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 IEEE EMBC 2011

Outline

Introduction Heart Development – what happens?

Anatomy, Tissue, Cell, Protein Current Simulations

In-vitro EMT, Mitosis Future Directions Conclusions

Introduction

4

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

11

Protein

14

Current Simulations

Cellular Potts Model – Compucell3D

22

',))'(()),(())'(()),(( )()()1( VvSsJE vs

xxxxxx

Compucell3D

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

23

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

25

Future Directions

26

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.

27

More realistic geometry

Compartmental models, polarised cells

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

28

Conclusions

The CPM simulations demonstrate some correspondence with the in vitro experiments they are based on

This supports the hypothesis that Notch activates EMT primarily through reducing endocardial cohesion

The simulations indicate a possible role of contact-inhibited mitosis in controlling EMT. This could be tested in vitro

29

THANK YOU! Maciej Swat, Randy Heiland, James Glazier,

Abbas Shirinifard

Ron Summers, Ryan Imms, Lucile Houyel, Jean-Marc Schleich

José Luis de la Pompa

Questions?