Systems Modelling of EMT Cell Signalling Pathways in Heart Valve Development Tariq Abdulla 1, Ryan Imms 1, Jean-Marc Schleich 2 and Ron Summers 1 VPH /10/ Dept. Electronic and Electrical Engineering, SEIC, Loughborough University, LEICS, UK, LE11 3TU Web: 2 LTSI, University of Rennes 1, Rennes, F-35000, France

“Epithelial to Mesenchymal Transition” 2

Outline  Heart Development – what happens?  Heart Looping  Neural Crest Cell Migration  Endocardial Cushion Growth  Congenital Heart Defects  Systems Modelling - how do we do it?  Conceptual Model  Network Modelling  Tissue Modelling  Integration  Conclusion and Future Work

Heart Development: what happens? Rear View

Membranous Septum Muscular Septum

Neural Crest Cell Migration

Endocardial Cushion Growth

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Heart Development: what happens?

Systems Modelling – how do we do it?  Different types of computational model are suitable for different levels of biological scale  E.g. Biochemical reactions can be represented as networks or ODEs. Cellular behaviour can be modelled with agent based models.  Use models at one level of scale, to pass information to models at another level of scale

Conceptual Modeling

Network Modelling 14 KEGG

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Notch Signalling 16

Notch Signalling 17

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Tissue Modelling 19  Tissues are often modelled as though they are continuous  But many of the interesting things that happen in tissues are to do with individual cell behaviour, and social behaviour (structure)  When there is an abnormality at tissue level we may need to know whether this is hypotrophic (fewer cells) or hypoplastic (smaller cells)

Tissue Modelling 20  A lot of the movement of cells around each other, and how they interact, can be explained by their relative adhesiveness to other cells  This is the Differential Adhesion Hypothesis

Compucell3D

Integration  We take a proactive approach in model annotation, and are even developing methods for multiscale annotation  This includes combining terms from multiple reference ontologies in post-composition  Use of common formats such as SBML

25 Molecules Cells Tissues Organs ? PMR2 Ontologies

Conclusion and Future Work  Modelling systems of such complexity is difficult, but it’s essential if we are to understand them  Comparison with in vivo or in vitro data is essential for model validation and improvement  This project has the potential to be applied to tissue engineering

Questions or suggestions?

Thanks to (in no order):  Ron Summers  Ryan Imms  Jean-Marc Schleich  Fanny Bajolle  Lucile Houyel