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

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.

Our overall aims are to determine the cellular and molecular mechanisms driving human heart development and to what extent this differs from development in model organisms such as mouse or zebrafish.

Understanding of heart development is largely based on work using model organisms, where there is conservation at a morphological level and an assumption that underlying mechanisms are similarly conserved. However, there are interspecies differences in cardiac physiology, structure and cellular function. This makes it essential to understand which of the key cell types and molecular events that regulate heart formation are truly conserved across vertebrates, and which are human-specific.

We therefore need to define the distinct human-specific cellular niches which guide key developmental events (such as coronary arteriogenesis, conduction system formation, ventricular compaction, and valvulogenesis) and understand the main molecular interactions required for healthy human heart development.

First, we will combine state-of-the-art multimodal single cell and spatial analyses with cutting edge bioinformatics and data science, and generate a human heart developmental atlas at unprecedented spatial and temporal resolution. These data will enable predictions of molecular regulators driving the development of key cardiac cell lineages in humans.

Next, we will use existing and novel human pluripotent stem cell-derived in vitro models to recreate specific developmental niches and experimentally determine the critical molecular regulators of cell-cell crosstalk and niche function in the dish. We will also generate comparable multiome and spatial datasets in mouse and zebrafish and employ deep learning approaches to define conserved niches and signalling events for functional testing.

These studies will transform our understanding of cardiac development from model organisms to human, and provide a template for similar studies of other major organs in the body.