The ECM as a coordinator of cardiac function, growth and morphogenesis during heart development

ECM 作为心脏发育过程中心脏功能、生长和形态发生的协调者

• 批准号: BB/W004305/1
• 负责人: Emily Noel
• 金额: $ 53.6万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW004305%2F1
• 关键词: ECM; coordinator; cardiac; function; growth

The heart is a complex organ whose shape is tightly linked to function. During embryonic development the heart is initially a linear tube which undergoes rearrangement to generate its final form. This process is called heart morphogenesis, and if it does not occur properly can lead to birth abnormalities known as congenital heart defects. While the heart is undergoing morphogenesis, two additional events also occur which are crucial for heart development. First, the heart grows in size through the addition of cells to the poles of the heart from a progenitor pool of cells in the surrounding mesoderm called the Second Heart Field (SHF). Although the addition of SHF cells to the heart is an essential part of heart morphogenesis, we understand very little about how these cells become incorporated into the heart. Second, the heart is already beating during morphogenesis. Our previous work suggests that heart contraction controls how SHF cells are added to the heart, and couples heart growth with morphogenesis.Cells and tissues do not exist in isolation - the environment around cells is a diverse assortment of protein and sugar molecules called the extracellular matrix (ECM), the composition of which is specific to different tissues. The ECM regulates biochemical signalling to surrounding cells, provides mechanical support and biomechanical cues, and is a key regulator of cell migration, tissue morphogenesis, and organ function. The ECM is therefore a crucial component of the heart tube and surrounding SHF. We have shown that the ECM component laminin regulates SHF addition, likely by regulating the impact of contractility on SHF cells, providing a new link between heart function and growth. However, the relationship between cardiac function, the ECM, and SHF addition in coupling growth and morphogenesis is unknown.In this proposal we use live imaging of heart development in zebrafish embryos where heart function is lost or increased to understand the relationship between contractility and the ECM in regulating SHF addition. Zebrafish represent a unique model organism allowing us to define this relationship. The embryos are transparent and develop externally, so we can visualise heart development in a live embryo. Furthermore, zebrafish can survive the first few days of development without a functioning heart, meaning we can investigate how heart function impacts heart development in a way that is challenging in other organisms.We will define this relationship via three objectives, all of which will exploit this ability to perform live in vivo imaging of the developing zebrafish heart and SHF. First, we will stop or speed up the embryonic zebrafish heart and assess how contractility affects the ECM itself. We will visualise the amount and distribution of ECM in the heart during morphogenesis, and will label specific ECM components to visualise ECM organisation and composition upon altered contractility. Second, we will define how loss of the ECM component laminin affects heart tube contractility and SHF cell movement by imaging the beating heart tube and migrating SHF cells over time. Third we will combine the experimental approaches from the first two objectives to define how changes in contractility and/or the ECM together affect the rate of heart growth. We will generate state-of-the-art 3D reconstructions of the developing heart in the experimental models from objectives 1 and 2, enabling us to define for the first time how contractility and the ECM together shape the heart by mediating growth. Defining how the ECM links heart function, growth, and morphology has many applications. It will help understand the processes driving heart development in humans, as well as how the ECM shapes other tissues in the body during development. The ECM has also been recently identified as a key driver of heart regeneration, so this work has important implications in advancing our ability to improve tissue regeneration after injury.

心脏是一个复杂的器官，其形状与功能密切相关。在胚胎发育过程中，心脏最初是一个线性管，经过重排产生其最终形式。这个过程被称为心脏形态发生，如果它没有正确发生，可能会导致出生异常，称为先天性心脏缺陷。当心脏正在经历形态发生时，还发生了两个对心脏发育至关重要的额外事件。首先，心脏的大小通过从周围中胚层中的祖细胞池（称为第二心脏场（SHF））向心脏两极添加细胞而增长。虽然SHF细胞加入心脏是心脏形态发生的重要组成部分，但我们对这些细胞如何融入心脏知之甚少。第二，心脏在形态发生期间已经在跳动。我们之前的研究表明，心脏收缩控制SHF细胞如何添加到心脏，并将心脏生长与形态发生结合起来。细胞和组织并不是孤立存在的-细胞周围的环境是一种称为细胞外基质（ECM）的蛋白质和糖分子的多样化组合，其组成对不同组织具有特异性。ECM调节周围细胞的生化信号传导，提供机械支持和生物力学线索，并且是细胞迁移、组织形态发生和器官功能的关键调节剂。因此，ECM是心管和周围SHF的重要组成部分。我们已经表明，ECM组分层粘连蛋白调节SHF添加，可能是通过调节收缩性对SHF细胞的影响，提供了心脏功能和生长之间的新联系。然而，心脏功能之间的关系，ECM，SHF除了耦合生长和morphogenesis.In这个建议中，我们使用心脏发育的斑马鱼胚胎心脏功能丧失或增加了解收缩性和ECM之间的关系，在调节SHF除了实时成像。斑马鱼代表了一种独特的模式生物，使我们能够定义这种关系。胚胎是透明的，在外部发育，因此我们可以在活胚胎中可视化心脏发育。此外，斑马鱼在没有功能性心脏的情况下也能在发育的最初几天存活下来，这意味着我们可以研究心脏功能如何以一种在其他生物中具有挑战性的方式影响心脏发育。我们将通过三个目标来定义这种关系，所有这些目标都将利用这种能力对发育中的斑马鱼心脏和SHF进行活体成像。首先，我们将停止或加速胚胎斑马鱼心脏，并评估收缩性如何影响ECM本身。我们将在形态发生过程中可视化心脏中ECM的数量和分布，并将标记特定的ECM成分，以可视化收缩性改变后的ECM组织和组成。其次，我们将通过对跳动的心管和随时间推移迁移的SHF细胞进行成像来确定ECM组分层粘连蛋白的丢失如何影响心管收缩性和SHF细胞运动。第三，我们将结合联合收割机的实验方法，从前两个目标，以确定如何在收缩性和/或ECM的变化一起影响心脏生长的速度。我们将在目标1和2的实验模型中生成发育中心脏的最先进的3D重建，使我们能够首次定义收缩性和ECM如何通过介导生长共同塑造心脏。确定ECM如何连接心脏功能、生长和形态具有许多应用。它将有助于了解驱动人类心脏发育的过程，以及ECM在发育过程中如何塑造体内其他组织。ECM最近也被确定为心脏再生的关键驱动因素，因此这项工作对提高我们改善损伤后组织再生的能力具有重要意义。