On modeling morphogenesis of the looping heart following mechanical perturbations

Looping is a crucial early phase during heart development, as the initially straight heart tube (HT) deforms into a curved tube to lay out the basic plan of the mature heart. This paper focuses on the first phase of looping, called c-looping, when the HT bends ventrally and twists dextrally (rightward) to create a c-shaped tube. Previous research has shown that bending is an intrinsic process, while dextral torsion is likely caused by external forces acting on the heart. However, the specific mechanisms that drive and regulate looping are not yet completely understood. Here, we present new experimental data and finite element models to help define these mechanisms for the torsional component of c-looping. First, with regions of growth and contraction specified according to experiments on chick embryos, a three-dimensional model exhibits morphogenetic deformation consistent with observations for normal looping. Next, the model is tested further using experiments in which looping is perturbed by removing structures that exert forces on the heart--a membrane (splanchnopleure (SPL)) that presses against the ventral surface of the heart and the left and right primitive atria. In all cases, the model predicts the correct qualitative behavior. Finally, a two-dimensional model of the HT cross section is used to study a feedback mechanism for stress-based regulation of looping. The model is tested using experiments in which the SPL is removed before, during, and after c-looping. In each simulation, the model predicts the correct response. Hence, these models provide new insight into the mechanical mechanisms that drive and regulate cardiac looping.