Sigolène Meilhac

We study how cells are coordinated in cardiac tissues and how their local behaviour generates shape changes in 3 dimensions (3D). Our research meets novel challenges which require interdisciplinary efforts, to quantify biological processes and shape changes or examine the clinical impact of the work. We use a combination of approaches, including mouse genetics, transcriptomics, embryology, primary cell cultures, 3D imaging, quantitative image analyses and computer simulations.

In a first research axis, we address the mechanisms of heart growth. We have previously characterized the lineages of myocardial cells. We have also developed interdisciplinary tools for the quantification of orientations in 3D tissues (Pop et al., 2013 ; Le Garrec et al., 2013) and revealed that myocardial cells coordinate locally their orientation of division during cardiac chamber expansion. Recently, we have identified a novel signaling pathway regulating the proliferation of cardiac muscle cells. We have shown that the atypical cadherin Fat4 is required to sequester the scaffold protein angiomotin-like 1 (Amotl1), whereas the nuclear translocation of Amotl1, which binds the co-factor of transcription Yap1, promotes cardiomycyte proliferation (Ragni et al. 2017). By promoting the growth of the cardiac muscle, manipulation of this novel signalling pathway has potential applications in the field of cardiac regenerative medicine. Further research is ongoing to identify other aspects of myocardial growth.

In a second research axis, we address the asymmetric morphogenesis of the heart. The severity of congenital heart defects is determined by the impact on the oxygenation of the blood, when the left and right halves of the heart are incompletely separated. The rightward looping of the embryonic heart tube is the initial process which determines the alignment of cardiac chambers. Although it had been identified morphologically by early embryologists, it has been mainly considered so far as a directional problem. By implementing High Resolution Episcopic Microscopy (HREM) at the Imagine Institute we have reconstructed mouse heart looping dynamics in 3D (Le Garrec et al., 2017). We have developed a computer model, to predict the specific shape of the looped heart tube, not just its direction, from initial mechanical constraints and left-right asymmetries. The relevance of our work in the mouse to congenital heart defects, such as malposition of the ventricles or the great vessels, is explored in collaboration with our colleagues of the Hospital Necker.

Achievements and news 2018

In the review Desgrange et al., 2018, we have compared heart looping mechanisms and dynamics in the main vertebrate models (the fish, chick and mouse). We argue that heart looping is not only a question of direction, but also one of fine tuning shape, with different mechanisms in the two-chambered fish heart compared to the four-chambered amniote heart.

Advances in understanding the mechanisms of laterality defects, such as heterotaxy, have been hindered by fragmented observations and incomplete phenotyping in mouse models. To face this challenge, we have developed a multimodality imaging pipeline, which combines non-invasive micro-ultrasound imaging, micro-CT and HREM, to acquire 3D images at multiple stages of development and at multiple scales. We can thus track in a single individual the progression of organ asymmetry, the situs of all visceral organs in their thoracic or abdominal environment, together with the fine anatomical left/right asymmetries of cardiac segments that are required to phenotype congenital heart defects.