Approximate Bayesian computation reveals the importance of repeated measurements for parameterising cell-based models of growing tissues.

The growth and dynamics of epithelial tissues govern many morphogenetic processes in embryonic development. A recent quantitative transition in data acquisition, facilitated by advances in genetic and live-imaging techniques, is paving the way for new insights to these processes. Computational models can help us understand and interpret observations, and then make predictions for future experiments that can distinguish between hypothesised mechanisms. Increasingly, cell-based modelling approaches such as vertex models are being used to help understand the mechanics underlying epithelial morphogenesis. These models typically seek to reproduce qualitative phenomena, such as cell sorting or tissue buckling. However, it remains unclear to what extent quantitative data can be used to constrain these models so that they can then be used to make quantitative, experimentally testable predictions. To address this issue, we perform an in silico study to investigate whether vertex model parameters can be inferred from imaging data, and explore methods to quantify the uncertainty of such estimates. Our approach requires the use of summary statistics to estimate parameters. Here, we focus on summary statistics of cellular packing and of laser ablation experiments, as are commonly reported from imaging studies. We find that including data from repeated experiments is necessary to generate reliable parameter estimates that can facilitate quantitative model predictions.

[1]  Dennis Prangle,et al.  Adapting the ABC distance function , 2015, 1507.00874.

[2]  Konrad Basler,et al.  Exploring the effects of mechanical feedback on epithelial topology , 2010, Development.

[3]  G. Oster,et al.  The mechanical basis of cell rearrangement. I. Epithelial morphogenesis during Fundulus epiboly. , 1990, Development.

[4]  Ursula Klingmüller,et al.  Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood , 2009, Bioinform..

[5]  Frank Jülicher,et al.  The Influence of Cell Mechanics, Cell-Cell Interactions, and Proliferation on Epithelial Packing , 2007, Current Biology.

[6]  Jaume Casademunt,et al.  Dynamics and Mechanical Stability of the Developing Dorsoventral Organizer of the Wing Imaginal Disc , 2011, PLoS Comput. Biol..

[7]  Andrew Parker,et al.  Using approximate Bayesian computation to quantify cell–cell adhesion parameters in a cell migratory process , 2016, npj Systems Biology and Applications.

[8]  N. Perrimon,et al.  Extrusion and Death of DPP/BMP-Compromised Epithelial Cells in the Developing Drosophila Wing , 2005, Science.

[9]  Lars Hufnagel,et al.  On the mechanism of wing size determination in fly development , 2007, Proceedings of the National Academy of Sciences.

[10]  Ruth E. Baker,et al.  Impact of implementation choices on quantitative predictions of cell-based computational models , 2017, J. Comput. Phys..

[11]  Mark M. Tanaka,et al.  Sequential Monte Carlo without likelihoods , 2007, Proceedings of the National Academy of Sciences.

[12]  Olivier François,et al.  Non-linear regression models for Approximate Bayesian Computation , 2008, Stat. Comput..

[13]  R. Kubo The fluctuation-dissipation theorem , 1966 .

[14]  Radhika Nagpal,et al.  Control of the Mitotic Cleavage Plane by Local Epithelial Topology , 2011, Cell.

[15]  Yanlan Mao,et al.  Planar polarization of the atypical myosin Dachs orients cell divisions in Drosophila. , 2011, Genes & development.

[16]  O. Jensen,et al.  Relating cell shape and mechanical stress in a spatially disordered epithelium using a vertex-based model , 2016, Mathematical medicine and biology : a journal of the IMA.

[17]  Guang-Kui Xu,et al.  Oriented cell division affects the global stress and cell packing geometry of a monolayer under stretch. , 2016, Journal of biomechanics.

[18]  David M. Umulis,et al.  Quantitative model analysis with diverse biological data: applications in developmental pattern formation. , 2013, Methods.

[19]  Lars Hufnagel,et al.  Supplementary Information for Mechanical Stress Inference for Two Dimensional Cell Arrays , 2012 .

[20]  Paul Marjoram,et al.  Markov chain Monte Carlo without likelihoods , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Philip K Maini,et al.  Implementing vertex dynamics models of cell populations in biology within a consistent computational framework. , 2013, Progress in biophysics and molecular biology.

[22]  Ruth E. Baker,et al.  Capabilities and Limitations of Tissue Size Control through Passive Mechanical Forces , 2015, bioRxiv.

[23]  Tatsuzo Nagai,et al.  A dynamic cell model for the formation of epithelial tissues , 2001 .

[24]  Alexander G. Fletcher,et al.  Chaste: An Open Source C++ Library for Computational Physiology and Biology , 2013, PLoS Comput. Biol..

[25]  Orestis Malaspinas,et al.  The mechanical properties of a cell-based numerical model of epithelium. , 2016, Soft matter.

[26]  G. Charras,et al.  Characterizing the mechanics of cultured cell monolayers , 2012, Proceedings of the National Academy of Sciences.

[27]  Jan Hasenauer,et al.  Parallelization and High-Performance Computing Enables Automated Statistical Inference of Multi-scale Models. , 2017, Cell systems.

[28]  Kaoru Sugimura,et al.  Bayesian inference of force dynamics during morphogenesis. , 2012, Journal of theoretical biology.

[29]  D. Balding,et al.  Approximate Bayesian computation in population genetics. , 2002, Genetics.

[30]  M. Beaumont Approximate Bayesian Computation in Evolution and Ecology , 2010 .

[31]  Rémi Bardenet,et al.  Robust cell tracking in epithelial tissues through identification of maximum common subgraphs , 2016, bioRxiv.

[32]  Andrew R. Harris,et al.  Emergence of homeostatic epithelial packing and stress dissipation through divisions oriented along the long cell axis , 2015, Proceedings of the National Academy of Sciences.

[33]  Paul Marjoram,et al.  Choice of Summary Statistic Weights in Approximate Bayesian Computation , 2011, Statistical applications in genetics and molecular biology.

[34]  Dapeng Bi,et al.  A density-independent rigidity transition in biological tissues , 2014, Nature Physics.

[35]  Ruth E Baker,et al.  Incorporating chemical signalling factors into cell-based models of growing epithelial tissues , 2011, Journal of Mathematical Biology.

[36]  Yang Liu,et al.  How do changes at the cell level affect the mechanical properties of epithelial monolayers? , 2015, Soft matter.

[37]  V. A. Epanechnikov Non-Parametric Estimation of a Multivariate Probability Density , 1969 .

[38]  F Graner,et al.  Comparative study of non-invasive force and stress inference methods in tissue , 2013, The European physical journal. E, Soft matter.

[39]  P. Lenne,et al.  Measuring forces and stresses in situ in living tissues , 2016, Development.

[40]  S. Eaton,et al.  Mechanics and remodelling of cell packings in epithelia , 2010, The European physical journal. E, Soft matter.

[41]  Fergus R. Cooper,et al.  Mechanocellular models of epithelial morphogenesis , 2017, Philosophical Transactions of the Royal Society B: Biological Sciences.

[42]  Christian von Mering,et al.  Cell-Sorting at the A/P Boundary in the Drosophila Wing Primordium: A Computational Model to Consolidate Observed Non-Local Effects of Hh Signaling , 2011, PLoS Comput. Biol..