This project is highly multidisciplinary involving expertise in HSC biology, biomaterials science and microfluidics. This project will assess the utility of a newly developed in vitro humanised 3D haematopoietic system as a relevant alternative to REPLACE mouse models for studying haematological disorders especially myeloid leukaemia. At present, no single model system exists, that accurately replicates the human haematopoietic system. The gold standard are in vivo animal models, usually involving xenotransplantation of human leukaemic cells into highly immunocompromised mice. However, these models are not ideal, with high variability observed between patient samples, low engraftment rates and often the leukaemia, which develops not accurately replicating the human disease. Even then, high numbers of LSCs are required resulting in low engraftment rates ~20% for chronic and 40-66% for acute myeloid leukaemia with <25% developing leukaemia. These assays also entail serial transplantation to assess the self-renewal of HSC/LSC, requiring multiple mice for prolonged periods of time. Another issue is the lack of an immune system and a tumour-specific and/or species-specific microenvironment in the experimental host. In fact, in myeloid leukaemia the interactions between LSCs/HSCs and the specific microenvironment may be essential for self-renewal of LSCs and thus disease evolution. Our system has several advantages; it is permissible to both normal HSC and malignant LSC proliferation and survival enabling normal and malignant haematopoiesis to be studied in parallel, and importantly patient samples, that do not engraft in vivo. In addition, it enables the early pre-leukaemic phase of the disease to be investigated and has the ability to add immune cells. Once validated this system would provide an excellent model for pre-clinical testing of novel therapies to target the LSCs, known to lead to persistent minimal residual disease (MRD) and relapse of leukaemia in patients.
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