Deciphering Cellular Niches and Cross-talk in Human Heart Development (CellTalkHHD)

我们将通过这个研究联盟回答的一个大问题是“人类心脏是如何生长的，它是如何组合在一起的？”心脏是由许多不同的细胞组成的，如心肌细胞、血管细胞、结缔组织细胞、炎症细胞等。这些不同的细胞是如何产生的，它们是如何聚集在一起的，它们是如何相互沟通的，以便在婴儿在子宫中成长的过程中建立一个健康的人类心脏？目前，我们对这些事件如何发生的大多数理解都是基于对老鼠或鱼等发育中的动物的研究。虽然人类心脏可能遵循一条大致相似的道路，但存在一些重要的差异，对人类心脏发育的详细了解仍然缺乏。我们将研究终止妊娠后获得的人类心脏的详细细胞组成，其中母亲完全同意将终止产品的组织用于生物医学研究。我们可以将这些捐赠的心脏组织分离到单细胞水平，使用先进的实验室技术，我们可以确定哪些基因在哪些细胞中被激活，以及每个细胞在生长的心脏中的确切位置。这将为我们提供细胞的快照，以及它们在一系列不同生长阶段的表现。我们将检查所有这些信息，并确定细胞可能用来相互交谈的分子。人类心脏的快照不能证明这些分子实际上是细胞用来相互通信的分子，所以我们将使用干细胞测试最有可能的候选分子。干细胞可以用来在体内产生任何类型的细胞，我们将使用人类干细胞来产生一系列不同的人类心脏细胞。基于我们的快照，我们将把合适的细胞类型组合在一起，以模拟人类心脏发育的不同部分和阶段，然后重要的是测试哪些信号是导致细胞之间的串扰和心脏正常生长的信号。最后，我们将看到老鼠和斑马鱼心脏发育准确模仿了人类心脏发育的哪些阶段，以及哪些阶段是不同的。我们还将测试在人类干细胞系统中被发现对不同心脏细胞之间的交流至关重要的某些分子是否也需要在小鼠或鱼的心脏发育中使用。这些研究将深入了解人类心脏发育的每个阶段是如何发生的，以及不同的细胞到底是如何相互沟通的。

The big question that we will answer through this research consortium is "how does the human heart grow and how is it put together?" The heart is made up of lots of different cells, such as heart muscle cells, blood vessel cells, connective tissue cells, inflammatory cells and so on. How do these different cells all get produced, how do they come together and how do they communicate with each other, in order to build a healthy human heart as a baby grows in the womb? At present, most of our understanding of how these events occur is based on studies of developing animals such as mice or fish. While human hearts may follow a broadly similar path, there are some important differences, and a detailed understanding of human heart development is still lacking. We will study the detailed cellular makeup of human hearts obtained following termination of pregnancy where the mothers have fully consented for tissues from the termination products to be used for biomedical research. We can take these donated heart tissues apart to the single cell level and using advanced laboratory techniques we can determine which genes are switched on in which cells, and where exactly each cell is positioned in the growing heart. This will give us a snapshot of cells and how they are behaving at a range of different growth stages. We will examine all this information and identify the molecules that the cells might be using to talk to each other. The snapshots of the human heart cannot prove these molecules are actually the ones used by cells to communicate with each other, so we will test the most likely candidates using stem cells. Stem cells can be used to generate any cell type in the body, and we will use human stem cells to generate a range of different human heart cells. Based on our snapshots we will put together appropriate cell types to mimic different parts and stages of human heart development, and then importantly test which signals are the ones that are responsible for crosstalk between cells and for normal heart growth. Finally, we will see which stages of human heart development are accurately mimicked by mouse and zebrafish heart development and which stages are different. We will also test whether certain molecules found to be important for the communication between different heart cells in the human stem cell system are also needed in mouse or fish heart development. These studies will provide a deep understanding of how each of the stages of heart growth in humans occurs and exactly how the different cells communicate with each other.