@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{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{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}, } @article{10530, abstract = {Cell dispersion from a confined area is fundamental in a number of biological processes, including cancer metastasis. To date, a quantitative understanding of the interplay of single cell motility, cell proliferation, and intercellular contacts remains elusive. In particular, the role of E- and N-Cadherin junctions, central components of intercellular contacts, is still controversial. Combining theoretical modeling with in vitro observations, we investigate the collective spreading behavior of colonies of human cancer cells (T24). The spreading of these colonies is driven by stochastic single-cell migration with frequent transient cell-cell contacts. We find that inhibition of E- and N-Cadherin junctions decreases colony spreading and average spreading velocities, without affecting the strength of correlations in spreading velocities of neighboring cells. Based on a biophysical simulation model for cell migration, we show that the behavioral changes upon disruption of these junctions can be explained by reduced repulsive excluded volume interactions between cells. This suggests that in cancer cell migration, cadherin-based intercellular contacts sharpen cell boundaries leading to repulsive rather than cohesive interactions between cells, thereby promoting efficient cell spreading during collective migration. }, author = {Zisis, Themistoklis and Brückner, David and Brandstätter, Tom and Siow, Wei Xiong and d’Alessandro, Joseph and Vollmar, Angelika M. and Broedersz, Chase P. and Zahler, Stefan}, issn = {0006-3495}, journal = {Biophysical Journal}, keywords = {Biophysics}, number = {1}, pages = {P44--60}, publisher = {Elsevier}, title = {{Disentangling cadherin-mediated cell-cell interactions in collective cancer cell migration}}, doi = {10.1016/j.bpj.2021.12.006}, volume = {121}, year = {2022}, } @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{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{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}, } @misc{13068, abstract = {Source data and source code for the graphs in "Spatiotemporal dynamics of self-organized branching pancreatic cancer-derived organoids".}, author = {Randriamanantsoa, Samuel and Papargyriou, Aristeidis and Maurer, Carlo and Peschke, Katja and Schuster, Maximilian and Zecchin, Giulia and Steiger, Katja and Öllinger, Rupert and Saur, Dieter and Scheel, Christina and Rad, Roland and Hannezo, Edouard B and Reichert, Maximilian and Bausch, Andreas R.}, publisher = {Zenodo}, title = {{Spatiotemporal dynamics of self-organized branching in pancreas-derived organoids}}, doi = {10.5281/ZENODO.5148117}, year = {2021}, } @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{9306, abstract = {Assemblies of actin and its regulators underlie the dynamic morphology of all eukaryotic cells. To understand how actin regulatory proteins work together to generate actin-rich structures such as filopodia, we analyzed the localization of diverse actin regulators within filopodia in Drosophila embryos and in a complementary in vitro system of filopodia-like structures (FLSs). We found that the composition of the regulatory protein complex where actin is incorporated (the filopodial tip complex) is remarkably heterogeneous both in vivo and in vitro. Our data reveal that different pairs of proteins correlate with each other and with actin bundle length, suggesting the presence of functional subcomplexes. This is consistent with a theoretical framework where three or more redundant subcomplexes join the tip complex stochastically, with any two being sufficient to drive filopodia formation. We provide an explanation for the observed heterogeneity and suggest that a mechanism based on multiple components allows stereotypical filopodial dynamics to arise from diverse upstream signaling pathways.}, author = {Dobramysl, Ulrich and Jarsch, Iris Katharina and Inoue, Yoshiko and Shimo, Hanae and Richier, Benjamin and Gadsby, Jonathan R. and Mason, Julia and Szałapak, Alicja and Ioannou, Pantelis Savvas and Correia, Guilherme Pereira and Walrant, Astrid and Butler, Richard and Hannezo, Edouard B and Simons, Benjamin D. and Gallop, Jennifer L.}, issn = {15408140}, journal = {Journal of Cell Biology}, number = {4}, publisher = {Rockefeller University Press}, title = {{Stochastic combinations of actin regulatory proteins are sufficient to drive filopodia formation}}, doi = {10.1083/jcb.202003052}, volume = {220}, 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{9952, abstract = {Proper control of division orientation and symmetry, largely determined by spindle positioning, is essential to development and homeostasis. Spindle positioning has been extensively studied in cells dividing in two-dimensional (2D) environments and in epithelial tissues, where proteins such as NuMA (also known as NUMA1) orient division along the interphase long axis of the cell. However, little is known about how cells control spindle positioning in three-dimensional (3D) environments, such as early mammalian embryos and a variety of adult tissues. Here, we use mouse embryonic stem cells (ESCs), which grow in 3D colonies, as a model to investigate division in 3D. We observe that, at the periphery of 3D colonies, ESCs display high spindle mobility and divide asymmetrically. Our data suggest that enhanced spindle movements are due to unequal distribution of the cell–cell junction protein E-cadherin between future daughter cells. Interestingly, when cells progress towards differentiation, division becomes more symmetric, with more elongated shapes in metaphase and enhanced cortical NuMA recruitment in anaphase. Altogether, this study suggests that in 3D contexts, the geometry of the cell and its contacts with neighbors control division orientation and symmetry.}, author = {Chaigne, Agathe and Smith, Matthew B. and Cavestany, R. L. and Hannezo, Edouard B and Chalut, Kevin J. and Paluch, Ewa K.}, issn = {14779137}, journal = {Journal of Cell Science}, number = {14}, publisher = {The Company of Biologists}, title = {{Three-dimensional geometry controls division symmetry in stem cell colonies}}, doi = {10.1242/jcs.255018}, volume = {134}, year = {2021}, } @article{10178, abstract = {In dense biological tissues, cell types performing different roles remain segregated by maintaining sharp interfaces. To better understand the mechanisms for such sharp compartmentalization, we study the effect of an imposed heterotypic tension at the interface between two distinct cell types in a fully 3D Voronoi model for confluent tissues. We find that cells rapidly sort and self-organize to generate a tissue-scale interface between cell types, and cells adjacent to this interface exhibit signature geometric features including nematic-like ordering, bimodal facet areas, and registration, or alignment, of cell centers on either side of the two-tissue interface. The magnitude of these features scales directly with the magnitude of the imposed tension, suggesting that biologists can estimate the magnitude of tissue surface tension between two tissue types simply by segmenting a 3D tissue. To uncover the underlying physical mechanisms driving these geometric features, we develop two minimal, ordered models using two different underlying lattices that identify an energetic competition between bulk cell shapes and tissue interface area. When the interface area dominates, changes to neighbor topology are costly and occur less frequently, which generates the observed geometric features.}, author = {Sahu, Preeti and Schwarz, J. M. and Manning, M. Lisa}, issn = {13672630}, journal = {New Journal of Physics}, number = {9}, publisher = {IOP Publishing}, title = {{Geometric signatures of tissue surface tension in a three-dimensional model of confluent tissue}}, doi = {10.1088/1367-2630/ac23f1}, volume = {23}, 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}, } @misc{13058, abstract = {The zip file includes source data used in the main text of the manuscript "Theory of branching morphogenesis by local interactions and global guidance", as well as a representative Jupyter notebook to reproduce the main figures. A sample script for the simulations of branching and annihilating random walks is also included (Sample_script_for_simulations_of_BARWs.ipynb) to generate exemplary branched networks under external guidance. A detailed description of the simulation setup is provided in the supplementary information of the manuscipt.}, author = {Ucar, Mehmet C}, publisher = {Zenodo}, title = {{Source data for the manuscript "Theory of branching morphogenesis by local interactions and global guidance"}}, doi = {10.5281/ZENODO.5257160}, year = {2021}, } @article{10573, abstract = {How tissues acquire complex shapes is a fundamental question in biology and regenerative medicine. Zebrafish semicircular canals form from invaginations in the otic epithelium (buds) that extend and fuse to form the hubs of each canal. We find that conventional actomyosin-driven behaviors are not required. Instead, local secretion of hyaluronan, made by the enzymes uridine 5′-diphosphate dehydrogenase (ugdh) and hyaluronan synthase 3 (has3), drives canal morphogenesis. Charged hyaluronate polymers osmotically swell with water and generate isotropic extracellular pressure to deform the overlying epithelium into buds. The mechanical anisotropy needed to shape buds into tubes is conferred by a polarized distribution of actomyosin and E-cadherin-rich membrane tethers, which we term cytocinches. Most work on tissue morphogenesis ascribes actomyosin contractility as the driving force, while the extracellular matrix shapes tissues through differential stiffness. Our work inverts this expectation. Hyaluronate pressure shaped by anisotropic tissue stiffness may be a widespread mechanism for powering morphological change in organogenesis and tissue engineering.}, author = {Munjal, Akankshi and Hannezo, Edouard B and Tsai, Tony Y.C. and Mitchison, Timothy J. and Megason, Sean G.}, issn = {1097-4172}, journal = {Cell}, number = {26}, pages = {6313--6325.e18}, publisher = {Elsevier ; Cell Press}, title = {{Extracellular hyaluronate pressure shaped by cellular tethers drives tissue morphogenesis}}, doi = {10.1016/j.cell.2021.11.025}, volume = {184}, 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{7166, abstract = {In the living cell, we encounter a large variety of motile processes such as organelle transport and cytoskeleton remodeling. These processes are driven by motor proteins that generate force by transducing chemical free energy into mechanical work. In many cases, the molecular motors work in teams to collectively generate larger forces. Recent optical trapping experiments on small teams of cytoskeletal motors indicated that the collectively generated force increases with the size of the motor team but that this increase depends on the motor type and on whether the motors are studied in vitro or in vivo. Here, we use the theory of stochastic processes to describe the motion of N motors in a stationary optical trap and to compute the N-dependence of the collectively generated forces. We consider six distinct motor types, two kinesins, two dyneins, and two myosins. We show that the force increases always linearly with N but with a prefactor that depends on the performance of the single motor. Surprisingly, this prefactor increases for weaker motors with a lower stall force. This counter-intuitive behavior reflects the increased probability with which stronger motors detach from the filament during strain generation. Our theoretical results are in quantitative agreement with experimental data on small teams of kinesin-1 motors.}, author = {Ucar, Mehmet C and Lipowsky, Reinhard}, issn = {1530-6992}, journal = {Nano Letters}, number = {1}, pages = {669--676}, publisher = {American Chemical Society}, title = {{Collective force generation by molecular motors is determined by strain-induced unbinding}}, doi = {10.1021/acs.nanolett.9b04445}, volume = {20}, year = {2020}, } @misc{9885, abstract = {Data obtained from the fine-grained simulations used in Figures 2-5, data obtained from the coarse-grained numerical calculations used in Figure 6, and a sample script for the fine-grained simulation as a Jupyter notebook (ZIP)}, author = {Ucar, Mehmet C and Lipowsky, Reinhard}, publisher = {American Chemical Society }, title = {{MURL_Dataz}}, doi = {10.1021/acs.nanolett.9b04445.s002}, year = {2020}, } @article{7431, abstract = {In many real-world systems, information can be transmitted in two qualitatively different ways: by copying or by transformation. Copying occurs when messages are transmitted without modification, e.g. when an offspring receives an unaltered copy of a gene from its parent. Transformation occurs when messages are modified systematically during transmission, e.g. when mutational biases occur during genetic replication. Standard information-theoretic measures do not distinguish these two modes of information transfer, although they may reflect different mechanisms and have different functional consequences. Starting from a few simple axioms, we derive a decomposition of mutual information into the information transmitted by copying versus the information transmitted by transformation. We begin with a decomposition that applies when the source and destination of the channel have the same set of messages and a notion of message identity exists. We then generalize our decomposition to other kinds of channels, which can involve different source and destination sets and broader notions of similarity. In addition, we show that copy information can be interpreted as the minimal work needed by a physical copying process, which is relevant for understanding the physics of replication. We use the proposed decomposition to explore a model of amino acid substitution rates. Our results apply to any system in which the fidelity of copying, rather than simple predictability, is of critical relevance.}, author = {Kolchinsky, Artemy and Corominas-Murtra, Bernat}, issn = {17425662}, journal = {Journal of the Royal Society Interface}, number = {162}, publisher = {The Royal Society}, title = {{Decomposing information into copying versus transformation}}, doi = {10.1098/rsif.2019.0623}, volume = {17}, year = {2020}, } @article{7789, abstract = {During embryonic and postnatal development, organs and tissues grow steadily to achieve their final size at the end of puberty. However, little is known about the cellular dynamics that mediate postnatal growth. By combining in vivo clonal lineage tracing, proliferation kinetics, single-cell transcriptomics, andin vitro micro-pattern experiments, we resolved the cellular dynamics taking place during postnatal skin epidermis expansion. Our data revealed that harmonious growth is engineered by a single population of developmental progenitors presenting a fixed fate imbalance of self-renewing divisions with an ever-decreasing proliferation rate. Single-cell RNA sequencing revealed that epidermal developmental progenitors form a more uniform population compared with adult stem and progenitor cells. Finally, we found that the spatial pattern of cell division orientation is dictated locally by the underlying collagen fiber orientation. Our results uncover a simple design principle of organ growth where progenitors and differentiated cells expand in harmony with their surrounding tissues.}, author = {Dekoninck, Sophie and Hannezo, Edouard B and Sifrim, Alejandro and Miroshnikova, Yekaterina A. and Aragona, Mariaceleste and Malfait, Milan and Gargouri, Souhir and De Neunheuser, Charlotte and Dubois, Christine and Voet, Thierry and Wickström, Sara A. and Simons, Benjamin D. and Blanpain, Cédric}, issn = {10974172}, journal = {Cell}, number = {3}, pages = {604--620.e22}, publisher = {Elsevier}, title = {{Defining the design principles of skin epidermis postnatal growth}}, doi = {10.1016/j.cell.2020.03.015}, volume = {181}, year = {2020}, } @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}, } @article{8669, abstract = {Pancreatic islets play an essential role in regulating blood glucose level. Although the molecular pathways underlying islet cell differentiation are beginning to be resolved, the cellular basis of islet morphogenesis and fate allocation remain unclear. By combining unbiased and targeted lineage tracing, we address the events leading to islet formation in the mouse. From the statistical analysis of clones induced at multiple embryonic timepoints, here we show that, during the secondary transition, islet formation involves the aggregation of multiple equipotent endocrine progenitors that transition from a phase of stochastic amplification by cell division into a phase of sublineage restriction and limited islet fission. Together, these results explain quantitatively the heterogeneous size distribution and degree of polyclonality of maturing islets, as well as dispersion of progenitors within and between islets. Further, our results show that, during the secondary transition, α- and β-cells are generated in a contemporary manner. Together, these findings provide insight into the cellular basis of islet development.}, author = {Sznurkowska, Magdalena K. and Hannezo, Edouard B and Azzarelli, Roberta and Chatzeli, Lemonia and Ikeda, Tatsuro and Yoshida, Shosei and Philpott, Anna and Simons, Benjamin D}, issn = {20411723}, journal = {Nature Communications}, publisher = {Springer Nature}, title = {{Tracing the cellular basis of islet specification in mouse pancreas}}, doi = {10.1038/s41467-020-18837-3}, volume = {11}, year = {2020}, } @article{8672, abstract = {Cell fate transitions are key to development and homeostasis. It is thus essential to understand the cellular mechanisms controlling fate transitions. Cell division has been implicated in fate decisions in many stem cell types, including neuronal and epithelial progenitors. In other stem cells, such as embryonic stem (ES) cells, the role of division remains unclear. Here, we show that exit from naive pluripotency in mouse ES cells generally occurs after a division. We further show that exit timing is strongly correlated between sister cells, which remain connected by cytoplasmic bridges long after division, and that bridge abscission progressively accelerates as cells exit naive pluripotency. Finally, interfering with abscission impairs naive pluripotency exit, and artificially inducing abscission accelerates it. Altogether, our data indicate that a switch in the division machinery leading to faster abscission regulates pluripotency exit. Our study identifies abscission as a key cellular process coupling cell division to fate transitions.}, author = {Chaigne, Agathe and Labouesse, Céline and White, Ian J. and Agnew, Meghan and Hannezo, Edouard B and Chalut, Kevin J. and Paluch, Ewa K.}, issn = {18781551}, journal = {Developmental Cell}, number = {2}, pages = {195--208}, publisher = {Elsevier}, title = {{Abscission couples cell division to embryonic stem cell fate}}, doi = {10.1016/j.devcel.2020.09.001}, volume = {55}, year = {2020}, } @misc{9726, abstract = {A detailed description of the two stochastic models, table of parameters, supplementary data for Figures 4 and 5, parameter dependence of the results, and an analysis on motors with different force–velocity functions (PDF)}, author = {Ucar, Mehmet C and Lipowsky, Reinhard}, publisher = {American Chemical Society }, title = {{Supplementary information - Collective force generation by molecular motors is determined by strain-induced unbinding}}, doi = {10.1021/acs.nanolett.9b04445.s001}, year = {2019}, } @article{5944, abstract = {Understanding the thermodynamics of the duplication process is a fundamental step towards a comprehensive physical theory of biological systems. However, the immense complexity of real cells obscures the fundamental tensions between energy gradients and entropic contributions that underlie duplication. The study of synthetic, feasible systems reproducing part of the key ingredients of living entities but overcoming major sources of biological complexity is of great relevance to deepen the comprehension of the fundamental thermodynamic processes underlying life and its prevalence. In this paper an abstract—yet realistic—synthetic system made of small synthetic protocell aggregates is studied in detail. A fundamental relation between free energy and entropic gradients is derived for a general, non-equilibrium scenario, setting the thermodynamic conditions for the occurrence and prevalence of duplication phenomena. This relation sets explicitly how the energy gradients invested in creating and maintaining structural—and eventually, functional—elements of the system must always compensate the entropic gradients, whose contributions come from changes in the translational, configurational, and macrostate entropies, as well as from dissipation due to irreversible transitions. Work/energy relations are also derived, defining lower bounds on the energy required for the duplication event to take place. A specific example including real ternary emulsions is provided in order to grasp the orders of magnitude involved in the problem. It is found that the minimal work invested over the system to trigger a duplication event is around ~ 10−13J , which results, in the case of duplication of all the vesicles contained in a liter of emulsion, in an amount of energy around ~ 1kJ . Without aiming to describe a truly biological process of duplication, this theoretical contribution seeks to explicitly define and identify the key actors that participate in it.}, author = {Corominas-Murtra, Bernat}, issn = {20751729}, journal = {Life}, number = {1}, publisher = {MDPI}, title = {{Thermodynamics of duplication thresholds in synthetic protocell systems}}, doi = {10.3390/life9010009}, volume = {9}, year = {2019}, } @article{6191, abstract = {The formation of self-organized patterns is key to the morphogenesis of multicellular organisms, although a comprehensive theory of biological pattern formation is still lacking. Here, we propose a minimal model combining tissue mechanics with morphogen turnover and transport to explore routes to patterning. Our active description couples morphogen reaction and diffusion, which impact cell differentiation and tissue mechanics, to a two-phase poroelastic rheology, where one tissue phase consists of a poroelastic cell network and the other one of a permeating extracellular fluid, which provides a feedback by actively transporting morphogens. While this model encompasses previous theories approximating tissues to inert monophasic media, such as Turing’s reaction–diffusion model, it overcomes some of their key limitations permitting pattern formation via any two-species biochemical kinetics due to mechanically induced cross-diffusion flows. Moreover, we describe a qualitatively different advection-driven Keller–Segel instability which allows for the formation of patterns with a single morphogen and whose fundamental mode pattern robustly scales with tissue size. We discuss the potential relevance of these findings for tissue morphogenesis.}, author = {Recho, Pierre and Hallou, Adrien and Hannezo, Edouard B}, issn = {10916490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {12}, pages = {5344--5349}, publisher = {National Academy of Sciences}, title = {{Theory of mechanochemical patterning in biphasic biological tissues}}, doi = {10.1073/pnas.1813255116}, volume = {116}, year = {2019}, } @article{6513, abstract = {Adult intestinal stem cells are located at the bottom of crypts of Lieberkühn, where they express markers such as LGR5 1,2 and fuel the constant replenishment of the intestinal epithelium1. Although fetal LGR5-expressing cells can give rise to adult intestinal stem cells3,4, it remains unclear whether this population in the patterned epithelium represents unique intestinal stem-cell precursors. Here we show, using unbiased quantitative lineage-tracing approaches, biophysical modelling and intestinal transplantation, that all cells of the mouse intestinal epithelium—irrespective of their location and pattern of LGR5 expression in the fetal gut tube—contribute actively to the adult intestinal stem cell pool. Using 3D imaging, we find that during fetal development the villus undergoes gross remodelling and fission. This brings epithelial cells from the non-proliferative villus into the proliferative intervillus region, which enables them to contribute to the adult stem-cell niche. Our results demonstrate that large-scale remodelling of the intestinal wall and cell-fate specification are closely linked. Moreover, these findings provide a direct link between the observed plasticity and cellular reprogramming of differentiating cells in adult tissues following damage5,6,7,8,9, revealing that stem-cell identity is an induced rather than a hardwired property.}, author = {Guiu, Jordi and Hannezo, Edouard B and Yui, Shiro and Demharter, Samuel and Ulyanchenko, Svetlana and Maimets, Martti and Jørgensen, Anne and Perlman, Signe and Lundvall, Lene and Mamsen, Linn Salto and Larsen, Agnete and Olesen, Rasmus H. and Andersen, Claus Yding and Thuesen, Lea Langhoff and Hare, Kristine Juul and Pers, Tune H. and Khodosevich, Konstantin and Simons, Benjamin D. and Jensen, Kim B.}, issn = {14764687}, journal = {Nature}, pages = {107--111}, publisher = {Springer Nature}, title = {{Tracing the origin of adult intestinal stem cells}}, doi = {10.1038/s41586-019-1212-5}, volume = {570}, year = {2019}, } @article{6559, abstract = {Branching morphogenesis is a prototypical example of complex three-dimensional organ sculpting, required in multiple developmental settings to maximize the area of exchange surfaces. It requires, in particular, the coordinated growth of different cell types together with complex patterning to lead to robust macroscopic outputs. In recent years, novel multiscale quantitative biology approaches, together with biophysical modelling, have begun to shed new light of this topic. Here, we wish to review some of these recent developments, highlighting the generic design principles that can be abstracted across different branched organs, as well as the implications for the broader fields of stem cell, developmental and systems biology.}, author = {Hannezo, Edouard B and Simons, Benjamin D.}, issn = {18790410}, journal = {Current Opinion in Cell Biology}, pages = {99--105}, publisher = {Elsevier}, title = {{Multiscale dynamics of branching morphogenesis}}, doi = {10.1016/j.ceb.2019.04.008}, volume = {60}, year = {2019}, } @article{6601, abstract = {There is increasing evidence that both mechanical and biochemical signals play important roles in development and disease. The development of complex organisms, in particular, has been proposed to rely on the feedback between mechanical and biochemical patterning events. This feedback occurs at the molecular level via mechanosensation but can also arise as an emergent property of the system at the cellular and tissue level. In recent years, dynamic changes in tissue geometry, flow, rheology, and cell fate specification have emerged as key platforms of mechanochemical feedback loops in multiple processes. Here, we review recent experimental and theoretical advances in understanding how these feedbacks function in development and disease.}, author = {Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {00928674}, journal = {Cell}, number = {1}, pages = {12--25}, publisher = {Elsevier}, title = {{Mechanochemical feedback loops in development and disease}}, doi = {10.1016/j.cell.2019.05.052}, volume = {178}, year = {2019}, } @article{6832, abstract = {Steady-state turnover is a hallmark of epithelial tissues throughout adult life. Intestinal epithelial turnover is marked by continuous cell migration, which is assumed to be driven by mitotic pressure from the crypts. However, the balance of forces in renewal remains ill-defined. Combining biophysical modeling and quantitative three-dimensional tissue imaging with genetic and physical manipulations, we revealed the existence of an actin-related protein 2/3 complex–dependent active migratory force, which explains quantitatively the profiles of cell speed, density, and tissue tension along the villi. Cells migrate collectively with minimal rearrangements while displaying dual—apicobasal and front-back—polarity characterized by actin-rich basal protrusions oriented in the direction of migration. We propose that active migration is a critical component of gut epithelial turnover.}, author = {Krndija, Denis and Marjou, Fatima El and Guirao, Boris and Richon, Sophie and Leroy, Olivier and Bellaiche, Yohanns and Hannezo, Edouard B and Vignjevic, Danijela Matic}, journal = {Science}, number = {6454}, pages = {705--710}, publisher = {American Association for the Advancement of Science}, title = {{Active cell migration is critical for steady-state epithelial turnover in the gut}}, doi = {10.1126/science.aau3429}, volume = {365}, year = {2019}, } @article{5789, abstract = {Tissue morphogenesis is driven by mechanical forces that elicit changes in cell size, shape and motion. The extent by which forces deform tissues critically depends on the rheological properties of the recipient tissue. Yet, whether and how dynamic changes in tissue rheology affect tissue morphogenesis and how they are regulated within the developing organism remain unclear. Here, we show that blastoderm spreading at the onset of zebrafish morphogenesis relies on a rapid, pronounced and spatially patterned tissue fluidization. Blastoderm fluidization is temporally controlled by mitotic cell rounding-dependent cell–cell contact disassembly during the last rounds of cell cleavages. Moreover, fluidization is spatially restricted to the central blastoderm by local activation of non-canonical Wnt signalling within the blastoderm margin, increasing cell cohesion and thereby counteracting the effect of mitotic rounding on contact disassembly. Overall, our results identify a fluidity transition mediated by loss of cell cohesion as a critical regulator of embryo morphogenesis.}, author = {Petridou, Nicoletta and Grigolon, Silvia and Salbreux, Guillaume and Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {14657392}, journal = {Nature Cell Biology}, pages = {169–178}, publisher = {Nature Publishing Group}, title = {{Fluidization-mediated tissue spreading by mitotic cell rounding and non-canonical Wnt signalling}}, doi = {10.1038/s41556-018-0247-4}, volume = {21}, year = {2019}, } @article{6508, abstract = {Segregation of maternal determinants within the oocyte constitutes the first step in embryo patterning. In zebrafish oocytes, extensive ooplasmic streaming leads to the segregation of ooplasm from yolk granules along the animal-vegetal axis of the oocyte. Here, we show that this process does not rely on cortical actin reorganization, as previously thought, but instead on a cell-cycle-dependent bulk actin polymerization wave traveling from the animal to the vegetal pole of the oocyte. This wave functions in segregation by both pulling ooplasm animally and pushing yolk granules vegetally. Using biophysical experimentation and theory, we show that ooplasm pulling is mediated by bulk actin network flows exerting friction forces on the ooplasm, while yolk granule pushing is achieved by a mechanism closely resembling actin comet formation on yolk granules. Our study defines a novel role of cell-cycle-controlled bulk actin polymerization waves in oocyte polarization via ooplasmic segregation.}, author = {Shamipour, Shayan and Kardos, Roland and Xue, Shi-lei and Hof, Björn and Hannezo, Edouard B and Heisenberg, Carl-Philipp J}, issn = {10974172}, journal = {Cell}, number = {6}, pages = {1463--1479.e18}, publisher = {Elsevier}, title = {{Bulk actin dynamics drive phase segregation in zebrafish oocytes}}, doi = {10.1016/j.cell.2019.04.030}, volume = {177}, year = {2019}, } @article{401, abstract = {The actomyosin cytoskeleton, a key stress-producing unit in epithelial cells, oscillates spontaneously in a wide variety of systems. Although much of the signal cascade regulating myosin activity has been characterized, the origin of such oscillatory behavior is still unclear. Here, we show that basal myosin II oscillation in Drosophila ovarian epithelium is not controlled by actomyosin cortical tension, but instead relies on a biochemical oscillator involving ROCK and myosin phosphatase. Key to this oscillation is a diffusive ROCK flow, linking junctional Rho1 to medial actomyosin cortex, and dynamically maintained by a self-activation loop reliant on ROCK kinase activity. In response to the resulting myosin II recruitment, myosin phosphatase is locally enriched and shuts off ROCK and myosin II signals. Coupling Drosophila genetics, live imaging, modeling, and optogenetics, we uncover an intrinsic biochemical oscillator at the core of myosin II regulatory network, shedding light on the spatio-temporal dynamics of force generation.}, author = {Qin, Xiang and Hannezo, Edouard B and Mangeat, Thomas and Liu, Chang and Majumder, Pralay and Liu, Jjiaying and Choesmel Cadamuro, Valerie and Mcdonald, Jocelyn and Liu, Yinyao and Yi, Bin and Wang, Xiaobo}, journal = {Nature Communications}, number = {1}, publisher = {Nature Publishing Group}, title = {{A biochemical network controlling basal myosin oscillation}}, doi = {10.1038/s41467-018-03574-5}, volume = {9}, year = {2018}, } @article{288, abstract = {Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.}, author = {Lilja, Anna and Rodilla, Veronica and Huyghe, Mathilde and Hannezo, Edouard B and Landragin, Camille and Renaud, Olivier and Leroy, Olivier and Rulands, Steffen and Simons, Benjamin and Fré, Silvia}, journal = {Nature Cell Biology}, number = {6}, pages = {677 -- 687}, publisher = {Nature Publishing Group}, title = {{Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland}}, doi = {10.1038/s41556-018-0108-1}, volume = {20}, year = {2018}, } @article{132, abstract = {Pancreas development involves a coordinated process in which an early phase of cell segregation is followed by a longer phase of lineage restriction, expansion, and tissue remodeling. By combining clonal tracing and whole-mount reconstruction with proliferation kinetics and single-cell transcriptional profiling, we define the functional basis of pancreas morphogenesis. We show that the large-scale organization of mouse pancreas can be traced to the activity of self-renewing precursors positioned at the termini of growing ducts, which act collectively to drive serial rounds of stochastic ductal bifurcation balanced by termination. During this phase of branching morphogenesis, multipotent precursors become progressively fate-restricted, giving rise to self-renewing acinar-committed precursors that are conveyed with growing ducts, as well as ductal progenitors that expand the trailing ducts and give rise to delaminating endocrine cells. These findings define quantitatively how the functional behavior and lineage progression of precursor pools determine the large-scale patterning of pancreatic sub-compartments.}, author = {Sznurkowska, Magdalena and Hannezo, Edouard B and Azzarelli, Roberta and Rulands, Steffen and Nestorowa, Sonia and Hindley, Christopher and Nichols, Jennifer and Göttgens, Berthold and Huch, Meritxell and Philpott, Anna and Simons, Benjamin}, journal = {Developmental Cell}, number = {3}, pages = {360 -- 375}, publisher = {Cell Press}, title = {{Defining lineage potential and fate behavior of precursors during pancreas development}}, doi = {10.1016/j.devcel.2018.06.028}, volume = {46}, year = {2018}, } @article{5787, abstract = {Branching morphogenesis remains a subject of abiding interest. Although much is known about the gene regulatory programs and signaling pathways that operate at the cellular scale, it has remained unclear how the macroscopic features of branched organs, including their size, network topology and spatial patterning, are encoded. Lately, it has been proposed that, these features can be explained quantitatively in several organs within a single unifying framework. Based on large- scale organ recon - structions and cell lineage tracing, it has been argued that morphogenesis follows from the collective dynamics of sublineage- restricted self- renewing progenitor cells, localized at ductal tips, that act cooperatively to drive a serial process of ductal elon - gation and stochastic tip bifurcation. By correlating differentiation or cell cycle exit with proximity to maturing ducts, this dynamic results in the specification of a com- plex network of defined density and statistical organization. These results suggest that, for several mammalian tissues, branched epithelial structures develop as a self- organized process, reliant upon a strikingly simple, but generic, set of local rules, without recourse to a rigid and deterministic sequence of genetically programmed events. Here, we review the basis of these findings and discuss their implications.}, author = {Hannezo, Edouard B and Simons, Benjamin D.}, issn = {00121592}, journal = {Development Growth and Differentiation}, number = {9}, pages = {512--521}, publisher = {Wiley}, title = {{Statistical theory of branching morphogenesis}}, doi = {10.1111/dgd.12570}, volume = {60}, year = {2018}, } @article{421, abstract = {Cell shape is determined by a balance of intrinsic properties of the cell as well as its mechanochemical environment. Inhomogeneous shape changes underlie many morphogenetic events and involve spatial gradients in active cellular forces induced by complex chemical signaling. Here, we introduce a mechanochemical model based on the notion that cell shape changes may be induced by external diffusible biomolecules that influence cellular contractility (or equivalently, adhesions) in a concentration-dependent manner—and whose spatial profile in turn is affected by cell shape. We map out theoretically the possible interplay between chemical concentration and cellular structure. Besides providing a direct route to spatial gradients in cell shape profiles in tissues, we show that the dependence on cell shape helps create robust mechanochemical gradients.}, author = {Dasbiswas, Kinjal and Hannezo, Claude-Edouard B and Gov, Nir}, journal = {Biophysical Journal}, number = {4}, pages = {968 -- 977}, publisher = {Biophysical Society}, title = {{Theory of eppithelial cell shape transitions induced by mechanoactive chemical gradients}}, doi = {10.1016/j.bpj.2017.12.022}, volume = {114}, year = {2018}, } @article{5860, abstract = {A major problem for evolutionary theory is understanding the so-called open-ended nature of evolutionary change, from its definition to its origins. Open-ended evolution (OEE) refers to the unbounded increase in complexity that seems to characterize evolution on multiple scales. This property seems to be a characteristic feature of biological and technological evolution and is strongly tied to the generative potential associated with combinatorics, which allows the system to grow and expand their available state spaces. Interestingly, many complex systems presumably displaying OEE, from language to proteins, share a common statistical property: the presence of Zipf's Law. Given an inventory of basic items (such as words or protein domains) required to build more complex structures (sentences or proteins) Zipf's Law tells us that most of these elements are rare whereas a few of them are extremely common. Using algorithmic information theory, in this paper we provide a fundamental definition for open-endedness, which can be understood as postulates. Its statistical counterpart, based on standard Shannon information theory, has the structure of a variational problem which is shown to lead to Zipf's Law as the expected consequence of an evolutionary process displaying OEE. We further explore the problem of information conservation through an OEE process and we conclude that statistical information (standard Shannon information) is not conserved, resulting in the paradoxical situation in which the increase of information content has the effect of erasing itself. We prove that this paradox is solved if we consider non-statistical forms of information. This last result implies that standard information theory may not be a suitable theoretical framework to explore the persistence and increase of the information content in OEE systems.}, author = {Corominas-Murtra, Bernat and Seoane, Luís F. and Solé, Ricard}, issn = {17425689}, journal = {Journal of the Royal Society Interface}, number = {149}, publisher = {Royal Society Publishing}, title = {{Zipf's Law, unbounded complexity and open-ended evolution}}, doi = {10.1098/rsif.2018.0395}, volume = {15}, year = {2018}, } @article{5859, abstract = {The emergence of syntax during childhood is a remarkable example of how complex correlations unfold in nonlinear ways through development. In particular, rapid transitions seem to occur as children reach the age of two, which seems to separate a two-word, tree-like network of syntactic relations among words from the scale-free graphs associated with the adult, complex grammar. Here, we explore the evolution of syntax networks through language acquisition using the chromatic number, which captures the transition and provides a natural link to standard theories on syntactic structures. The data analysis is compared to a null model of network growth dynamics which is shown to display non-trivial and sensible differences. At a more general level, we observe that the chromatic classes define independent regions of the graph, and thus, can be interpreted as the footprints of incompatibility relations, somewhat as opposed to modularity considerations.}, author = {Corominas-Murtra, Bernat and Fibla, Martí Sànchez and Valverde, Sergi and Solé, Ricard}, issn = {2054-5703}, journal = {Royal Society Open Science}, number = {12}, publisher = {The Royal Society}, title = {{Chromatic transitions in the emergence of syntax networks}}, doi = {10.1098/rsos.181286}, volume = {5}, year = {2018}, } @article{3, abstract = {SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder.}, author = {Deliu, Elena and Arecco, Niccoló and Morandell, Jasmin and Dotter, Christoph and Contreras, Ximena and Girardot, Charles and Käsper, Eva and Kozlova, Alena and Kishi, Kasumi and Chiaradia, Ilaria and Noh, Kyung and Novarino, Gaia}, journal = {Nature Neuroscience}, number = {12}, pages = {1717 -- 1727}, publisher = {Nature Publishing Group}, title = {{Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition}}, doi = {10.1038/s41593-018-0266-2}, volume = {21}, year = {2018}, } @article{726, abstract = {The morphogenesis of branched organs remains a subject of abiding interest. Although much is known about the underlying signaling pathways, it remains unclear how macroscopic features of branched organs, including their size, network topology, and spatial patterning, are encoded. Here, we show that, in mouse mammary gland, kidney, and human prostate, these features can be explained quantitatively within a single unifying framework of branching and annihilating random walks. Based on quantitative analyses of large-scale organ reconstructions and proliferation kinetics measurements, we propose that morphogenesis follows from the proliferative activity of equipotent tips that stochastically branch and randomly explore their environment but compete neutrally for space, becoming proliferatively inactive when in proximity with neighboring ducts. These results show that complex branched epithelial structures develop as a self-organized process, reliant upon a strikingly simple but generic rule, without recourse to a rigid and deterministic sequence of genetically programmed events.}, author = {Hannezo, Edouard B and Scheele, Colinda and Moad, Mohammad and Drogo, Nicholas and Heer, Rakesh and Sampogna, Rosemary and Van Rheenen, Jacco and Simons, Benjamin}, issn = {00928674}, journal = {Cell}, number = {1}, pages = {242 -- 255}, publisher = {Cell Press}, title = {{A unifying theory of branching morphogenesis}}, doi = {10.1016/j.cell.2017.08.026}, volume = {171}, year = {2017}, }