Tuning tyrosine kinase signalling to improve haematopoietic stem cell expansion and bone marrow transplantation

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Overview. In this project, we will develop new ways to grow umbilical cord blood derived stem cells for bone marrow transplantation and regenerative medicine. We have recently demonstrated multiple new therapeutic targets on haematopoietic (blood) stem cells (HSCs), which can have major impacts on the regenerative potential of these cells. Dr. Grey has demonstrated the efficacy of targeting the receptor tyrosine kinase, RET, to improve human HSC outgrowth and Prof. Hitchcock has developed new modified cytokines to tailor thrombopoietin signalling in HSCs. Together, with our iCASE partner (Plasticell Ltd), our clinical collaborators (Anthony Nolan) and The Francis Crick Institute (London), this PhD studentship will develop the most effective combination of treatments to improve HSC outgrowth, transplantation and unpick the molecular signalling pathways underlying these phenotypes.Background. Historically, the study of haematopoiesis and HSCs has led the way in identification of hierarchical organisation, fate mapping and single cell approaches. Indeed, HSCs are defined by their ability to reform the entire haematopoietic system upon transplantation, with bone marrow transplantation (BMT) being the first regenerative approach to enter the clinic. BMT was initially used to treat patients who had received high dose radiation and suffered bone marrow failure, and as a clinical approach has since developed both regenerative and immunotherapeutic aims.HSCs are known to reside in the bone marrow of adults and umbilical cord blood (UCB) during pregnancy. Although a bone marrow biopsy is invasive and mobilisation of peripheral blood requires chemokine treatment, collection of UCB represents a less invasive, clinically important source of HSCs and progenitors (HSPCs) for the treatment of a wide range of malignant and non-malignant disorders. UCB has a lower incidence of graft-versus-host disease, with less stringent donor HLA-matching required compared with classical donor sources, thus increasing its value for both haematologic and non-haematologic malignancies.Despite increased UCB banking, limited progenitor cell dose, delay of engraftment and immune reconstitution and the cost of double UCB transplantation in adults underscore the need to improve expansion and potency of these cells for the purposes of transplantation.Objectives.To improve the production of HSCs from UCB donors by targeting tyrosine kinase signallingUnderstand the mechanism by which tuning tyrosine kinase signalling improves HSC expansion.Translate findings to clinical grade systems.Experimental approaches.In preliminary work, Dr. Grey has curated a large cohort of UCB donors of varying expansion potential with collaborators at Anthony Nolan. Dr. Grey and Prof. Hitchcock have developed new molecules to tune key signalling pathways in stem cells. Together, we will use our previously published protocols for assessment of HSC functionality and expansion in culture through a myriad of in vivo and in vitro approaches and molecularly tune kinase signalling to improve HSC expansion for transplantation.Plasticell Ltd