Tariq Abdulla

An overview of cardiac morphogenesis.

Accurate knowledge of normal cardiac development is essential for properly understanding the morphogenesis of congenital cardiac malformations that represent the most common congenital anomaly in newborns. The heart is the first organ to function during embryonic development and is fully formed at 8 weeks of gestation. Recent studies stemming from molecular genetics have allowed specification of the role of cellular precursors in the field of heart development. In this article we review the different steps of heart development, focusing on the processes of alignment and septation. We also show, as often as possible, the links between abnormalities of cardiac development and the main congenital heart defects. The development of animal models has permitted the unraveling of many mechanisms that potentially lead to cardiac malformations. A next step towards a better knowledge of cardiac development could be multiscale cardiac modelling.

Epithelial to mesenchymal transition-The roles of cell morphology, labile adhesion and junctional coupling

Epithelial to mesenchymal transition (EMT) is a fundamental process during development and disease, including development of the heart valves and tumour metastases. An extended cellular Potts model was implemented to represent the behaviour emerging from autonomous cell morphology, labile adhesion, junctional coupling and cell motility. Computer simulations normally focus on these functional changes independently whereas this model facilitates exploration of the interplay between cell shape changes, adhesion and migration. The simulation model is fitted to an in vitro model of endocardial EMT, and agrees with the finding that Notch signalling increases cell-matrix adhesion in addition to modulating cell-cell adhesion.

Advances in modelling of epithelial to mesenchymal transition

This paper presents simulations of in vitro Epithelial to Mesenchymal Transition (EMT). The conditions of 2D migration on the surface, and 3D invasion into a collagen gel are represented as a cellular Potts model. The model demonstrates that a loss of endocardial adhesion is a sufficient condition for 2D migration behaviour, while a simultaneous loss of endocardial cohesion and gain in endocardial to collagen gel adhesion is a sufficient condition for 3D invasion. The 3D model captures the hierarchy effective surface tensions that correspond to the three experimental conditions of stable monolayer, 2D migration, and 3D invasion. A 2D cellular Potts model is used to investigate the relationship between cell shape changes, motility and adhesion during the condition of 2D migration.

Multiscale systems modeling of the tetralogy of Fallot

This paper provides a first description of a multiscale systems modeling approach applied to the congenital birth defect known as the tetralogy of Fallot. The multiscale approach adopted owes a lot to the effort of the world-wide physiome consortium and the work of research groups within the European Union on the Virtual Physiological Human. Both a spatial scale and time scale are used to establish the systems boundaries of the application. The tetralogy of Fallot includes up to four simultaneously occurring anatomic abnormalities that underpin the defect. The use of finite state machines and cellular automata pave the way to understand the processes in time and space that contribute to the defect.

Multiscale information modelling for heart morphogenesis

Science is made feasible by the adoption of common systems of units. As research has become more data intensive, especially in the biomedical domain, it requires the adoption of a common system of information models, to make explicit the relationship between one set of data and another, regardless of format. This is being realised through the OBO Foundry to develop a suite of reference ontologies, and NCBO Bioportal to provide services to integrate biomedical resources and functionality to visualise and create mappings between ontology terms. Biomedical experts tend to be focused at one level of spatial scale, be it biochemistry, cell biology, or anatomy. Likewise, the ontologies they use tend to be focused at a particular level of scale. There is increasing interest in a multiscale systems approach, which attempts to integrate between different levels of scale to gain understanding of emergent effects. This is a return to physiological medicine with a computational emphasis, exemplified by the worldwide Physiome initiative, and the European Union funded Network of Excellence in the Virtual Physiological Human. However, little work has been done on how information modelling itself may be tailored to a multiscale systems approach. We demonstrate how this can be done for the complex process of heart morphogenesis, which requires multiscale understanding in both time and spatial domains. Such an effort enables the integration of multiscale metrology.

Towards multiscale systems modeling of endocardial to mesenchymal transition

Cell behavior during endocardial to mesenchymal transition (EMT) was simulated using the cellular Potts formalism in Compucell 3D. The processes of loss of endocardial cohesion and invasion into the extracellular matrix (ECM) were stimulated by changing surface energy parameters. The simulations match in vitro results which suggest that endocardial motility on the surface of collagen gel can be induced separately from 3D invasion of the gel, via Notch signaling in the absence of BMP2. A principle by which the rate of mitosis would regulate the monolayer was demonstrated; suggesting a route for Vascular Endothelial Growth Factor (VEGF) control of EMT. A conceptual model of the system of protein interactions during EMT was assembled from multiple studies. A route for subcellular models to be formalized as Systems Biology Markup Language (SBML) differential equations is indicated. Scale linking would be achieved through Compucell 3D periodically integrating the SBML models for each cell during a simulation run, and updating parameters for protein concentrations assigned to individual cells. The surface energy parameters for the cells would be recalculated at each step from their simulated protein concentrations. Such scale linking opens up the potential for complexity to be gradually introduced, while maintaining experimental validation.

Multiscale modelling of Notch-mediated lateral induction

A published model of Notch-mediated lateral induction is re-implemented as a multiscale model using Compucell3D. The implications of the model for regulatory processes during the growth of the endocardial cushions are investigated. During embryonic heart development, Notch signaling operates by lateral induction to demarcate the endocardial cells capable of an epithelial to mesenchymal transition (EMT). This process underlies much of the inner structure of the heart, including the heart valves. Thus it is key to an understanding of congenital heart defects. Notch has a direct role to play in regulating endocardial cadherin proteins. The resulting loss of endocardial cohesion contributes to EMT. Thus cells with a higher Notch activation are more disposed to EMT. The simulations indicate that Notch-mediated lateral induction could provide a simple mechanism for preferential growth towards the centers of the endocardial cushions.

3D Simulation of an invitro Epithelial to Mesenchymal Transition

A 3D simulation of in vitro epithelial to mesenchymal transition (EMT) is presented. The simulation uses Compucell3D to realize a cellular Potts model of this process. The purpose of the model is to test the hypothesis that EMT can be achieved through a combination of a) the loss of endocardial cohesion; and b) a gain of endocardial to extracellular matrix adhesion. The results of the simulation demonstrate confirmation of the hypothesis. A mechanism by which EMT could be regulated by mitosis is demonstrated. Further, the implication of the study to heart development is explored.