Mathematical modeling of tissue growth and repair

Participants :

Bénédicte Delaval (organisatrice), Jocelyn Etienne, Christophe Godin, Jérôme Gros, Zoher Gueroui, Dagmar Iber, Jens Januschke, Benoît Ladoux, Rolande Le Borgne (organisateur), Patrick Lemaire, Stephan Luschnig, Fernando Martín-Belmonte, Xavier Morin, Mauricio Rocha Martins, Guillaume Salbreux, Jérôme Solon, Magali Suzanne, Hervé Turlié, Julien Vermot
Et Héloïse Dufour (Cercle FSER) et Claude Tran (Educavox) pour la matinée « Meeting Scientifique Ouvert au Public » (rencontre lycéens / chercheurs)

Mathematical modeling of tissue growth and repair
by Benedicte Delaval and Roland Le Borgne
8 – 13 October, 2018

Summary

Nineteen researchers (cell biologists, biophysicists, computational modelling researchers) including a postdoctoral fellow, a young researcher who recently started his own group and group leaders at different stages of their career gathered in the inspiring site of Les Treilles to discuss, from an interdisciplinary point of view the “Contribution of cell mechanics to cell fate determination and tissue integrity”. Together, they discussed cell mechanics at different scales and from different perspectives. A wide diversity of cell biology systems was presented from in vitro and single cells approaches up to in vivo model organisms allowing to bridge, thanks to cutting edge microscopy techniques, the cellular to the tissue scale. After lively and fruitful discussions on each participant presentation with a particular emphasis on ongoing research projects, round tables were organized to initiate brainstorming sessions on recent technical advances in the represented research fields. Overall, by putting at the forefront communication between researcher from different backgrounds the meeting fostered interdisciplinary stimulating discussions, led to the establishment of new collaborations between participants and highlighted future objectives and challenges to be addressed. This seminar was not only an exciting time for participants to exchange on their projects and views, but also allowed them to share and communicate their interest for research to a younger audience by participating to speed meetings with local high school students as part of a “Meeting in Science Open to Public” initiative. Judging by the numerous questions and the look in the eyes of the high school students, sometimes surprised, but always enthusiastic, these exchanges were a great success. Overall, bringing together a small group of people from diverse research background ready to share their enthusiasm for research, the serenity of the meeting venue combined to the warm and generous welcome of the team working in les Treilles were all instrumental to make this meeting a success.

Keywords:  Epithelia, morphogenesis, cell junctions, polarity, asymmetric cell division, model organisms, fate acquisition, cell and tissue mechanics, biophysics, modeling, machine learning

Review

The first days of the meeting were focused on presentations by participants with a particular emphasis on ongoing and future projects in order to address, from different perspectives and at different scales, the contribution of cell mechanics to tissue integrity. Starting from in vitro reconstituted assays, Zoher Gueroui described his original study on how architecture of the actin meshwork affects microtubule dynamics and impacts on microtubule asters mobility. Controlling cytoskeleton architecture is, indeed, key throughout cell division and more specifically to control the orientation and geometry of cell division, which has a direct impact on cell fate choices and tissue morphogenesis. Combining live-imaging, genetics and laser-induced cell ablation approaches in Drosophila larval neuroblasts, Jens Januschke reported that maintenance of the division axis of the neuroblast relies on the last born-daughter cells. The external basal cue provided by the last-born daughter cell was shown to contribute to the orientation of the apico-basal polarity axis. Drosophila Sensory organ precursor (SOP) also divides asymmetrically and Roland Le Borgne reported how remodeling of the junctional complexes and polarity modules at cytokinesis regulates the mechanical properties of SOP daughter cells interface to control Notch-dependent fate acquisition. Xavier Morin then described that cell-cell contact remodeling also plays an important role in interphase as neural progenitors commit to differentiation. He more specifically discussed the molecular mechanisms by which the ubiquitin E3 ligase Mind Bomb 1 prevents Notch cis-inhibition to defer differentiation and maintain neuroepithelial integrity throughout neural delamination. Cell division and interkinetic nuclear movement is also central to the lamination and acquisition of fate in the stratified epithelia of the zebrafish retina as presented by Mauricio Rocha Martins (Caren Norden’s laboratory) linking nuclear movement to tissue shape. In addition to cell division and rearrangements, cell shape changes also contribute to tissue deformation. During Drosophila gastrulation, actomyosin contractility drives apical constriction in ventral cells leading to furrow formation and mesoderm invagination. Magali Suzanne presented evidences that in addition to apical constriction, apico-basal actomyosin cables are formed in ventral cells and exert forces driving epithelium folding. On a similar theme, using Drosophila wing imaginal disc as a model, Guillaume Salbreux also describe two modes of epithelia folding that do not involve apical constriction. A first one relies on lateral myosin that exert apico-basal forces axis in a manner akin to that described by M. Suzanne for mesoderm invagination. The second mode involves the release of basal tension caused by the local remodeling of contacts with the extracellular matrix. Tissue integrity also relies on specialized tricellular junctions (TCJs) that mediate cell contact at three-cell vertices. In a genetic screen aimed to identify genes involved in the morphogenesis of the Drosophila embryo trachea, a tubular epithelium, Stefan Luschnig identified the triple repeat protein Anakonada and characterized how it initiates and controls tricellular junction formation to regulate epithelia homeostasis. Several participants then continued to address the mechanics of epithelia focusing on the impact of dynamic cellular processes to tubular structure and lumen organization. Based on recent finding showing that proper cytokinesis geometry is required for lumen positioning and on recently developed 3D cultures of kidney tubules and zebrafish as an in vivo model organism, Benedicte Delaval continued the theme of epithelial cell division with an analysis of how perturbations of the geometry of cell division can impact kidney epithelial tube morphogenesis and lumen organization. Fernando Martin-Belmonte also discussed in molecular details how smoothelin and actin regulators control epithelial tube formation in zebrafish. Then, from a biophysical perspective combining force measurements on kidney cells grown under specific confinements, Benoit Ladoux further discussed recent data on the establishment of polarity and coordinated cell behavior. He also mentioned recent results where they mimic collective cell migration by forming epithelial cell sheets surrounding central lumen under tubular confinement. Finally, combining light sheet microscopy, simulations and mathematical modelling Dagmar Iber presented recent work on kidney and lung epithelial organization using mouse organ cultures. The experimental data are combined with image-based computational modelling approaches to evaluate candidate mechanisms for the morphogenesis of epithelia of complex 3D organizations. Lumen and cavity formation was also addressed from a physical point of view by Hervé Turlier focusing on early mammalian embryo morphogenesis. Building of various multicellular systems from embryonic structures up to plants and ascidian embryos were also extensively discussed. Indeed, cell division was shown to be the main driver of cell rearrangements during gastrulation of quail embryo. Jérôme Gros presented a quantitative analysis of gastrulation of an entire embryo. He reported that formation of the primitive streak arises from tissue-wide rotational flows driven by a large scale supracellular actomyosin ring. Transmission of these forces across embryonic disk were elegantly modeled and recapitulated by a fluid mechanical model based on Stokes equations for viscous flow. As illustrated in quail embryo, understanding the tissue-scale behavior is challenging in part because mechanical resistance of neighboring epithelia feeds back on individual cells. Using Drosophila embryonic axis extensions as a model system, Jocelyn Etienne described a novel numerical approach to compute the whole-embryo dynamics of the actomyosin-rich apical epithelial surface. Epithelia were modeled using a rheological law that relates the rate of deformation to the local stresses and actomyosin anisotropic contractility. The agreement between model and experimental data of cell flows observed indicates that localized anisotropic contractility of planar-polarised actomyosin can directly cause the tissue-scale deformations of the whole embryo. Cellular mechanics and cell shape changes are also at work during Drosophila dorsal closure that involves the contraction of amnioserosa that promotes fusion and sealing of the adjacent epidermis. Based on an elegant combination of experimental evidences and modeling, Jérôme Solon presented a model according which reduction of apical surface over time is constant and follows a phase diagram in which junction length and cell area are controlled by the rate of endocytosis and adherens junction stretching. Christophe Godin also addressed combining physics, mathematical approaches and numerical simulations how patterning and morphogenesis is achieved in multicellular systems focusing on plant development. Finally, Patrick Lemaire combined live light-sheet microscopy imaging, digital reconstruction and physical approaches to quantify individual cell behavior in ascidian embryos and explore the forces and cellular behavior that constrain their development.

On the third and fourth days of the meeting round tables were organized where several researchers presented the development of new methodologies to tackle technological barrier. The first round table was dedicated to discuss assays aimed to regulate or monitor biological activities in a spatio-temporal controlled manner. Indeed, a main limitation in current genetics approaches is that gene function is usually inferred from mutant or RNAi after several days. Roland Le Borgne discussed a versatile optogenetic system to anchor away endogenously GFP-tagged, cytosolic proteins of interest onto mitochondria. This allows rapid and reversible inactivation/delocalization of GFP-tagged gene product. Kinase activities are key biological timers whose activities can be modulated by chemical inhibitor but they often present off target effects. Jens Januschke introduced point mutation in Drosophila aPKC to enlarge the ATP binding pocket of the kinase such that it accommodates binding of ATP as well as a non-hydrolysable ATP analog. This elegant strategy allows to block aPKC in a spatio-temporal controlled and reversible manner to control aPKC activity in physiological condition. Being able to quantitatively monitor polarized trafficking in epithelia was a challenge addressed by Stefan Luschnig. The development of tools to synchronize membrane trafficking and to monitor the sorting and polarized delivery of various cargoes in epithelial tissues in vivo was discussed. Finally, Zoher Gueroui raised the emerging concept of phase transition as a way to measure local viscosity or to sequester and thus spatio-temporally control specific activities. The second round table focused on force measurements at the tissue scale for which approaches were presented by Jerome Solon and ended with the obvious challenge of image segmentation, big data analysis when dealing with 3D/4D systems. In this context Patrick Lemaire discussed the advantage of using machine learning to facilitate segmentation.

Overall, during these five days in a wonderful environment and surrounded by the warm and welcoming team of the “Fondation des Treilles” outstanding science was presented, new collaboration emerged and fruitful discussions identified future challenges and raised new ideas on how to facilitate in the future interdisciplinary interactions that will beyond any doubt be a requirement to push research forward in the coming years.

Bénédicte Delaval Héloïse Dufour Jocelyn Etienne Christophe Godin Jérôme Gros Zoher Gueroui Dagmar Iber Jens Januschke Benoît Ladoux Roland Le Borgne Patrick Lemaire Stephan Luschnig Fernando Martín-Belmonte Xavier Morin Mauricio Rocha Martins Guillaume Salbreux Jérôme Solon Magali Suzanne Hervé Turlier Julien Vermot Contribution de la mécanique cellulaire à l'intégrité des tissus
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