Synergy between experiments and modelling in understanding morphogenetic processes

Wednesday, June 16 at 04:15am (PDT)
Wednesday, June 16 at 12:15pm (BST)
Wednesday, June 16 08:15pm (KST)

SMB2021 SMB2021 Follow Tuesday (Wednesday) during the "MS12" time block.
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Alessandra Bonfanti (Sainsbury Laboratory University of Cambridge, United Kingdom), Alexandre Kabla (University of Cambridge, United Kingdom)


Physical forces play a key role in shaping groups of cells into functional tissues. The study of forces during developmental processes started over a century ago with Sir D’Arcy Thompson. Since then, a multidisciplinary approach has been taken up by the scientific community aiming at identifying the physical principles underlying morphogenesis. During the last few years, new breakthroughs have been achieved by combining experimental data with a wide variety of theoretical approaches, from continuum to discrete models, and more recently by integrating artificial Intelligence within the analysis process. In this mini-symposium, we seek to bring together researchers developing advanced quantitative models using different approaches, in close collaboration with leading experimentalists. While providing new insights into developmental processes, the presentations will highlight how the diversity of modelling approaches lead to different interaction and use of experimental data.

Shiladitya Banerjee

(Carnegie Mellon University, USA)
"Cell-scale modeling of epithelial morphogenesis using quantitative theory and optogenetics"
During development, epithelial tissues form complex structures like organs through precise spatiotemporal coordination of cell shape changes. In vivo, many morphogenetic events are driven by pulsatile cellular contractions, which are rectified to produce irreversible tissue deformations. The functional significance of these pulsed contractions and their underlying mechanochemical circuits remain unknown. Here we develop quantitative cell-resolution models of epithelial tissues using live-cell imaging and optogenetic control of cytoskeletal force generation. We demonstrate that pulsed contraction acts as a mechanical ratchet to guide directed morphogenesis in epithelia and uncover the underlying feedback designs between cellular force generation and cell-cell adhesion. Our data and mathematical modeling provide new insights into how the localized production of cytoskeletal forces encode a fine-tuned instruction for cellular deformations that mediate epithelial morphogenesis.

Jean-François Rupprecht

(CNRS & Turing Centre for Living Systems Group Leader, Aix-Marseille University., France)
"Epithelial tissues flows over hills, valleys and around potholes"
Epithelial tissues constantly flow and renew while acting as a barrier against environmental stress and abrasion. Flows within epithelial tissues are known to be associated with cell shape changes - e.g. with shear flows contributing to cell stretching – yet, by exerting forces on their neighbours, elongated cells could in turn contribute to flows. Hydrodynamic theories incorporating such cell shape/tissue flow mechanical feedback have been proposed to explain the specific flow patterns observed within in vitro confluent epithelial tissues [1,2]. In this talk, I will present our recent results on the role of flows and cell-shape driven stresses in processes related to: (i) the loss of epithelial integrity [3]. Motivated by recent experiments revealing the spontaneous formation of holes within MDCK cell monolayers cultured on soft hydrogels, we implemented a cell-based computational framework (called vertex model) whereby cell-cell junctions can rupture. We also introduced cell-based nematic stresses which we show triggers global spontaneous flows. In both experiments and simulations, we observe the onset of specific patterns in cell shapes called topological defects. While cells at the tip of comet-like +1/2 defects were shown to be compressed and highly prone to extrusion [1], here, our simulations explain the experimental observation that holes are created in high tension regions located either at the tail of comet-like +1/2 defects or near trefoil-like -1/2 defects. In addition, our work indicate that the progressive deformation of cells at the border of the hole further drives the hole opening process itself, hence suggesting an unexpected role of active stresses in regulating tissue integrity [3]. (ii) tissue flows and renewal within curved environment [4]. Several recent experimental work have shown that epithelial cells spread over curved substrates with a preferential orientation along specific curvature directions. In a recent preprint [4], we work out a set of hydrodynamic equations governing the cell shape and long-time flows of confluent tissues on non-deformable curved substrate. We derive analytical expressions for the threshold value of the local curvature and active stress strength above which a spontaneous global tissue flow arise at steady state. In particular, we predict the stability of a double-shear flow pattern which I will argue shares some similarities with the one observed during the Drosophila embryogenesis process of germ band extension. 1. Saw, T. B. et al. Topological defects in epithelia govern cell death and extrusion, Nature, (2017). 2. Duclos, G. et al. Spontaneous shear flow in confined cellular nematics, Nature Physics (2018). 3. S. Sonam, L. Balasubramaniam, S-Z. Lin, Y. M. Yow Ivan, C. Jebane, Y. Toyama, Philippe Marcq, J. Prost, R.-M. Mège, J-F. R., B. Ladoux, Mechanical stress driven by rigidity sensing governs epithelial stability (2021). 4. Shear transitions of an active nematic in curved geometries, S. Bell, S.-Z. Lin, J-F. R., and Jacques Prost (2021).

Alan Lowe

(University College London, UK)
"Learning the rules of cell competition"
Cell competition is a quality control mechanism through which tissues eliminate unfit cells. In biochemical and mechanical competition, individual cell fate is determined by the local cellular neighbourhood. Despite this, cell competition remains poorly understood -- we do not know the interaction 'rules' that determine each cell's fate. This is largely because most studies only quantify whole population shifts for very few time points and for few cells. One major obstacle to understanding how population shifts occur as a result of single cell behaviours is that it requires thousands of cells to be tracked over long periods of time. To address this challenge, we recently built the first deep learning and automated single-cell microscopy system to analyse cell competition. We used this to analyse the cell cycle state of millions of single cells in mechanical competition, including cell division and death. These data suggest that tissue-scale population shifts are strongly affected by cellular-scale tissue organization. We find that local density has a dramatic effect on the rate of division and apoptosis under competitive conditions. Strikingly, our analysis reveals that proliferation of the winner cells is up-regulated in neighbourhoods mostly populated by loser cells. Finally, I present our current progress on developing a machine learning approach to learn interpretable “rules” of cell competition, by predicting the fate of cells in an evolving tissue.

Pasquale Ciarletta

(Politecnico di Milano, Italy)
"Pattern formation and self-organization during cancer cell budding in-vitro"
Tissue self-organization into defined and well-controlled three-dimensional structures is essential during development for the generation of organs. A similar, but highly deranged process might also occur during the aberrant growth of cancers, which frequently display a loss of the orderly structures of the tissue of origin, but retain a multicellular organization in the form of spheroids, strands, and buds. The latter structures are often seen when tumor masses switch to an invasive behavior into surrounding tissues. However, the general physical principles governing the self-organized architectures of tumor cell populations remain by and large unclear. In this work, we perform in-vitro experiments to characterize the growth properties of glioblastoma budding emerging from monolayers. We further propose a theoretical model and its finite element implementation to characterize such a topological transition, that is modelled as a self-organised, non-equilibrium phenomenon driven by the trade–off of mechanical forces and physical interactions exerted at cell-cell and cell–substrate adhesions. Notably, the unstable disorder states of uncontrolled cellular proliferation macroscopically emerge as complex spatio–temporal patterns that evolve statistically correlated by a universal law.

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