Role of epicardial-derived Slit signalling in heart development

心脏是胚胎中形成的第一个器官，在人类的一生中，心脏通过不断向组织和器官输送血液和营养物质发挥着至关重要的作用。在过去的几年里，在世界各地许多实验室进行的深入研究提高了我们对复杂的心脏形成过程所需的细胞和分子的理解。尽管如此，心脏残疾仍然是出生时最常见的器官畸形，导致先天性心脏病（CHD），在大多数情况下，我们仍然不了解它们是如何在人类胚胎中产生的，这使得预防和治疗具有挑战性。同样，虽然心血管疾病是全世界最常见的死亡原因，但与其他医学领域（如癌症）相比，治疗患病心脏的新疗法的开发滞后。阻碍进展的一个主要瓶颈是对影响心脏病的生物过程缺乏足够的了解。因此，更好地了解调节正常心脏形成和功能的复杂机制将对我们如何预防或治疗新生儿冠心病和成人心脏病患者产生关键影响。我的研究小组研究了这种机制，这项工作的重点是形成心脏外表面心外膜的一组细胞的作用。在怀孕期间，来自心外膜的细胞（心外膜衍生细胞或EPDCs）在一个称为上皮-间质转化（EMT）的过程中被激活，并有助于心脏血管（冠状动脉）和肌肉（心肌）的生长和功能。我们最近鉴定了EPDCs产生的两种分泌蛋白Slit2和Slit3，并发现心外膜中缺乏Slit2和Slit3的小鼠胚胎表现出与患有冠心病的新生儿相似的心脏畸形。我们的观察结果表明，心外膜产生的Slit2和Slit3在正常心脏发育中具有先前未被怀疑的作用。在这个项目中，我们将扩展我们最初的发现，详细介绍心脏发育的多个方面，从冠状动脉和淋巴管扩张到心肌生长和瓣膜形成，在这些和其他更具体的小鼠模型中。然后，我们将研究心外膜细胞如何调节EMT激活，以支持正常发育，通过采用尖端方法，如下一代测序，能够分析一种特定细胞类型在给定时间内的所有活性基因。这将导致鉴定Slit2和Slit3刺激的细胞和分子网络。这些细胞和分子将在细胞培养系统中通过使用药物或抗体来抑制或刺激其生物活性进行药理学测试。

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.