Development of a site-directed chromatin interactome technology to map transcriptional drivers of hematopoietic stem cell (HSC) ex vivo expansion

Haematopoietic stem cells (HSCs) are the fundamental component of regenerative medicine applications involving the blood and immune system. Despite significant efforts and investment, researchers have largely failed to maintain fully functional HSCs for substantial periods of time. As a result, the limiting factor for cell and gene therapies is often obtaining a sufficient number of HSCs to seed the production of mature cells in vitro (e.g., red blood cells, platelets) or to durably engraft during bone marrow transplantation (e.g., gene therapy).

Recent advances in mouse and human HSC expansion put us on the cusp of breaking through a decades-old barrier and this novel cell culture system urgently requires molecular characterisation.

Transcription factors are at the heart of determining cell fate. They determine which genes are expressed, and when, leading to the expression of proteins which determine the type of cells an HSC will become. There is an urgent need to understand which TF complexes are formed in expanding and differentiating HSCs, and to devise new ways of targeting them.

This project will directly address this problem, by developing a new method to identify critical transcription factors/co-factors involved in the expansion of HSCs.