Sigolène Meilhac

Heart morphogenesis

Sigolène Meilhac
  • Jean-François Le Garrec
  • Tommaso Lucchesi
  • Laurent Guillemot
  • Audrey Desgrange
  • Lisa Kitasato
  • Daniel Darby
  • Dong Han
  • Johanna Vanderhaeghe

The Imagine-Pasteur group of Heart Morphogenesis studies how cells are coordinated at the level of the tissue and how their local behaviour generates global changes of organ shape.

We address these questions in the context of heart morphogenesis, using approaches of genetics, cell biology and computer modelling. Our work in the mouse is relevant to congenital heart defects in humans.

Morphogenesis, that is the acquisition of a shape, is essential for organ function. It has been well characterised at a molecular level, with the identification of signalling pathways regulating gene expression. A current question is to understand how these pathways orchestrate cell behaviour and how local cell behaviour generates the global shape of an organ. Insight into the cellular mechanisms of morphogenesis has been gained in the 2D epithelia of the fly. In mammals, morphogenesis is often a 3D process, which involves non-epithelial tissues, and this raises novel challenges. The heart provides a striking model of morphogenesis in 3D, in which the myocardial architecture is key for the circulation of the blood.

We have previously characterised the lineages and behaviour of myocardial cells during heart morphogenesis. Recently, we have developed interdisciplinary tools for the quantification of tissue anisotropy in 3D and revealed that myocardial cells coordinate locally their orientation of division during cardiac chamber expansion.

Meilhac et al., 2004 - Clone of β-galactosidase positive cardiomyocytes showing the oriented growth of the embryonic myocardium

Meilhac et al., 2004 - Clone of β-galactosidase positive cardiomyocytes showing the oriented growth of the embryonic myocardium

Le Garrec et al., 2013– Oriented cell divisions in the developing heart

Our research project aims at further understanding the coordination of cardiac cell behaviour and its impact on heart morphogenesis. We use a combination of approaches to address these questions, including mouse genetics, primary cultures of cardiac cell, quantitative image analysis and computer modelling.

Growth of the heart is essential to adapt the hemodynamics to the size of the growing organism. Physiologically, heart growth is mainly driven by the proliferation of myocardial cells in utero and by cell size increase after birth. Re-activation of myocardial cell proliferation in the adult, for example when inhibition by the Hippo pathway is relieved, opens the possibility of myocardium regeneration after injury. Work in our lab is exploring how cell interactions restrict heart growth. We study the atypical cadherin Fat, a cell adhesion protein, which was initially discovered in the fly as a major regulator of organ size. However, how the Fat pathway is connected to the Hippo pathway in mammals remains poorly understood. Another project focuses on primary cilia, which mediate cell interactions by integrating a number of signalling pathways. Primary cilia are required for the formation of the heart, yet little is known about how primary cilia regulate cardiac cell behaviour.

N. Diguet – Primary cilia (red) of cardiomyocytes (green)

 

Looping of the heart tube, in the early embryo, provides an example of a 3D shape change, which is essential to align cardiac chambers and establish the double blood circulation. The direction of heart looping depends on the establishment of left-right patterning of the embryo.

However, the cellular mechanisms underlying this have remained unclear. In this context, we address the question of how a combination of local cell behaviour generates global shape changes.

 

J-F. Le Garrec – Computer modelling of the looping of the heart tube

Our work on mouse heart morphogenesis is relevant to congenital heart defects in humans, such as misalignment of cardiac chambers. Congenital heart diseases represent a major concern for public health, affecting 8‰ newborns and leading to 30% of embryonic deaths in utero. However, the genetic bases of these defects and the underlying pathophysiological processes remain poorly understood.