We are interested in understanding how the cardiovascular system is formed and how it makes blood stem cells that endow organisms with a lifetime supply of blood cells. We think that understanding the mechanisms underlying normal cardiovascular development is fundamental for finding strategies to correct those mechanisms when they are perturbed in disease.
Blood stem cells (HSCs) arise during embryonic development from a subset of the arterial endothelium – the haemogenic endothelium – and supply blood cells throughout adult life. How does a cell that has already differentiated to a particular lineage (endothelium) gain the capability to de-differentiate and become a stem cell for a different tissue type (blood)? Can we harness that capacity for our benefit?
We focus on the Transforming Growth Factor β (TGFβ) pathway as a paradigm, aiming to understand how TGFβ is deployed during development to make HSCs, and how that relates to its function in making blood vessels. Gaining insights into the role of TGFβ in stem cell biology in vivo is particularly relevant, given that it is an attractive therapeutic target in haematopoietic malignancies and cardiovascular disease.
The lab uses a combination of classical developmental biology, transgenesis and other technologies including gene editing, transcriptional profiling and genome-wide analysis of cis-regulatory elements, using zebrafish (Danio rerio) as a model. Zebrafish have become an important resource for biomedical research, helping us to understand human disease and addressing critical questions in regenerative medicine. Because zebrafish share the same genes with other vertebrates, including humans, and angiogenesis and haematopoiesis are so well conserved, the lessons we learn from this model can be directly applied to other vertebrate systems and to human health.
Nicola Joseph (BHF Doctoral Programme)