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A research consortium of DPAG/IDRM and University of Cambridge scientists have been awarded a major strategic grant by the Biotechnology and Biological Sciences Research Council (BBSRC) to answer the pressing long-standing questions of how the human heart grows, how it is put together, and how the different heart cells communicate with each other during pregnancy.

Overall representation of developing human heart cells (RNA space). Single cell and nuclear RNAseq analysis of 16 human fetal and embryonic hearts (ages 6-9 weeks) identifies 41 cardiac cell types and subtypes

The BBSRC 2022-2023 Longer and Larger (sLoLa) grant connects DPAG’s Director of the IDRM Professor Paul Riley and IDRM group leader Dr Filipa Simões with principal investigator of the project Professor Sanjay Sinha of the University of Cambridge, the 2022 J.S. Haldane Prize Lecture speaker Dr Sarah Teichmann of the Wellcome Trust Sanger Institute, and former DPAG researcher Dr Richard Tyser, now a group leader at the Wellcome – MRC Cambridge Stem Cell Institute, to define the cellular and molecular mechanisms of human heart development.

A myriad of muscle, blood vessel, connective tissue, inflammatory, and a great number of other cell types come together to build a baby’s heart during pregnancy. Presently, the scientific world has a good understanding of how these different cells are produced, come together and communicate in cardiac development through animal studies. But while human hearts may follow a broadly similar path, there are some important differences, and a detailed understanding of human heart development remains lacking.

In a pioneering new BBSRC-funded project titled “Deciphering Cellular Niches and Cross-talk in Human Heart Development (CellTalkHHD)”, the Oxford-Cambridge consortium will study the detailed cellular makeup of human hearts in donated foetal heart tissues. These tissues will be obtained following elected termination of pregnancy where the mothers have fully consented for tissues from the termination products to be used for biomedical research.

Using advanced cell atlasing techniques, the team will take the donated tissues apart to the single cell level, determine which genes are switched on in which cells, and where exactly each cell is positioned in the growing heart. The resultant Human Developmental Heart Cell Atlas will give the team a detailed snapshot of cells and how they are behaving at a range of different growth stages, enabling them to identify the molecules that the cells might be using to talk to each other. The most likely candidates will be tested using stem cells to generate a range of human heart cells in a dish in 2D or in more complex 3D structures called cardiac “organoids”, to mimic different parts and stages of human heart development, followed by testing which signals are responsible for crosstalk between cells and for normal heart growth.

The team will then compare human heart development with mouse and zebrafish models to see which stages are accurately mimicked by these models and which stages are different. Finally, researchers will 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.

The research team say: “These findings 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.”