Bending and twisting the embryonic heart: a computational model for c-looping based on realistic geometry

Abstract

The morphogenetic process of cardiac looping transforms the straight heart tube into a curved tube that resembles the shape of the future four-chambered heart. Although great progress has been made in identifying the molecular and genetic factors involved in looping, the physical mechanisms that drive this process have remained poorly understood. Recent work, however, has shed new light on this complicated problem. After briefly reviewing the current state of knowledge, we propose a relatively comprehensive hypothesis for the mechanics of the first phase of looping, termed c-looping, as the straight heart tube deforms into a c-shaped tube. According to this hypothesis, differential hypertrophic growth in the myocardium supplies the main forces that cause the heart tube to bend ventrally, while regional growth and cytoskeletal contraction in the omphalomesenteric veins (primitive atria) and compressive loads exerted by the splanchnopleuric membrane drive rightward torsion. A computational model based on realistic embryonic heart geometry is used to test the physical plausibility of this hypothesis. The behavior of the model is in reasonable agreement with available experimental data from control and perturbed embryos, offering support for our hypothesis. The results also suggest, however, that several other mechanisms contribute secondarily to normal looping, and we speculate that these mechanisms play backup roles when looping is perturbed. Finally, some outstanding questions are discussed for future study.

Why is cytoskeletal contraction required for cardiac fusion before but not after looping begins?

“…The mechanical forces that physically create and shape the HT, however, have remained poorly understood. Recent studies in our lab have shown that nonmuscle myosin II-based contraction is required to bring the heart fields together to create the HT before the onset of looping at HH10 [13, 15, 16]. In particular, our data suggest that the endoderm actively contracts along the AIP and pulls the mesodermal heart fields toward the midline (figure 2(a),(a′)).…”

From cytoskeletal dynamics to organ asymmetry: a nonlinear, regulative pathway underlies left–right patterning

“…In heart looping, a similar role for actin and myosin in driving dextral looping has been exhibited in zebrafish [171] and chick [177]. Recently, computational modelling has supported evidence suggesting that differential growth supplies the forces that cause the heart tube to bend ventrally, while cytoskeletal movements can drive rightward torsion [178]. The maintenance of symmetry could also be due to differences in the composition of the extracellular matrix (ECM) as observed in perturbations of ECM composition in frog and chick embryos [18,179].…”

The role of the protein tyrosine phosphatase SHP2 in cardiac development and disease

“…The rapid elongation of the heart tube, by addition of progenitors cells from another cardiogenic area, termed second heart field [35, 41], at both sides of the tube is thought to create compressive loads resulting from growth differences between the heart and the confined space of the embryonic pericardial cavity [42]. Several computational models have supported the idea that these external physical forces drive the deformation of the straight-shaped heart tube into a helicoidal configuration [43, 44]. However, the fact that explanted embryonic hearts are able to undergo partial looping in-vitro suggests that other intrinsic mechanisms play a role during this process [45].…”