Role of epicardial-derived Slit signalling in heart development

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The heart is the first organ to form in the embryo and plays an essential role by continuously pumping blood and nutrients to tissues and organs during the human lifespan. Over the last years, intensive research conducted in numerous laboratories around the world has improved our understanding of the cells and molecules required for the complex process of heart formation. Nonetheless, cardiac disabilities remain the most common organ malformations present at birth leading to congenital heart disease (CHD), and in the majority of cases, we still do not understand how they arise in the human embryo, making prevention and treatment challenging. Likewise, while cardiovascular disease is the most common cause of death worldwide, the development of new therapies to treat the diseased heart is lagging, compared with other fields of medicine (e.g. cancer). One major bottleneck hampering progress is the lack of sufficient knowledge on the biological processes affected in heart disease. A greater understanding of the intricate mechanisms regulating normal heart formation and function would therefore have a critical impact on how we prevent or treat CHD in newborns and heart disease in adult patients. My research group investigates such mechanisms and this work focus on the role of a group of cells forming the external surface of the heart, the epicardium. During pregnancy, cells from the epicardium (epicardial-derived cells or EPDCs) become activated in a process called epithelial-to-mesenchymal transition (EMT) and contribute to heart blood vessels (coronaries) and muscle (myocardium) growth and function. We recently, identified two secreted proteins called Slit2 and Slit3 produced by EPDCs, and found that mouse embryos lacking Slit2 and Slit3 in the epicardium exhibited heart malformations similar to what have been described in newborns suffering from CHD. Our observations suggest a previously unsuspected role for Slit2 and Slit3 produced by the epicardium in normal heart development. In the project, we will expand our initial findings by detailing multiple aspects of heart development from coronary and lymphatic vessel expansion to cardiac muscle growth and valve formation in these and other, more specific mouse models. Then, we will investigate how cells from the epicardium regulate EMT activation to support normal development by employing cutting-edge approaches such as next-generation sequencing that enables the analysis of all the genes active in one specific cell type at a given time. This will lead to the identification of the network of cells and molecules stimulated by Slit2 and Slit3. Such cells and molecules will be tested pharmacologically in cell culture systems via the use of drugs or antibodies to inhibit or stimulate their biological activity.