methodologies at the interface of physics, chemistry and biology to build an integrated understanding of tissue morphodynamics.
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References
Goodwin, K. & Nelson, C. M. Mechanics of development. Dev. Cell 56, 240–250 (2021).
Liberali, P. & Schier, A. F. The evolution of developmental biology through conceptual and technological revolutions. Cell 187, 3461–3495 (2024).
Heisenberg, C.-P. & Bellaïche, Y. Forces in tissue morphogenesis and patterning. Cell 153, 948–962 (2013).
Vining, K. H. & Mooney, D. J. Mechanical forces direct stem cell behaviour in development and regeneration. Nat. Rev. Mol. Cell Biol. 18, 728–742 (2017).
Dupont, S. & Wickström, S. A. Mechanical regulation of chromatin and transcription. Nat. Rev. Genet. 23, 624–643 (2022).
Dahmann, C., Oates, A. C. & Brand, M. Boundary formation and maintenance in tissue development. Nat. Rev. Genet. 12, 43–55 (2011).
Maniou, E. et al. Quantifying mechanical forces during vertebrate morphogenesis. Nat. Mater. 23, 1575–1581 (2024).
Negrete, J. & Oates, A. C. Towards a physical understanding of developmental patterning. Nat. Rev. Genet. 22, 518–531 (2021).
Aigouy, B., Umetsu, D. & Eaton, S. Segmentation and quantitative analysis of epithelial tissues. Methods Mol. Biol. 1478, 227–239 (2016).
Weigert, M., Schmidt, U., Haase, R., Sugawara, K. & Myers, G. Star-convex polyhedra for 3D object detection and segmentation in microscopy. In Proc. 2020 IEEE Winter Conference on Applications of Computer Vision (WACV) 3655–3662 (IEEE, 2020).
Stringer, C., Wang, T., Michaelos, M. & Pachitariu, M. Cellpose: a generalist algorithm for cellular segmentation. Nat. Methods 18, 100–106 (2021).
Berg, S. et al. ilastik: interactive machine learning for (bio)image analysis. Nat. Methods 16, 1226–1232 (2019).
Classen, A.-K., Anderson, K. I., Marois, E. & Eaton, S. Hexagonal packing of Drosophila wing epithelial cells by the planar cell polarity pathway. Dev. Cell 9, 805–817 (2005).
Guirao, B. et al. Unified quantitative characterization of epithelial tissue development. eLife 4, e08519 (2015).
Miroshnikova, Y. A. et al. Adhesion forces and cortical tension couple cell proliferation and differentiation to drive epidermal stratification. Nat. Cell Biol. 20, 69–80 (2018).
Wang, X. et al. Anisotropy links cell shapes to tissue flow during convergent extension. Proc. Natl Acad. Sci. USA 117, 13541–13551 (2020).
Bocanegra-Moreno, L., Singh, A., Hannezo, E., Zagorski, M. & Kicheva, A. Cell cycle dynamics control fluidity of the developing mouse neuroepithelium. Nat. Phys. 19, 1050–1058 (2023).
Kemp, H. A., Cooke, J. E. & Moens, C. B. EphA4 and EfnB2a maintain rhombomere coherence by independently regulating intercalation of progenitor cells in the zebrafish neural keel. Dev. Biol. 327, 313–326 (2009).
Jülich, D., Mould, A. P., Koper, E. & Holley, S. A. Control of extracellular matrix assembly along tissue boundaries via Integrin and Eph/Ephrin signaling. Development 136, 2913–2921 (2009).
Park, S., Greco, V. & Cockburn, K. Live imaging of stem cells: answering old questions and raising new ones. Curr. Opin. Cell Biol. 43, 30–37 (2016).
Garcia-Gonzalez, I. et al. iFlpMosaics enable the multispectral barcoding and high-throughput comparative analysis of mutant and wildtype cells. Preprint at bioRxiv https://doi.org/10.1101/2023.05.09.540000 (2023).
Roffay, C., Chan, C. J., Guirao, B., Hiiragi, T. & Graner, F. Inferring cell junction tension and pressure from cell geometry. Development 148, dev192773 (2021).
Thompson, D. W. On Growth and Form (Cambridge Univ., 1992).
Kim, S., Pochitaloff, M., Stooke-Vaughan, G. A. & Campàs, O. Embryonic tissues as active foams. Nat. Phys. 17, 859–866 (2021).
Ichbiah, S., Delbary, F., McDougall, A., Dumollard, R. & Turlier, H. Embryo mechanics cartography: inference of 3D force atlases from fluorescence microscopy. Nat. Methods 20, 1989–1999 (2023).
Kong, W. et al. Experimental validation of force inference in epithelia from cell to tissue scale. Sci. Rep. 9, 14647 (2019).
Mao, Y. & Wickström, S. A. Mechanical state transitions in the regulation of tissue form and function. Nat. Rev. Mol. Cell Biol. 25, 654–670 (2024).
Merkel, M. & Manning, M. L. Using cell deformation and motion to predict forces and collective behavior in morphogenesis. Semin. Cell Dev. Biol. 67, 161–169 (2017).
Villeneuve, C. et al. Mechanical forces across compartments coordinate cell shape and fate transitions to generate tissue architecture. Nat. Cell Biol. 26, 207–218 (2024).
Aigouy, B. et al. Cell flow reorients the axis of planar polarity in the wing epithelium of Drosophila. Cell 142, 773–786 (2010).
Petridou, N. I., Grigolon, S., Salbreux, G., Hannezo, E. & Heisenberg, C.-P. Fluidization-mediated tissue spreading by mitotic cell rounding and non-canonical Wnt signalling. Nat. Cell Biol. 21, 169–178 (2019).
Pinheiro, D., Kardos, R., Hannezo, É. & Heisenberg, C.-P. Morphogen gradient orchestrates pattern-preserving tissue morphogenesis via motility-driven unjamming. Nat. Phys. 18, 1482–1493 (2022).
Jain, A. et al. Regionalized tissue fluidization is required for epithelial gap closure during insect gastrulation. Nat. Commun. 11, 5604 (2020).
Sanz-Fraile, H. & Otero, J. in Handbook of the Extracellular Matrix (eds Maia, F. R. et al.) 73–88 (Springer, 2024).
Walma, D. A. C. & Yamada, K. M. The extracellular matrix in development. Development 147, dev175596 (2020).
Wang, S. & Larin, K. V. Optical coherence elastography for tissue characterization: a review. J. Biophotonics 8, 279–302 (2015).
Zoumi, A., Yeh, A. & Tromberg, B. J. Imaging cells and extracellular matrix in vivo by using second-harmonic generation and two-photon excited fluorescence. Proc. Natl Acad. Sci. USA 99, 11014–11019 (2002).
Ghosh, S., Cuevas, V. C., Seelbinder, B. & Neu, C. P. Image-based elastography of heterochromatin and euchromatin domains in the deforming cell nucleus. Small 17, e2006109 (2021).
Prevedel, R., Diz-Muñoz, A., Ruocco, G. & Antonacci, G. Brillouin microscopy: an emerging tool for mechanobiology. Nat. Methods 16, 969–977 (2019).
Regan, K. et al. Multiscale elasticity mapping of biological samples in 3D at optical resolution. Acta Biomater. 176, 250–266 (2024).
Krouskop, T. A., Dougherty, D. R. & Vinson, F. S. A pulsed Doppler ultrasonic system for making noninvasive measurements of the mechanical properties of soft tissue. J. Rehabil. Res. Dev. 24, 1–8 (1987).
Muthupillai, R. et al. Magnetic resonance elastography by direct visualization of propagating acoustic strain waves. Science 269, 1854–1857 (1995).
Larin, K. V., Scarcelli, G. & Yakovlev, V. V. Optical elastography and tissue biomechanics. J. Biomed. Opt. 24, 110901 (2019).
Singh, M. et al. Whole embryo biomechanics with reverberant optical coherence elastography. Optica 11, 686–692 (2024).
Nallet, C. et al. Prenatal quantification of human foetal lung and liver elasticities between 24 and 39 weeks of gestation using 2D shear wave elastography. Eur. Radiol. 32, 5559–5567 (2022).
Raghunathan, R. et al. Evaluating biomechanical properties of murine embryos using Brillouin microscopy and optical coherence tomography. J. Biomed. Opt. 22, 1–6 (2017).
Handler, C., Scarcelli, G. & Zhang, J. Time-lapse mechanical imaging of neural tube closure in live embryo using Brillouin microscopy. Sci. Rep. 13, 263 (2023).
Chan, C. J., Bevilacqua, C. & Prevedel, R. Mechanical mapping of mammalian follicle development using Brillouin microscopy. Commun. Biol. 4, 1133 (2021).
Riquelme-Guzmán, C. et al. In vivo assessment of mechanical properties during axolotl development and regeneration using confocal Brillouin microscopy. Open Biol. 12, 220078 (2022).
Altartouri, B. et al. Pectin chemistry and cellulose crystallinity govern pavement cell morphogenesis in a multi-step mechanism. Plant Physiol. 181, 127–141 (2019).
Mammoto, T. & Ingber, D. E. Mechanical control of tissue and organ development. Development 137, 1407–1420 (2010).
Bailles, A., Gehrels, E. W. & Lecuit, T. Mechanochemical principles of spatial and temporal patterns in cells and tissues. Annu. Rev. Cell Dev. Biol. 38, 321–347 (2022).
Davidson, L., von Dassow, M. & Zhou, J. Multi-scale mechanics from molecules to morphogenesis. Int. J. Biochem. Cell Biol. 41, 2147–2162 (2009).
Hove, J. R. et al. Intracardiac fluid forces are an essential epigenetic factor for embryonic cardiogenesis. Nature 421, 172–177 (2003).
Campàs, O. et al. Quantifying cell-generated mechanical forces within living embryonic tissues. Nat. Methods 11, 183–189 (2014).
Serwane, F. et al. In vivo quantification of spatially varying mechanical properties in developing tissues. Nat. Methods 14, 181–186 (2017).
Doubrovinski, K., Swan, M., Polyakov, O. & Wieschaus, E. F. Measurement of cortical elasticity in Drosophila melanogaster embryos using ferrofluids. Proc. Natl Acad. Sci. USA 114, 1051–1056 (2017).
Mongera, A. et al. A fluid-to-solid jamming transition underlies vertebrate body axis elongation. Nature 561, 401–405 (2018).
D’Angelo, A., Dierkes, K., Carolis, C., Salbreux, G. & Solon, J. In vivo force application reveals a fast tissue softening and external friction increase during early embryogenesis. Curr. Biol. 29, 1564–1571.e6 (2019).
Vian, A. et al. In situ quantification of osmotic pressure within living embryonic tissues. Nat. Commun. 14, 7023 (2023).
Dolega, M. E. et al. Cell-like pressure sensors reveal increase of mechanical stress towards the core of multicellular spheroids under compression. Nat. Commun. 8, 14056 (2017).
Lee, W. et al. Dispersible hydrogel force sensors reveal patterns of solid mechanical stress in multicellular spheroid cultures. Nat. Commun. 10, 144 (2019).
Träber, N. et al. Polyacrylamide bead sensors for in vivo quantification of cell-scale stress in zebrafish development. Sci. Rep. 9, 17031 (2019).
Hiscock, T. W., Miesfeld, J. B., Mosaliganti, K. R., Link, B. A. & Megason, S. G. Feedback between tissue packing and neurogenesis in the zebrafish neural tube. Development 145, dev157040 (2018).
Urciuolo, A. et al. Hydrogel-in-hydrogel live bioprinting for guidance and control of organoids and organotypic cultures. Nat. Commun. 14, 3128 (2023).
Mittasch, M. et al. Non-invasive perturbations of intracellular flow reveal physical principles of cell organization. Nat. Cell Biol. 20, 344–351 (2018).
Chartier, N. T. et al. A hydraulic instability drives the cell death decision in the nematode germline. Nat. Phys. 17, 920–925 (2021).
Murrell, M., Oakes, P. W., Lenz, M. & Gardel, M. L. Forcing cells into shape: the mechanics of actomyosin contractility. Nat. Rev. Mol. Cell Biol. 16, 486–498 (2015).
Miao, H. & Blankenship, J. T. The pulse of morphogenesis: actomyosin dynamics and regulation in epithelia. Development 147, dev186502 (2020).
Rauzi, M., Lenne, P.-F. & Lecuit, T. Planar polarized actomyosin contractile flows control epithelial junction remodelling. Nature 468, 1110–1114 (2010).
Rauzi, M. & Lenne, P.-F. in Current Topics in Developmental Biology (ed. Labouesse, M.) Vol. 95, 93–144 (Academic Press, 2011).
Day, C. & Irish, V. Cell ablation and the analysis of plant development. Trends Plant Sci. 2, 106–111 (1997).
Behrndt, M. et al. Forces driving epithelial spreading in zebrafish gastrulation. Science 338, 257–260 (2012).
Shivakumar, P. C. & Lenne, P.-F. Laser ablation to probe the epithelial mechanics in Drosophila. Methods Mol. Biol. 1478, 241–251 (2016).
Kiehart, D. P., Galbraith, C. G., Edwards, K. A., Rickoll, W. L. & Montague, R. A. Multiple forces contribute to cell sheet morphogenesis for dorsal closure in Drosophila. J. Cell Biol. 149, 471–490 (2000).
Rauzi, M., Verant, P., Lecuit, T. & Lenne, P.-F. Nature and anisotropy of cortical forces orienting Drosophila tissue morphogenesis. Nat. Cell Biol. 10, 1401–1410 (2008).
Collinet, C., Rauzi, M., Lenne, P.-F. & Lecuit, T. Local and tissue-scale forces drive oriented junction growth during tissue extension. Nat. Cell Biol. 17, 1247–1258 (2015).
Krieg, M. et al. Atomic force microscopy-based mechanobiology. Nat. Rev. Phys. 1, 41–57 (2019).
Yang, S. et al. Morphogens enable interacting supracellular phases that generate organ architecture. Science 382, eadg5579 (2023).
Xu, X., Li, Z., Cai, L., Calve, S. & Neu, C. P. Mapping the nonreciprocal micromechanics of individual cells and the surrounding matrix within living tissues. Sci. Rep. 6, 24272 (2016).
Haase, K. & Pelling, A. E. Investigating cell mechanics with atomic force microscopy. J. R. Soc. Interface 12, 20140970 (2015).
Schaeffer, J., Weber, I. P., Thompson, A. J., Keynes, R. J. & Franze, K. Axons in the chick embryo follow soft pathways through developing somite segments. Front. Cell Dev. Biol. 10, 917589 (2022).
Shellard, A. & Mayor, R. Collective durotaxis along a self-generated stiffness gradient in vivo. Nature 600, 690–694 (2021).
Bergert, M. & Diz-Muñoz, A. Quantification of apparent membrane tension and membrane-to-cortex attachment in animal cells using atomic force microscopy-based force spectroscopy. Methods Mol. Biol. 2600, 45–62 (2023).
Sitarska, E. et al. Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles. Nat. Commun. 14, 5644 (2023).
Yeung, A. & Evans, E. Cortical shell-liquid core model for passive flow of liquid-like spherical cells into micropipets. Biophys. J. 56, 139–149 (1989).
Guevorkian, K. & Maître, J.-L. in Methods in Cell Biology (ed. Lecuit, T.) Vol. 139, 187–201 (Academic Press, 2017).
Maître, J.-L., Niwayama, R., Turlier, H., Nédélec, F. & Hiiragi, T. Pulsatile cell-autonomous contractility drives compaction in the mouse embryo. Nat. Cell Biol. 17, 849–855 (2015).
Plater de, L., Firmin, J. & Maître, J.-L. Mechanical strengthening of cell-cell adhesion during mouse embryo compaction. Biophys. J. 10.1016/j.bpj.2024.03.028 (2024).
Maître, J.-L. et al. Adhesion functions in cell sorting by mechanically coupling the cortices of adhering cells. Science 338, 253–256 (2012).
Maître, J.-L. et al. Asymmetric division of contractile domains couples cell positioning and fate specification. Nature 536, 344–348 (2016).
Ahmine, A. N., Bdiri, M., Féréol, S. & Fodil, R. A comprehensive study of AFM stiffness measurements on inclined surfaces: theoretical, numerical and experimental evaluation using a Hertz approach. Sci. Rep. 14, 25869 (2024).
Sabass, B., Gardel, M. L., Waterman, C. M. & Schwarz, U. S. High resolution traction force microscopy based on experimental and computational advances. Biophys. J. 94, 207–220 (2008).
Oliver, T., Dembo, M. & Jacobson, K. Traction forces in locomoting cells. Cell Motil. Cytoskeleton 31, 225–240 (1995).
Rodriguez, M. L. et al. Measuring the contractile forces of human induced pluripotent stem cell-derived cardiomyocytes with arrays of microposts. J. Biomech. Eng. 136, 051005 (2014).
Faure, L. M. et al. 3D micropatterned traction force microscopy: a technique to control three-dimensional cell shape while measuring cell-substrate force transmission. Preprint at bioRxiv https://doi.org/10.1101/2024.07.10.602889 (2024).
Legant, W. R. et al. Multidimensional traction force microscopy reveals out-of-plane rotational moments about focal adhesions. Proc. Natl Acad. Sci. USA 110, 881–886 (2013).
Fu, J. et al. Mechanical regulation of cell function with geometrically modulated elastomeric substrates. Nat. Methods 7, 733–736 (2010).
Palmquist, K. H. et al. Reciprocal cell-ECM dynamics generate supracellular fluidity underlying spontaneous follicle patterning. Cell 185, 1960–1973.e11 (2022).
Lee, M. et al. High-resolution assessment of multidimensional cellular mechanics using label-free refractive-index traction force microscopy. Commun. Biol. 7, 115 (2024).
Tambe, D. T. et al. Monolayer stress microscopy: limitations, artifacts and accuracy of recovered intercellular stresses. PLoS ONE 8, e55172 (2013).
Tambe, D. T. et al. Collective cell guidance by cooperative intercellular forces. Nat. Mater. 10, 469–475 (2011).
Pérez-González, C. et al. Mechanical compartmentalization of the intestinal organoid enables crypt folding and collective cell migration. Nat. Cell Biol. 23, 745–757 (2021).
Collinet, C. & Lecuit, T. Programmed and self-organized flow of information during morphogenesis. Nat. Rev. Mol. Cell Biol. 22, 245–265 (2021).
Mishra, N. & Heisenberg, C.-P. Dissecting organismal morphogenesis by bridging genetics and biophysics. Annu. Rev. Genet. 55, 209–233 (2021).
Miller, C. J. & Davidson, L. The interplay between cell signaling and mechanics in developmental processes. Nat. Rev. Genet. 14, 733–744 (2013).
Campàs, O., Noordstra, I. & Yap, A. S. Adherens junctions as molecular regulators of emergent tissue mechanics. Nat. Rev. Mol. Cell Biol. 25, 252–269 (2024).
Kechagia, J. Z., Ivaska, J. & Roca-Cusachs, P. Integrins as biomechanical sensors of the microenvironment. Nat. Rev. Mol. Cell Biol. 20, 457–473 (2019).
Ashkin, A., Dziedzic, J. M., Bjorkholm, J. E. & Chu, S. Observation of a single-beam gradient force optical trap for dielectric particles. Opt. Lett. 11, 288–290 (1986).
Bustamante, C. J., Chemla, Y. R., Liu, S. & Wang, M. D. Optical tweezers in single-molecule biophysics. Nat. Rev. Methods Primers 1, 25 (2021).
Català-Castro, F., Schäffer, E. & Krieg, M. Exploring cell and tissue mechanics with optical tweezers. J. Cell Sci. 135, jcs259355 (2022).
Almonacid, M. et al. Active diffusion positions the nucleus in mouse oocytes. Nat. Cell Biol. 17, 470–479 (2015).
Syrchina, M. S., Shakhov, A. M., Aybush, A. V. & Nadtochenko, V. A. Optical trapping of nucleolus reveals viscoelastic properties of nucleoplasm inside mouse germinal vesicle oocytes. Preprint at bioRxiv https://doi.org/10.1101/2020.03.19.999342 (2020).
Köster, D. V. Pulling of tethers from the cell plasma membrane using optical tweezers. Methods Mol. Biol. 2169, 167–174 (2020).
De Belly, H. et al. Cell protrusions and contractions generate long-range membrane tension propagation. Cell 186, 3049–3061.e15 (2023).
Meissner, R., Sugden, W. W., Siekmann, A. F. & Cornelia Denz, V. Multimodal in vivo blood flow sensing combining particle image velocimetry and optical tweezers-based blood steering. In Proc. SPIE Diagnostic and Therapeutic Applications of Light in Cardiology 2018, Vol. 10471, 29–34 (SPIE, 2018).
Johansen, P. L., Fenaroli, F., Evensen, L., Griffiths, G. & Koster, G. Optical micromanipulation of nanoparticles and cells inside living zebrafish. Nat. Commun. 7, 10974 (2016).
Nishizawa, K., Chardès, C., Clément, R. & Lenne, P.-F. Two-point optical manipulation of cell junctions in the early epithelium of the Drosophila embryo. Methods Mol. Biol. 2600, 107–118 (2023).
Perkins, T. T. Ångström-precision optical traps and applications. Annu. Rev. Biophys. 43, 279–302 (2014).
Vos, B. E., Muenker, T. M. & Betz, T. Characterizing intracellular mechanics via optical tweezers-based microrheology. Curr. Opin. Cell Biol. 88, 102374 (2024).
Mason, T. G., Ganesan, K., van Zanten, J. H., Wirtz, D. & Kuo, S. C. Particle tracking microrheology of complex fluids. Phys. Rev. Lett. 79, 3282–3285 (1997).
Szórádi, T. et al. nucGEMs probe the biophysical properties of the nucleoplasm. Preprint at bioRxiv https://doi.org/10.1101/2021.11.18.469159 (2022).
Delarue, M. et al. mTORC1 controls phase separation and the biophysical properties of the cytoplasm by tuning crowding. Cell 174, 338–349.e20 (2018).
Szoradi, T. et al. Genetically encoded multimeric (GEM) nanoparticles probe the biophysical properties of the nucleus. Biophys. J. 121, 496A (2022).
McCreery, K. P. et al. Mechano-osmotic signals control chromatin state and fate transitions in pluripotent stem cells. Preprint at bioRxiv https://doi.org/10.1101/2024.09.07.611779 (2024).
Kefauver, J. M., Ward, A. B. & Patapoutian, A. Discoveries in structure and physiology of mechanically activated ion channels. Nature 587, 567–576 (2020).
Roffay, C. et al. Technical insights into fluorescence lifetime microscopy of mechanosensitive Flipper probes. Preprint at bioRxiv https://doi.org/10.1101/2022.09.28.509885 (2023).
Colom, A. et al. A fluorescent membrane tension probe. Nat. Chem. 10, 1118–1125 (2018).
Straková, K. et al. HaloFlippers: a general tool for the fluorescence imaging of precisely localized membrane tension changes in living cells. ACS Cent. Sci. 6, 1376–1385 (2020).
Verma, A. K., Noumani, A., Yadav, A. K. & Solanki, P. R. FRET based biosensor: principle applications recent advances and challenges. Diagnostics (Basel) 13, 1375 (2023).
De Belly, H. et al. Membrane tension gates ERK-mediated regulation of pluripotent cell fate. Cell Stem Cell 28, 273–284.e6 (2021).
Grashoff, C. et al. Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature 466, 263–266 (2010).
Borghi, N. et al. E-cadherin is under constitutive actomyosin-generated tension that is increased at cell-cell contacts upon externally applied stretch. Proc. Natl Acad. Sci. USA 109, 12568–12573 (2012).
Smith, M. L. et al. Force-induced unfolding of fibronectin in the extracellular matrix of living cells. PLoS Biol. 5, e268 (2007).
Lemke, S. B., Weidemann, T., Cost, A.-L., Grashoff, C. & Schnorrer, F. A small proportion of Talin molecules transmit forces at developing muscle attachments in vivo. PLoS Biol. 17, e3000057 (2019).
Lagendijk, A. K. et al. Live imaging molecular changes in junctional tension upon VE-cadherin in zebrafish. Nat. Commun. 8, 1402 (2017).
Fenelon, K. D. et al. Transgenic force sensors and software to measure force transmission across the mammalian nuclear envelope in vivo. Biol. Open 11, bio059656 (2022).
Hu, Y. et al. DNA-based ForceChrono probes for deciphering single-molecule force dynamics in living cells. Cell 187, 3445–3459.e15 (2024).
Combs, J. D. et al. Measuring integrin force loading rates using a two-step DNA tension sensor. J. Am. Chem. Soc. 146, 23034–23043 (2024).
Zeki, S. & Crick, F. The impact of molecular biology on neuroscience. Philos. Trans. R. Soc. Lond. B 354, 2021–2025 (1999).
Zemelman, B. V., Lee, G. A., Ng, M. & Miesenböck, G. Selective photostimulation of genetically ChARGed neurons. Neuron 33, 15–22 (2002).
Guglielmi, G., Barry, J. D., Huber, W. & De Renzis, S. An optogenetic method to modulate cell contractility during tissue morphogenesis. Dev. Cell 35, 646–660 (2015).
Izquierdo, E., Quinkler, T. & De Renzis, S. Guided morphogenesis through optogenetic activation of Rho signalling during early Drosophila embryogenesis. Nat. Commun. 9, 2366 (2018).
Martínez-Ara, G. et al. Optogenetic control of apical constriction induces synthetic morphogenesis in mammalian tissues. Nat. Commun. 13, 5400 (2022).
Oriola, D. et al. Arrested coalescence of multicellular aggregates. Soft Matter 18, 3771–3780 (2022).
Mohammadi, H., Arora, P. D., Simmons, C. A., Janmey, P. A. & McCulloch, C. A. Inelastic behaviour of collagen networks in cell-matrix interactions and mechanosensation. J. R. Soc. Interface 12, 20141074 (2015).
Jansen, K. A. et al. A guide to mechanobiology: where biology and physics meet. Biochim. Biophys. Acta 1853, 3043–3052 (2015).
Tikka, P. et al. Computational modelling of nephron progenitor cell movement and aggregation during kidney organogenesis. Math. Biosci. 344, 108759 (2022).
Hirashima, T., Rens, E. G. & Merks, R. M. H. Cellular Potts modeling of complex multicellular behaviors in tissue morphogenesis. Dev. Growth Differ. 59, 329–339 (2017).
Brézin, L. & Korolev, K. S. Mechanically-driven growth and competition in a Voronoi model of tissues. Preprint at https://arxiv.org/abs/2405.07899v1 (2024).
Damavandi, O. K., Arzash, S., Lawson-Keister, E. & Manning, M. L. Universality in the mechanical behavior of vertex models for biological tissues. Preprint at bioRxiv https://doi.org/10.1101/2022.06.01.494406 (2024).
Yang, F. et al. Pulsed stimulated Brillouin microscopy enables high-sensitivity mechanical imaging of live and fragile biological specimens. Nat. Methods 20, 1971–1979 (2023).
Azioune, A., Carpi, N., Tseng, Q., Théry, M. & Piel, M. Protein micropatterns: a direct printing protocol using deep UVs. Methods Cell. Biol. 97, 133–146 (2010).
Watt, F. M., Jordan, P. W. & O’Neill, C. H. Cell shape controls terminal differentiation of human epidermal keratinocytes. Proc. Natl Acad. Sci. USA 85, 5576–5580 (1988).
Connelly, J. T. et al. Actin and serum response factor transduce physical cues from the microenvironment to regulate epidermal stem cell fate decisions. Nat. Cell Biol. 12, 711–718 (2010).
Chen, C. S., Mrksich, M., Huang, S., Whitesides, G. M. & Ingber, D. E. Geometric control of cell life and death. Science 276, 1425–1428 (1997).
Warmflash, A., Sorre, B., Etoc, F., Siggia, E. D. & Brivanlou, A. H. A method to recapitulate early embryonic spatial patterning in human embryonic stem cells. Nat. Methods 11, 847–854 (2014).
Muncie, J. M. et al. Mechanical tension promotes formation of gastrulation-like nodes and patterns mesoderm specification in human embryonic stem cells. Dev. Cell 55, 679–694.e11 (2020).
Karzbrun, E. et al. Human neural tube morphogenesis in vitro by geometric constraints. Nature 599, 268–272 (2021).
Nelson, C. M., VanDuijn, M. M., Inman, J. L., Fletcher, D. A. & Bissell, M. J. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science 314, 298–300 (2006).
Gjorevski, N. et al. Tissue geometry drives deterministic organoid patterning. Science 375, eaaw9021 (2022).
Nikolaev, M. et al. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis. Nature 585, 574–578 (2020).
Wang, Y. et al. A microengineered collagen scaffold for generating a polarized crypt-villus architecture of human small intestinal epithelium. Biomaterials 128, 44–55 (2017).
Davies, P. F., Remuzzi, A., Gordon, E. J., Dewey, C. F. & Gimbrone, M. A. Turbulent fluid shear stress induces vascular endothelial cell turnover in vitro. Proc. Natl Acad. Sci. USA 83, 2114–2117 (1986).
Souilhol, C. et al. Endothelial responses to shear stress in atherosclerosis: a novel role for developmental genes. Nat. Rev. Cardiol. 17, 52–63 (2020).
Mannion, A. J. & Holmgren, L. Nuclear mechanosensing of the aortic endothelium in health and disease. Dis. Models Mech. 16, dmm050361 (2023).
Barriga, E. H., Franze, K., Charras, G. & Mayor, R. Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo. Nature 554, 523–527 (2018).
Chaudhuri, O. et al. Hydrogels with tunable stress relaxation regulate stem cell fate and activity. Nat. Mater. 15, 326–334 (2016).
Brownfield, D. G. et al. Patterned collagen fibers orient branching mammary epithelium through distinct signaling modules. Curr. Biol. 23, 703–709 (2013).
Dekoninck, S. et al. Defining the design principles of skin epidermis postnatal growth. Cell 181, 604–620.e22 (2020).
Box, K., Joyce, B. W. & Devenport, D. Epithelial geometry regulates spindle orientation and progenitor fate during formation of the mammalian epidermis. eLife 8, e47102 (2019).
Nava, M. M. et al. Heterochromatin-driven nuclear softening protects the genome against mechanical stress-induced damage. Cell 181, 800–817.e22 (2020).
McGinn, J. et al. A biomechanical switch regulates the transition towards homeostasis in oesophageal epithelium. Nat. Cell Biol. 23, 511–525 (2021).
Acknowledgements
We are grateful for the mechanobiology field for developing the methods discussed here and apologize for omitting citations due to space limitations. We thank A. Hussien, M. Albu and L. Biggs for commenting on the manuscript. Mechanobiology studies in the Wickström laboratory are supported by the Academy of Finland Center of Excellence BarrierForce, the Max Planck Society (to S.A.W.) and European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement no. 101032331 (to C.V.).
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Villeneuve, C., McCreery, K.P. & Wickström, S.A. Measuring and manipulating mechanical forces during development. Nat Cell Biol 27, 575–590 (2025). https://doi.org/10.1038/s41556-025-01632-x
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DOI: https://doi.org/10.1038/s41556-025-01632-x
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