abdulla ieee embc 2011
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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, [email protected]://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
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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
Cellular Potts Model – Compucell3D
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',))'(()),(())'(()),(( )()()1( VvSsJE vs
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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
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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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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
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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?