@article{14378, abstract = {Branching morphogenesis is a ubiquitous process that gives rise to high exchange surfaces in the vasculature and epithelial organs. Lymphatic capillaries form branched networks, which play a key role in the circulation of tissue fluid and immune cells. Although mouse models and correlative patient data indicate that the lymphatic capillary density directly correlates with functional output, i.e., tissue fluid drainage and trafficking efficiency of dendritic cells, the mechanisms ensuring efficient tissue coverage remain poorly understood. Here, we use the mouse ear pinna lymphatic vessel network as a model system and combine lineage-tracing, genetic perturbations, whole-organ reconstructions and theoretical modeling to show that the dermal lymphatic capillaries tile space in an optimal, space-filling manner. This coverage is achieved by two complementary mechanisms: initial tissue invasion provides a non-optimal global scaffold via self-organized branching morphogenesis, while VEGF-C dependent side-branching from existing capillaries rapidly optimizes local coverage by directionally targeting low-density regions. With these two ingredients, we show that a minimal biophysical model can reproduce quantitatively whole-network reconstructions, across development and perturbations. Our results show that lymphatic capillary networks can exploit local self-organizing mechanisms to achieve tissue-scale optimization.}, author = {Ucar, Mehmet C and Hannezo, Edouard B and Tiilikainen, Emmi and Liaqat, Inam and Jakobsson, Emma and Nurmi, Harri and Vaahtomeri, Kari}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Self-organized and directed branching results in optimal coverage in developing dermal lymphatic networks}}, doi = {10.1038/s41467-023-41456-7}, volume = {14}, year = {2023}, } @article{14426, abstract = {To meet the physiological demands of the body, organs need to establish a functional tissue architecture and adequate size as the embryo develops to adulthood. In the liver, uni- and bipotent progenitor differentiation into hepatocytes and biliary epithelial cells (BECs), and their relative proportions, comprise the functional architecture. Yet, the contribution of individual liver progenitors at the organ level to both fates, and their specific proportion, is unresolved. Combining mathematical modelling with organ-wide, multispectral FRaeppli-NLS lineage tracing in zebrafish, we demonstrate that a precise BEC-to-hepatocyte ratio is established (i) fast, (ii) solely by heterogeneous lineage decisions from uni- and bipotent progenitors, and (iii) independent of subsequent cell type–specific proliferation. Extending lineage tracing to adulthood determined that embryonic cells undergo spatially heterogeneous three-dimensional growth associated with distinct environments. Strikingly, giant clusters comprising almost half a ventral lobe suggest lobe-specific dominant-like growth behaviours. We show substantial hepatocyte polyploidy in juveniles representing another hallmark of postembryonic liver growth. Our findings uncover heterogeneous progenitor contributions to tissue architecture-defining cell type proportions and postembryonic organ growth as key mechanisms forming the adult liver.}, author = {Unterweger, Iris A. and Klepstad, Julie and Hannezo, Edouard B and Lundegaard, Pia R. and Trusina, Ala and Ober, Elke A.}, issn = {1545-7885}, journal = {PLoS Biology}, number = {10}, publisher = {Public Library of Science}, title = {{Lineage tracing identifies heterogeneous hepatoblast contribution to cell lineages and postembryonic organ growth dynamics}}, doi = {10.1371/journal.pbio.3002315}, volume = {21}, year = {2023}, } @article{14274, abstract = {Immune responses rely on the rapid and coordinated migration of leukocytes. Whereas it is well established that single-cell migration is often guided by gradients of chemokines and other chemoattractants, it remains poorly understood how these gradients are generated, maintained, and modulated. By combining experimental data with theory on leukocyte chemotaxis guided by the G protein–coupled receptor (GPCR) CCR7, we demonstrate that in addition to its role as the sensory receptor that steers migration, CCR7 also acts as a generator and a modulator of chemotactic gradients. Upon exposure to the CCR7 ligand CCL19, dendritic cells (DCs) effectively internalize the receptor and ligand as part of the canonical GPCR desensitization response. We show that CCR7 internalization also acts as an effective sink for the chemoattractant, dynamically shaping the spatiotemporal distribution of the chemokine. This mechanism drives complex collective migration patterns, enabling DCs to create or sharpen chemotactic gradients. We further show that these self-generated gradients can sustain the long-range guidance of DCs, adapt collective migration patterns to the size and geometry of the environment, and provide a guidance cue for other comigrating cells. Such a dual role of CCR7 as a GPCR that both senses and consumes its ligand can thus provide a novel mode of cellular self-organization.}, author = {Alanko, Jonna H and Ucar, Mehmet C and Canigova, Nikola and Stopp, Julian A and Schwarz, Jan and Merrin, Jack and Hannezo, Edouard B and Sixt, Michael K}, issn = {2470-9468}, journal = {Science Immunology}, keywords = {General Medicine, Immunology}, number = {87}, publisher = {American Association for the Advancement of Science}, title = {{CCR7 acts as both a sensor and a sink for CCL19 to coordinate collective leukocyte migration}}, doi = {10.1126/sciimmunol.adc9584}, volume = {8}, year = {2023}, } @article{14277, abstract = {Living tissues are characterized by an intrinsically mechanochemical interplay of active physical forces and complex biochemical signaling pathways. Either feature alone can give rise to complex emergent phenomena, for example, mechanically driven glassy dynamics and rigidity transitions, or chemically driven reaction-diffusion instabilities. An important question is how to quantitatively assess the contribution of these different cues to the large-scale dynamics of biological materials. We address this in Madin-Darby canine kidney (MDCK) monolayers, considering both mechanochemical feedback between extracellular signal-regulated kinase (ERK) signaling activity and cellular density as well as a mechanically active tissue rheology via a self-propelled vertex model. We show that the relative strength of active migration forces to mechanochemical couplings controls a transition from a uniform active glass to periodic spatiotemporal waves. We parametrize the model from published experimental data sets on MDCK monolayers and use it to make new predictions on the correlation functions of cellular dynamics and the dynamics of topological defects associated with the oscillatory phase of cells. Interestingly, MDCK monolayers are best described by an intermediary parameter region in which both mechanochemical couplings and noisy active propulsion have a strong influence on the dynamics. Finally, we study how tissue rheology and ERK waves produce feedback on one another and uncover a mechanism via which tissue fluidity can be controlled by mechanochemical waves at both the local and global levels.}, author = {Boocock, Daniel R and Hirashima, Tsuyoshi and Hannezo, Edouard B}, issn = {2835-8279}, journal = {PRX Life}, number = {1}, publisher = {American Physical Society}, title = {{Interplay between mechanochemical patterning and glassy dynamics in cellular monolayers}}, doi = {10.1103/prxlife.1.013001}, volume = {1}, year = {2023}, } @article{12162, abstract = {Homeostatic balance in the intestinal epithelium relies on a fast cellular turnover, which is coordinated by an intricate interplay between biochemical signalling, mechanical forces and organ geometry. We review recent modelling approaches that have been developed to understand different facets of this remarkable homeostatic equilibrium. Existing models offer different, albeit complementary, perspectives on the problem. First, biomechanical models aim to explain the local and global mechanical stresses driving cell renewal as well as tissue shape maintenance. Second, compartmental models provide insights into the conditions necessary to keep a constant flow of cells with well-defined ratios of cell types, and how perturbations can lead to an unbalance of relative compartment sizes. A third family of models address, at the cellular level, the nature and regulation of stem fate choices that are necessary to fuel cellular turnover. We also review how these different approaches are starting to be integrated together across scales, to provide quantitative predictions and new conceptual frameworks to think about the dynamics of cell renewal in complex tissues.}, author = {Corominas-Murtra, Bernat and Hannezo, Edouard B}, issn = {1084-9521}, journal = {Seminars in Cell & Developmental Biology}, keywords = {Cell Biology, Developmental Biology}, pages = {58--65}, publisher = {Elsevier}, title = {{Modelling the dynamics of mammalian gut homeostasis}}, doi = {10.1016/j.semcdb.2022.11.005}, volume = {150-151}, year = {2023}, } @article{10825, abstract = {In development, lineage segregation is coordinated in time and space. An important example is the mammalian inner cell mass, in which the primitive endoderm (PrE, founder of the yolk sac) physically segregates from the epiblast (EPI, founder of the fetus). While the molecular requirements have been well studied, the physical mechanisms determining spatial segregation between EPI and PrE remain elusive. Here, we investigate the mechanical basis of EPI and PrE sorting. We find that rather than the differences in static cell surface mechanical parameters as in classical sorting models, it is the differences in surface fluctuations that robustly ensure physical lineage sorting. These differential surface fluctuations systematically correlate with differential cellular fluidity, which we propose together constitute a non-equilibrium sorting mechanism for EPI and PrE lineages. By combining experiments and modeling, we identify cell surface dynamics as a key factor orchestrating the correct spatial segregation of the founder embryonic lineages.}, author = {Yanagida, Ayaka and Corujo-Simon, Elena and Revell, Christopher K. and Sahu, Preeti and Stirparo, Giuliano G. and Aspalter, Irene M. and Winkel, Alex K. and Peters, Ruby and De Belly, Henry and Cassani, Davide A.D. and Achouri, Sarra and Blumenfeld, Raphael and Franze, Kristian and Hannezo, Edouard B and Paluch, Ewa K. and Nichols, Jennifer and Chalut, Kevin J.}, issn = {10974172}, journal = {Cell}, number = {5}, pages = {777--793.e20}, publisher = {Cell Press}, title = {{Cell surface fluctuations regulate early embryonic lineage sorting}}, doi = {10.1016/j.cell.2022.01.022}, volume = {185}, year = {2022}, } @article{12209, abstract = {Embryo development requires biochemical signalling to generate patterns of cell fates and active mechanical forces to drive tissue shape changes. However, how these processes are coordinated, and how tissue patterning is preserved despite the cellular flows occurring during morphogenesis, remains poorly understood. Gastrulation is a crucial embryonic stage that involves both patterning and internalization of the mesendoderm germ layer tissue. Here we show that, in zebrafish embryos, a gradient in Nodal signalling orchestrates pattern-preserving internalization movements by triggering a motility-driven unjamming transition. In addition to its role as a morphogen determining embryo patterning, graded Nodal signalling mechanically subdivides the mesendoderm into a small fraction of highly protrusive leader cells, able to autonomously internalize via local unjamming, and less protrusive followers, which need to be pulled inwards by the leaders. The Nodal gradient further enforces a code of preferential adhesion coupling leaders to their immediate followers, resulting in a collective and ordered mode of internalization that preserves mesendoderm patterning. Integrating this dual mechanical role of Nodal signalling into minimal active particle simulations quantitatively predicts both physiological and experimentally perturbed internalization movements. This provides a quantitative framework for how a morphogen-encoded unjamming transition can bidirectionally couple tissue mechanics with patterning during complex three-dimensional morphogenesis.}, author = {Nunes Pinheiro, Diana C and Kardos, Roland and Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {1745-2481}, journal = {Nature Physics}, keywords = {General Physics and Astronomy}, number = {12}, pages = {1482--1493}, publisher = {Springer Nature}, title = {{Morphogen gradient orchestrates pattern-preserving tissue morphogenesis via motility-driven unjamming}}, doi = {10.1038/s41567-022-01787-6}, volume = {18}, year = {2022}, } @article{12217, abstract = {The development dynamics and self-organization of glandular branched epithelia is of utmost importance for our understanding of diverse processes ranging from normal tissue growth to the growth of cancerous tissues. Using single primary murine pancreatic ductal adenocarcinoma (PDAC) cells embedded in a collagen matrix and adapted media supplementation, we generate organoids that self-organize into highly branched structures displaying a seamless lumen connecting terminal end buds, replicating in vivo PDAC architecture. We identify distinct morphogenesis phases, each characterized by a unique pattern of cell invasion, matrix deformation, protein expression, and respective molecular dependencies. We propose a minimal theoretical model of a branching and proliferating tissue, capturing the dynamics of the first phases. Observing the interaction of morphogenesis, mechanical environment and gene expression in vitro sets a benchmark for the understanding of self-organization processes governing complex organoid structure formation processes and branching morphogenesis.}, author = {Randriamanantsoa, S. and Papargyriou, A. and Maurer, H. C. and Peschke, K. and Schuster, M. and Zecchin, G. and Steiger, K. and Öllinger, R. and Saur, D. and Scheel, C. and Rad, R. and Hannezo, Edouard B and Reichert, M. and Bausch, A. R.}, issn = {2041-1723}, journal = {Nature Communications}, keywords = {General Physics and Astronomy, General Biochemistry, Genetics and Molecular Biology, General Chemistry, Multidisciplinary}, publisher = {Springer Nature}, title = {{Spatiotemporal dynamics of self-organized branching in pancreas-derived organoids}}, doi = {10.1038/s41467-022-32806-y}, volume = {13}, year = {2022}, } @article{12253, abstract = {The sculpting of germ layers during gastrulation relies on the coordinated migration of progenitor cells, yet the cues controlling these long-range directed movements remain largely unknown. While directional migration often relies on a chemokine gradient generated from a localized source, we find that zebrafish ventrolateral mesoderm is guided by a self-generated gradient of the initially uniformly expressed and secreted protein Toddler/ELABELA/Apela. We show that the Apelin receptor, which is specifically expressed in mesodermal cells, has a dual role during gastrulation, acting as a scavenger receptor to generate a Toddler gradient, and as a chemokine receptor to sense this guidance cue. Thus, we uncover a single receptor–based self-generated gradient as the enigmatic guidance cue that can robustly steer the directional migration of mesoderm through the complex and continuously changing environment of the gastrulating embryo.}, author = {Stock, Jessica and Kazmar, Tomas and Schlumm, Friederike and Hannezo, Edouard B and Pauli, Andrea}, issn = {2375-2548}, journal = {Science Advances}, number = {37}, publisher = {American Association for the Advancement of Science}, title = {{A self-generated Toddler gradient guides mesodermal cell migration}}, doi = {10.1126/sciadv.add2488}, volume = {8}, year = {2022}, } @article{12274, abstract = {The morphology and functionality of the epithelial lining differ along the intestinal tract, but tissue renewal at all sites is driven by stem cells at the base of crypts1,2,3. Whether stem cell numbers and behaviour vary at different sites is unknown. Here we show using intravital microscopy that, despite similarities in the number and distribution of proliferative cells with an Lgr5 signature in mice, small intestinal crypts contain twice as many effective stem cells as large intestinal crypts. We find that, although passively displaced by a conveyor-belt-like upward movement, small intestinal cells positioned away from the crypt base can function as long-term effective stem cells owing to Wnt-dependent retrograde cellular movement. By contrast, the near absence of retrograde movement in the large intestine restricts cell repositioning, leading to a reduction in effective stem cell number. Moreover, after suppression of the retrograde movement in the small intestine, the number of effective stem cells is reduced, and the rate of monoclonal conversion of crypts is accelerated. Together, these results show that the number of effective stem cells is determined by active retrograde movement, revealing a new channel of stem cell regulation that can be experimentally and pharmacologically manipulated.}, author = {Azkanaz, Maria and Corominas-Murtra, Bernat and Ellenbroek, Saskia I. J. and Bruens, Lotte and Webb, Anna T. and Laskaris, Dimitrios and Oost, Koen C. and Lafirenze, Simona J. A. and Annusver, Karl and Messal, Hendrik A. and Iqbal, Sharif and Flanagan, Dustin J. and Huels, David J. and Rojas-Rodríguez, Felipe and Vizoso, Miguel and Kasper, Maria and Sansom, Owen J. and Snippert, Hugo J. and Liberali, Prisca and Simons, Benjamin D. and Katajisto, Pekka and Hannezo, Edouard B and van Rheenen, Jacco}, issn = {1476-4687}, journal = {Nature}, keywords = {Multidisciplinary}, number = {7919}, pages = {548--554}, publisher = {Springer Nature}, title = {{Retrograde movements determine effective stem cell numbers in the intestine}}, doi = {10.1038/s41586-022-04962-0}, volume = {607}, year = {2022}, } @article{8602, abstract = {Collective cell migration offers a rich field of study for non-equilibrium physics and cellular biology, revealing phenomena such as glassy dynamics, pattern formation and active turbulence. However, how mechanical and chemical signalling are integrated at the cellular level to give rise to such collective behaviours remains unclear. We address this by focusing on the highly conserved phenomenon of spatiotemporal waves of density and extracellular signal-regulated kinase (ERK) activation, which appear both in vitro and in vivo during collective cell migration and wound healing. First, we propose a biophysical theory, backed by mechanical and optogenetic perturbation experiments, showing that patterns can be quantitatively explained by a mechanochemical coupling between active cellular tensions and the mechanosensitive ERK pathway. Next, we demonstrate how this biophysical mechanism can robustly induce long-ranged order and migration in a desired orientation, and we determine the theoretically optimal wavelength and period for inducing maximal migration towards free edges, which fits well with experimentally observed dynamics. We thereby provide a bridge between the biophysical origin of spatiotemporal instabilities and the design principles of robust and efficient long-ranged migration.}, author = {Boocock, Daniel R and Hino, Naoya and Ruzickova, Natalia and Hirashima, Tsuyoshi and Hannezo, Edouard B}, issn = {17452481}, journal = {Nature Physics}, pages = {267--274}, publisher = {Springer Nature}, title = {{Theory of mechanochemical patterning and optimal migration in cell monolayers}}, doi = {10.1038/s41567-020-01037-7}, volume = {17}, year = {2021}, } @article{9244, abstract = {Organ function depends on tissues adopting the correct architecture. However, insights into organ architecture are currently hampered by an absence of standardized quantitative 3D analysis. We aimed to develop a robust technology to visualize, digitalize, and segment the architecture of two tubular systems in 3D: double resin casting micro computed tomography (DUCT). As proof of principle, we applied DUCT to a mouse model for Alagille syndrome (Jag1Ndr/Ndr mice), characterized by intrahepatic bile duct paucity, that can spontaneously generate a biliary system in adulthood. DUCT identified increased central biliary branching and peripheral bile duct tortuosity as two compensatory processes occurring in distinct regions of Jag1Ndr/Ndr liver, leading to full reconstitution of wild-type biliary volume and phenotypic recovery. DUCT is thus a powerful new technology for 3D analysis, which can reveal novel phenotypes and provide a standardized method of defining liver architecture in mouse models.}, author = {Hankeova, Simona and Salplachta, Jakub and Zikmund, Tomas and Kavkova, Michaela and Van Hul, Noémi and Brinek, Adam and Smekalova, Veronika and Laznovsky, Jakub and Dawit, Feven and Jaros, Josef and Bryja, Vítězslav and Lendahl, Urban and Ellis, Ewa and Nemeth, Antal and Fischler, Björn and Hannezo, Edouard B and Kaiser, Jozef and Andersson, Emma Rachel}, issn = {2050084X}, journal = {eLife}, publisher = {eLife Sciences Publications}, title = {{DUCT reveals architectural mechanisms contributing to bile duct recovery in a mouse model for alagille syndrome}}, doi = {10.7554/eLife.60916}, volume = {10}, year = {2021}, } @article{9316, abstract = {Embryo morphogenesis is impacted by dynamic changes in tissue material properties, which have been proposed to occur via processes akin to phase transitions (PTs). Here, we show that rigidity percolation provides a simple and robust theoretical framework to predict material/structural PTs of embryonic tissues from local cell connectivity. By using percolation theory, combined with directly monitoring dynamic changes in tissue rheology and cell contact mechanics, we demonstrate that the zebrafish blastoderm undergoes a genuine rigidity PT, brought about by a small reduction in adhesion-dependent cell connectivity below a critical value. We quantitatively predict and experimentally verify hallmarks of PTs, including power-law exponents and associated discontinuities of macroscopic observables. Finally, we show that this uniform PT depends on blastoderm cells undergoing meta-synchronous divisions causing random and, consequently, uniform changes in cell connectivity. Collectively, our theoretical and experimental findings reveal the structural basis of material PTs in an organismal context.}, author = {Petridou, Nicoletta and Corominas-Murtra, Bernat and Heisenberg, Carl-Philipp J and Hannezo, Edouard B}, issn = {10974172}, journal = {Cell}, number = {7}, pages = {1914--1928.e19}, publisher = {Elsevier}, title = {{Rigidity percolation uncovers a structural basis for embryonic tissue phase transitions}}, doi = {10.1016/j.cell.2021.02.017}, volume = {184}, year = {2021}, } @article{9349, abstract = {The way in which interactions between mechanics and biochemistry lead to the emergence of complex cell and tissue organization is an old question that has recently attracted renewed interest from biologists, physicists, mathematicians and computer scientists. Rapid advances in optical physics, microscopy and computational image analysis have greatly enhanced our ability to observe and quantify spatiotemporal patterns of signalling, force generation, deformation, and flow in living cells and tissues. Powerful new tools for genetic, biophysical and optogenetic manipulation are allowing us to perturb the underlying machinery that generates these patterns in increasingly sophisticated ways. Rapid advances in theory and computing have made it possible to construct predictive models that describe how cell and tissue organization and dynamics emerge from the local coupling of biochemistry and mechanics. Together, these advances have opened up a wealth of new opportunities to explore how mechanochemical patterning shapes organismal development. In this roadmap, we present a series of forward-looking case studies on mechanochemical patterning in development, written by scientists working at the interface between the physical and biological sciences, and covering a wide range of spatial and temporal scales, organisms, and modes of development. Together, these contributions highlight the many ways in which the dynamic coupling of mechanics and biochemistry shapes biological dynamics: from mechanoenzymes that sense force to tune their activity and motor output, to collectives of cells in tissues that flow and redistribute biochemical signals during development.}, author = {Lenne, Pierre François and Munro, Edwin and Heemskerk, Idse and Warmflash, Aryeh and Bocanegra, Laura and Kishi, Kasumi and Kicheva, Anna and Long, Yuchen and Fruleux, Antoine and Boudaoud, Arezki and Saunders, Timothy E. and Caldarelli, Paolo and Michaut, Arthur and Gros, Jerome and Maroudas-Sacks, Yonit and Keren, Kinneret and Hannezo, Edouard B and Gartner, Zev J. and Stormo, Benjamin and Gladfelter, Amy and Rodrigues, Alan and Shyer, Amy and Minc, Nicolas and Maître, Jean Léon and Di Talia, Stefano and Khamaisi, Bassma and Sprinzak, David and Tlili, Sham}, issn = {1478-3975}, journal = {Physical biology}, number = {4}, publisher = {IOP Publishing}, title = {{Roadmap for the multiscale coupling of biochemical and mechanical signals during development}}, doi = {10.1088/1478-3975/abd0db}, volume = {18}, year = {2021}, } @article{9629, abstract = {Intestinal organoids derived from single cells undergo complex crypt–villus patterning and morphogenesis. However, the nature and coordination of the underlying forces remains poorly characterized. Here, using light-sheet microscopy and large-scale imaging quantification, we demonstrate that crypt formation coincides with a stark reduction in lumen volume. We develop a 3D biophysical model to computationally screen different mechanical scenarios of crypt morphogenesis. Combining this with live-imaging data and multiple mechanical perturbations, we show that actomyosin-driven crypt apical contraction and villus basal tension work synergistically with lumen volume reduction to drive crypt morphogenesis, and demonstrate the existence of a critical point in differential tensions above which crypt morphology becomes robust to volume changes. Finally, we identified a sodium/glucose cotransporter that is specific to differentiated enterocytes that modulates lumen volume reduction through cell swelling in the villus region. Together, our study uncovers the cellular basis of how cell fate modulates osmotic and actomyosin forces to coordinate robust morphogenesis.}, author = {Yang, Qiutan and Xue, Shi-lei and Chan, Chii Jou and Rempfler, Markus and Vischi, Dario and Maurer-Gutierrez, Francisca and Hiiragi, Takashi and Hannezo, Edouard B and Liberali, Prisca}, issn = {1476-4679}, journal = {Nature Cell Biology}, pages = {733–744}, publisher = {Springer Nature}, title = {{Cell fate coordinates mechano-osmotic forces in intestinal crypt formation}}, doi = {10.1038/s41556-021-00700-2}, volume = {23}, year = {2021}, } @article{10365, abstract = {The early development of many organisms involves the folding of cell monolayers, but this behaviour is difficult to reproduce in vitro; therefore, both mechanistic causes and effects of local curvature remain unclear. Here we study epithelial cell monolayers on corrugated hydrogels engineered into wavy patterns, examining how concave and convex curvatures affect cellular and nuclear shape. We find that substrate curvature affects monolayer thickness, which is larger in valleys than crests. We show that this feature generically arises in a vertex model, leading to the hypothesis that cells may sense curvature by modifying the thickness of the tissue. We find that local curvature also affects nuclear morphology and positioning, which we explain by extending the vertex model to take into account membrane–nucleus interactions, encoding thickness modulation in changes to nuclear deformation and position. We propose that curvature governs the spatial distribution of yes-associated proteins via nuclear shape and density changes. We show that curvature also induces significant variations in lamins, chromatin condensation and cell proliferation rate in folded epithelial tissues. Together, this work identifies active cell mechanics and nuclear mechanoadaptation as the key players of the mechanistic regulation of epithelia to substrate curvature.}, author = {Luciano, Marine and Xue, Shi-lei and De Vos, Winnok H. and Redondo-Morata, Lorena and Surin, Mathieu and Lafont, Frank and Hannezo, Edouard B and Gabriele, Sylvain}, issn = {1745-2481}, journal = {Nature Physics}, number = {12}, pages = {1382–1390}, publisher = {Springer Nature}, title = {{Cell monolayers sense curvature by exploiting active mechanics and nuclear mechanoadaptation}}, doi = {10.1038/s41567-021-01374-1}, volume = {17}, year = {2021}, } @article{10402, abstract = {Branching morphogenesis governs the formation of many organs such as lung, kidney, and the neurovascular system. Many studies have explored system-specific molecular and cellular regulatory mechanisms, as well as self-organizing rules underlying branching morphogenesis. However, in addition to local cues, branched tissue growth can also be influenced by global guidance. Here, we develop a theoretical framework for a stochastic self-organized branching process in the presence of external cues. Combining analytical theory with numerical simulations, we predict differential signatures of global vs. local regulatory mechanisms on the branching pattern, such as angle distributions, domain size, and space-filling efficiency. We find that branch alignment follows a generic scaling law determined by the strength of global guidance, while local interactions influence the tissue density but not its overall territory. Finally, using zebrafish innervation as a model system, we test these key features of the model experimentally. Our work thus provides quantitative predictions to disentangle the role of different types of cues in shaping branched structures across scales.}, author = {Ucar, Mehmet C and Kamenev, Dmitrii and Sunadome, Kazunori and Fachet, Dominik C and Lallemend, Francois and Adameyko, Igor and Hadjab, Saida and Hannezo, Edouard B}, issn = {2041-1723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Theory of branching morphogenesis by local interactions and global guidance}}, doi = {10.1038/s41467-021-27135-5}, volume = {12}, year = {2021}, } @article{8220, abstract = {Understanding to what extent stem cell potential is a cell-intrinsic property or an emergent behavior coming from global tissue dynamics and geometry is a key outstanding question of systems and stem cell biology. Here, we propose a theory of stem cell dynamics as a stochastic competition for access to a spatially localized niche, giving rise to a stochastic conveyor-belt model. Cell divisions produce a steady cellular stream which advects cells away from the niche, while random rearrangements enable cells away from the niche to be favorably repositioned. Importantly, even when assuming that all cells in a tissue are molecularly equivalent, we predict a common (“universal”) functional dependence of the long-term clonal survival probability on distance from the niche, as well as the emergence of a well-defined number of functional stem cells, dependent only on the rate of random movements vs. mitosis-driven advection. We test the predictions of this theory on datasets of pubertal mammary gland tips and embryonic kidney tips, as well as homeostatic intestinal crypts. Importantly, we find good agreement for the predicted functional dependency of the competition as a function of position, and thus functional stem cell number in each organ. This argues for a key role of positional fluctuations in dictating stem cell number and dynamics, and we discuss the applicability of this theory to other settings.}, author = {Corominas-Murtra, Bernat and Scheele, Colinda L.G.J. and Kishi, Kasumi and Ellenbroek, Saskia I.J. and Simons, Benjamin D. and Van Rheenen, Jacco and Hannezo, Edouard B}, issn = {10916490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {29}, pages = {16969--16975}, publisher = {National Academy of Sciences}, title = {{Stem cell lineage survival as a noisy competition for niche access}}, doi = {10.1073/pnas.1921205117}, volume = {117}, year = {2020}, }