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

通过这个研究联盟，我们要回答的一个大问题是“人类心脏是如何生长的，又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？它们又是如何相互交流的？为了让胎儿在子宫里发育成健康的人类心脏？目前，我们对这些事件如何发生的理解大多是基于对发育中的动物（如老鼠或鱼）的研究。虽然人类的心脏可能遵循大致相似的路径，但存在一些重要的差异，并且仍然缺乏对人类心脏发育的详细了解。我们将研究终止妊娠后获得的人类心脏的详细细胞组成，如果母亲完全同意将终止妊娠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个细胞水平，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中的心脏中的确切位置。这将给我们一个细胞的快照，以及它们在一系列不同生长阶段的行为。我们将检查所有这些信息，并确定细胞可能用来相互交流的分子。人类心脏的快照不能证明这些分子实际上是细胞相互交流所使用的分子，所以我们将使用干细胞来测试最有可能的候选分子。干细胞可用于生成体内任何类型的细胞，我们将使用人类干细胞来生成一系列不同的人类心脏细胞。基于我们的快照，我们将把适当的细胞类型放在一起来模拟人类心脏发育的不同部分和阶段，然后重要地测试哪些信号是负责细胞之间的串扰和正常心脏生长的信号。最后，我们将看到老鼠和斑马鱼的心脏发育准确地模仿了人类心脏发育的哪些阶段，哪些阶段是不同的。我们还将测试某些对人类干细胞系统中不同心脏细胞之间的交流很重要的分子是否也需要在小鼠或鱼类的心脏发育中使用。这些研究将使我们深入了解人类心脏生长的每个阶段是如何发生的，以及不同细胞之间是如何相互交流的。

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.