Investigating the mechanosensitive interplays between genetic control and self-organisation during the emergence of cardiac tissue curvature

Cardiovascular Diseases (CVDs) are the leading causes of death in the world. Congenital heart malformations account for as many as 30% of embryos or foetuses lost before birth. To properly develop, the heart needs to generate mechanical forces during the growth of the whole structure. This, in combination with genetic information, is required for assembling a functional heart.

Currently, most studies focus on how genetic programmes control cell identities and their subsequent roles in cardiac development. In contrast, the mechanical forces that are integral to the growth and assembly of the heart are much less explored. This is surprising as abnormal mechanical forces can deregulate gene expression and lead to diseases such as congenital heart disease and cardiomyopathies. Understanding how biomechanics regulates cardiac morphogenesis is thus of utmost importance. This project will explore the interplay between genetic control and self-organization emerging from cell mechanics during cardiogenesis. Our hypothesis is that mechanotransduction is at the centre of this interplay. We will study the role of mechanotransduction in the emergence of multicellular flow and the mechanism of a newly characterized cell shape change associated with cardiac chamber morphogenesis.

Cardiac morphogenesis is unique in the fact that development occurs while the heart beats. It thus requires the understanding of developmental patterning that explains how cells acquire positional information and control cell behaviours. Additionally, it requires the description of biological processes in physical terms. Developmental patterning explains how genetic and biochemical information controls cellular mechanics, in particular contractility mediated by actomyosin networks, and thus cell and tissue shape changes. However, morphogenetic processes in the cardiac system cannot completely be explained in this framework. Additional reported forces, namely strain and shear due to cardiomyocyte contractility, osmotic forces, along with tissue curvature and stiffness dictate cell identity and shape. These forces are self-organized in that they depend on local mechano-chemical interactions and feedback that cannot be fully accounted for by upstream genetic control. This project will explore the interplay between genetic control and self-organization emerging from cell mechanics during cardiogenesis. Our hypothesis is that mechanotransduction is at the centre of this interplay. We will study the role of mechanotransduction in the emergence of multicellular flow and the mechanism of a newly characterized cell shape change associated with cardiac chamber morphogenesis.

We will use an interdisciplinary approach, combining live imaging, capturing the 3D shape of cells/tissues, genetic/optogenetic/mechanical perturbations and tissue engineering/theoretical/computational methods