@article{14795, abstract = {Metazoan development relies on the formation and remodeling of cell-cell contacts. Dynamic reorganization of adhesion receptors and the actomyosin cell cortex in space and time plays a central role in cell-cell contact formation and maturation. Nevertheless, how this process is mechanistically achieved when new contacts are formed remains unclear. Here, by building a biomimetic assay composed of progenitor cells adhering to supported lipid bilayers functionalized with E-cadherin ectodomains, we show that cortical F-actin flows, driven by the depletion of myosin-2 at the cell contact center, mediate the dynamic reorganization of adhesion receptors and cell cortex at the contact. E-cadherin-dependent downregulation of the small GTPase RhoA at the forming contact leads to both a depletion of myosin-2 and a decrease of F-actin at the contact center. At the contact rim, in contrast, myosin-2 becomes enriched by the retraction of bleb-like protrusions, resulting in a cortical tension gradient from the contact rim to its center. This tension gradient, in turn, triggers centrifugal F-actin flows, leading to further accumulation of F-actin at the contact rim and the progressive redistribution of E-cadherin from the contact center to the rim. Eventually, this combination of actomyosin downregulation and flows at the contact determines the characteristic molecular organization, with E-cadherin and F-actin accumulating at the contact rim, where they are needed to mechanically link the contractile cortices of the adhering cells.}, author = {Arslan, Feyza N and Hannezo, Edouard B and Merrin, Jack and Loose, Martin and Heisenberg, Carl-Philipp J}, issn = {1879-0445}, journal = {Current Biology}, number = {1}, pages = {171--182.e8}, publisher = {Elsevier}, title = {{Adhesion-induced cortical flows pattern E-cadherin-mediated cell contacts}}, doi = {10.1016/j.cub.2023.11.067}, volume = {34}, year = {2024}, } @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}, } @misc{13116, abstract = {The emergence of large-scale order in self-organized systems relies on local interactions between individual components. During bacterial cell division, FtsZ -- a prokaryotic homologue of the eukaryotic protein tubulin -- polymerizes into treadmilling filaments that further organize into a cytoskeletal ring. In vitro, FtsZ filaments can form dynamic chiral assemblies. However, how the active and passive properties of individual filaments relate to these large-scale self-organized structures remains poorly understood. Here, we connect single filament properties with the mesoscopic scale by combining minimal active matter simulations and biochemical reconstitution experiments. We show that density and flexibility of active chiral filaments define their global order. At intermediate densities, curved, flexible filaments organize into chiral rings and polar bands. An effectively nematic organization dominates for high densities and for straight, mutant filaments with increased rigidity. Our predicted phase diagram captures these features quantitatively, demonstrating how the flexibility, density and chirality of active filaments affect their collective behaviour. Our findings shed light on the fundamental properties of active chiral matter and explain how treadmilling FtsZ filaments organize during bacterial cell division. }, author = {Dunajova, Zuzana and Prats Mateu, Batirtze and Radler, Philipp and Lim, Keesiang and Brandis, Dörte and Velicky, Philipp and Danzl, Johann G and Wong, Richard W. and Elgeti, Jens and Hannezo, Edouard B and Loose, Martin}, publisher = {Institute of Science and Technology Austria}, title = {{Chiral and nematic phases of flexible active filaments}}, doi = {10.15479/AT:ISTA:13116}, year = {2023}, } @article{13314, abstract = {The emergence of large-scale order in self-organized systems relies on local interactions between individual components. During bacterial cell division, FtsZ—a prokaryotic homologue of the eukaryotic protein tubulin—polymerizes into treadmilling filaments that further organize into a cytoskeletal ring. In vitro, FtsZ filaments can form dynamic chiral assemblies. However, how the active and passive properties of individual filaments relate to these large-scale self-organized structures remains poorly understood. Here we connect single-filament properties with the mesoscopic scale by combining minimal active matter simulations and biochemical reconstitution experiments. We show that the density and flexibility of active chiral filaments define their global order. At intermediate densities, curved, flexible filaments organize into chiral rings and polar bands. An effectively nematic organization dominates for high densities and for straight, mutant filaments with increased rigidity. Our predicted phase diagram quantitatively captures these features, demonstrating how the flexibility, density and chirality of the active filaments affect their collective behaviour. Our findings shed light on the fundamental properties of active chiral matter and explain how treadmilling FtsZ filaments organize during bacterial cell division.}, author = {Dunajova, Zuzana and Prats Mateu, Batirtze and Radler, Philipp and Lim, Keesiang and Brandis, Dörte and Velicky, Philipp and Danzl, Johann G and Wong, Richard W. and Elgeti, Jens and Hannezo, Edouard B and Loose, Martin}, issn = {1745-2481}, journal = {Nature Physics}, pages = {1916--1926}, publisher = {Springer Nature}, title = {{Chiral and nematic phases of flexible active filaments}}, doi = {10.1038/s41567-023-02218-w}, volume = {19}, year = {2023}, } @article{13971, abstract = {When in equilibrium, thermal forces agitate molecules, which then diffuse, collide and bind to form materials. However, the space of accessible structures in which micron-scale particles can be organized by thermal forces is limited, owing to the slow dynamics and metastable states. Active agents in a passive fluid generate forces and flows, forming a bath with active fluctuations. Two unanswered questions are whether those active agents can drive the assembly of passive components into unconventional states and which material properties they will exhibit. Here we show that passive, sticky beads immersed in a bath of swimming Escherichia coli bacteria aggregate into unconventional clusters and gels that are controlled by the activity of the bath. We observe a slow but persistent rotation of the aggregates that originates in the chirality of the E. coli flagella and directs aggregation into structures that are not accessible thermally. We elucidate the aggregation mechanism with a numerical model of spinning, sticky beads and reproduce quantitatively the experimental results. We show that internal activity controls the phase diagram and the structure of the aggregates. Overall, our results highlight the promising role of active baths in designing the structural and mechanical properties of materials with unconventional phases.}, author = {Grober, Daniel and Palaia, Ivan and Ucar, Mehmet C and Hannezo, Edouard B and Šarić, Anđela and Palacci, Jérémie A}, issn = {1745-2481}, journal = {Nature Physics}, pages = {1680--1688}, publisher = {Springer Nature}, title = {{Unconventional colloidal aggregation in chiral bacterial baths}}, doi = {10.1038/s41567-023-02136-x}, volume = {19}, 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}, } @inbook{12428, abstract = {The mammary gland consists of a bilayered epithelial structure with an extensively branched morphology. The majority of this epithelial tree is laid down during puberty, during which actively proliferating terminal end buds repeatedly elongate and bifurcate to form the basic structure of the ductal tree. Mammary ducts consist of a basal and luminal cell layer with a multitude of identified sub-lineages within both layers. The understanding of how these different cell lineages are cooperatively driving branching morphogenesis is a problem of crossing multiple scales, as this requires information on the macroscopic branched structure of the gland, as well as data on single-cell dynamics driving the morphogenic program. Here we describe a method to combine genetic lineage tracing with whole-gland branching analysis. Quantitative data on the global organ structure can be used to derive a model for mammary gland branching morphogenesis and provide a backbone on which the dynamics of individual cell lineages can be simulated and compared to lineage-tracing approaches. Eventually, these quantitative models and experiments allow to understand the couplings between the macroscopic shape of the mammary gland and the underlying single-cell dynamics driving branching morphogenesis.}, author = {Hannezo, Edouard B and Scheele, Colinda L.G.J.}, booktitle = {Cell Migration in Three Dimensions}, editor = {Margadant, Coert}, isbn = {9781071628867}, issn = {1940-6029}, pages = {183--205}, publisher = {Springer Nature}, title = {{A Guide Toward Multi-scale and Quantitative Branching Analysis in the Mammary Gland}}, doi = {10.1007/978-1-0716-2887-4_12}, volume = {2608}, year = {2023}, } @article{12710, abstract = {Surface curvature both emerges from, and influences the behavior of, living objects at length scales ranging from cell membranes to single cells to tissues and organs. The relevance of surface curvature in biology is supported by numerous experimental and theoretical investigations in recent years. In this review, first, a brief introduction to the key ideas of surface curvature in the context of biological systems is given and the challenges that arise when measuring surface curvature are discussed. Giving an overview of the emergence of curvature in biological systems, its significance at different length scales becomes apparent. On the other hand, summarizing current findings also shows that both single cells and entire cell sheets, tissues or organisms respond to curvature by modulating their shape and their migration behavior. Finally, the interplay between the distribution of morphogens or micro-organisms and the emergence of curvature across length scales is addressed with examples demonstrating these key mechanistic principles of morphogenesis. Overall, this review highlights that curved interfaces are not merely a passive by-product of the chemical, biological, and mechanical processes but that curvature acts also as a signal that co-determines these processes.}, author = {Schamberger, Barbara and Ziege, Ricardo and Anselme, Karine and Ben Amar, Martine and Bykowski, Michał and Castro, André P.G. and Cipitria, Amaia and Coles, Rhoslyn A. and Dimova, Rumiana and Eder, Michaela and Ehrig, Sebastian and Escudero, Luis M. and Evans, Myfanwy E. and Fernandes, Paulo R. and Fratzl, Peter and Geris, Liesbet and Gierlinger, Notburga and Hannezo, Edouard B and Iglič, Aleš and Kirkensgaard, Jacob J.K. and Kollmannsberger, Philip and Kowalewska, Łucja and Kurniawan, Nicholas A. and Papantoniou, Ioannis and Pieuchot, Laurent and Pires, Tiago H.V. and Renner, Lars D. and Sageman-Furnas, Andrew O. and Schröder-Turk, Gerd E. and Sengupta, Anupam and Sharma, Vikas R. and Tagua, Antonio and Tomba, Caterina and Trepat, Xavier and Waters, Sarah L. and Yeo, Edwina F. and Roschger, Andreas and Bidan, Cécile M. and Dunlop, John W.C.}, issn = {1521-4095}, journal = {Advanced Materials}, number = {13}, publisher = {Wiley}, title = {{Curvature in biological systems: Its quantification, emergence, and implications across the scales}}, doi = {10.1002/adma.202206110}, volume = {35}, year = {2023}, } @article{12837, abstract = {As developing tissues grow in size and undergo morphogenetic changes, their material properties may be altered. Such changes result from tension dynamics at cell contacts or cellular jamming. Yet, in many cases, the cellular mechanisms controlling the physical state of growing tissues are unclear. We found that at early developmental stages, the epithelium in the developing mouse spinal cord maintains both high junctional tension and high fluidity. This is achieved via a mechanism in which interkinetic nuclear movements generate cell area dynamics that drive extensive cell rearrangements. Over time, the cell proliferation rate declines, effectively solidifying the tissue. Thus, unlike well-studied jamming transitions, the solidification uncovered here resembles a glass transition that depends on the dynamical stresses generated by proliferation and differentiation. Our finding that the fluidity of developing epithelia is linked to interkinetic nuclear movements and the dynamics of growth is likely to be relevant to multiple developing tissues.}, author = {Bocanegra, Laura and Singh, Amrita and Hannezo, Edouard B and Zagórski, Marcin P and Kicheva, Anna}, issn = {1745-2481}, journal = {Nature Physics}, pages = {1050--1058}, publisher = {Springer Nature}, title = {{Cell cycle dynamics control fluidity of the developing mouse neuroepithelium}}, doi = {10.1038/s41567-023-01977-w}, volume = {19}, year = {2023}, } @article{10705, abstract = {Although rigidity and jamming transitions have been widely studied in physics and material science, their importance in a number of biological processes, including embryo development, tissue homeostasis, wound healing, and disease progression, has only begun to be recognized in the past few years. The hypothesis that biological systems can undergo rigidity/jamming transitions is attractive, as it would allow these systems to change their material properties rapidly and strongly. However, whether such transitions indeed occur in biological systems, how they are being regulated, and what their physiological relevance might be, is still being debated. Here, we review theoretical and experimental advances from the past few years, focusing on the regulation and role of potential tissue rigidity transitions in different biological processes.}, author = {Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {1879-3088}, journal = {Trends in Cell Biology}, number = {5}, pages = {P433--444}, publisher = {Cell Press}, title = {{Rigidity transitions in development and disease}}, doi = {10.1016/j.tcb.2021.12.006}, volume = {32}, year = {2022}, } @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{12277, abstract = {Cell migration in confining physiological environments relies on the concerted dynamics of several cellular components, including protrusions, adhesions with the environment, and the cell nucleus. However, it remains poorly understood how the dynamic interplay of these components and the cell polarity determine the emergent migration behavior at the cellular scale. Here, we combine data-driven inference with a mechanistic bottom-up approach to develop a model for protrusion and polarity dynamics in confined cell migration, revealing how the cellular dynamics adapt to confining geometries. Specifically, we use experimental data of joint protrusion-nucleus migration trajectories of cells on confining micropatterns to systematically determine a mechanistic model linking the stochastic dynamics of cell polarity, protrusions, and nucleus. This model indicates that the cellular dynamics adapt to confining constrictions through a switch in the polarity dynamics from a negative to a positive self-reinforcing feedback loop. Our model further reveals how this feedback loop leads to stereotypical cycles of protrusion-nucleus dynamics that drive the migration of the cell through constrictions. These cycles are disrupted upon perturbation of cytoskeletal components, indicating that the positive feedback is controlled by cellular migration mechanisms. Our data-driven theoretical approach therefore identifies polarity feedback adaptation as a key mechanism in confined cell migration.}, author = {Brückner, David and Schmitt, Matthew and Fink, Alexandra and Ladurner, Georg and Flommersfeld, Johannes and Arlt, Nicolas and Hannezo, Edouard B and Rädler, Joachim O. and Broedersz, Chase P.}, issn = {2160-3308}, journal = {Physical Review X}, keywords = {General Physics and Astronomy}, number = {3}, publisher = {American Physical Society}, title = {{Geometry adaptation of protrusion and polarity dynamics in confined cell migration}}, doi = {10.1103/physrevx.12.031041}, volume = {12}, year = {2022}, } @article{9794, abstract = {Lymph nodes (LNs) comprise two main structural elements: fibroblastic reticular cells that form dedicated niches for immune cell interaction and capsular fibroblasts that build a shell around the organ. Immunological challenge causes LNs to increase more than tenfold in size within a few days. Here, we characterized the biomechanics of LN swelling on the cellular and organ scale. We identified lymphocyte trapping by influx and proliferation as drivers of an outward pressure force, causing fibroblastic reticular cells of the T-zone (TRCs) and their associated conduits to stretch. After an initial phase of relaxation, TRCs sensed the resulting strain through cell matrix adhesions, which coordinated local growth and remodeling of the stromal network. While the expanded TRC network readopted its typical configuration, a massive fibrotic reaction of the organ capsule set in and countered further organ expansion. Thus, different fibroblast populations mechanically control LN swelling in a multitier fashion.}, author = {Assen, Frank P and Abe, Jun and Hons, Miroslav and Hauschild, Robert and Shamipour, Shayan and Kaufmann, Walter and Costanzo, Tommaso and Krens, Gabriel and Brown, Markus and Ludewig, Burkhard and Hippenmeyer, Simon and Heisenberg, Carl-Philipp J and Weninger, Wolfgang and Hannezo, Edouard B and Luther, Sanjiv A. and Stein, Jens V. and Sixt, Michael K}, issn = {1529-2916}, journal = {Nature Immunology}, pages = {1246--1255}, publisher = {Springer Nature}, title = {{Multitier mechanics control stromal adaptations in swelling lymph nodes}}, doi = {10.1038/s41590-022-01257-4}, volume = {23}, year = {2022}, }