A donated human heart, smaller than a thumbnail, is broken apart cell by cell to reveal how the organ builds itself in the womb. Most of what scientists know about heart development comes from mice and fish, but human hearts differ in crucial ways. This consortium will fill that gap by studying real human heart tissue from early development, using advanced techniques to map which genes are active in each cell and where those cells sit within the growing organ. The snapshots will identify molecules that cells might use to talk to one another. Because snapshots alone cannot prove communication is happening, the team will then test the most promising candidates by building miniature heart models from human stem cells, mixing different cell types to recreate specific stages of development. This is fundamental science. It will not produce a treatment or device tomorrow. But understanding exactly how human heart cells coordinate their growth and communication could eventually help researchers spot what goes wrong in congenital heart defects, or guide efforts to grow replacement heart tissue in the lab. Past discoveries in developmental biology—such as the genes that control body patterning—led directly to new approaches in regenerative medicine and cancer therapy. This project lays similar groundwork.
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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.
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