Computational Modelling of Epithelial to Mesenchymal Transition

Tariq Abdulla1, Lucile Houyel2, Ryan Imms1,

Jean-Marc Schleich3, Ron Summers1

1.Dept Electronic & Electrical Engineering, Loughborough University, UK2. Hospital Marie Lannelongue, Paris, France3. LTSI, University of Rennes 1, FranceT.Abdulla@lboro.ac.ukhttp://www-staff.lboro.ac.uk/~lsrs1 Compucell3D & SBW Workshop 2011

Outline

Introduction Heart Development – what happens?

Anatomy, Tissue, Cell, Protein Current Simulations

In-vitro EMT, Mitosis Future Directions

Introduction

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Heart Development: what happens?

F. Bajolle, S. Zaffran and D. Bonnet, Genetics and embryological mechanisms of congenital heart diseases Archives of Cardiovascular Diseases, Volume 102, Issue 1, January 2009, Pages 59-63

Anatomy

Rear View

Tissue

MyocardiumEndocardium

Cardiac Jelly

Cell

Hign Notch,Low Delta

Hign Delta,Low Notch

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Protein

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Current Simulations

In vitro EMT

Wildtype Notch1 BMP2

L. Luna-zurita et al. “Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation,” The Journal of Clinical Investigation, vol. 120, 2010.

JEC,medium >JECM,medium >JECM,ECM >JEC,ECM >JEC,EC >Jmedium,medium =0

JEC,medium >JECM,medium >JEC,EC >JECM,ECM >JEC,ECM >Jmedium,medium =0

Reduce endocardial cohesion

Reduce endocardial cohesionandIncrease endocardial-ECM adhesion

JEC,medium >JECM,medium >JEC,EC >JECM,ECM >JEC,ECM >Jmedium,medium =0

Mitosis Simulations

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E. J. Armstrong, J. Bischoff, Heart Valve DevelopmentCirculation Research.2004; 95: 459-470

Mitosis Simulations

How does an increase in mitosis prevent EMT from happening?

2D Separation

No Mitosis No MitosisMitosis Mitosis

3D Invasion

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Future Directions

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Create a steppable to calculate the 2D and 3D “TI” of cells in a simulation, and use this to fit simulations to the experimental data

L. Luna-zurita et al. “Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation,” The Journal of Clinical Investigation, vol. 120, 2010.

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More realistic geometry

Compartmental models, polarised cells

AdhesionFlex plugin for levels of VE-Cadherin and Integrin for each cell

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Subcellular SBML model of the regualtion of Snail1 and Snail2 (Slug) by TGFβ and Notch1

Zavadil, J. et al. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. The EMBO journal. 23, 5, 1155-65 (2004).

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THANK YOU!

Questions?