Validation of an in vitro humanised 3D haematopoietic system to investigate haematological malignancies

Why did we fund this project?

This award aims to replace the use of mouse xenograft models for studying haematological disorders, particularly myeloid leukaemia, with an in vitro 3D microfluidic model.

Myeloid leukaemias arise in the bone marrow from haematopoietic stem cells (HSCs) and remodel the bone marrow niche to promote tumorigenesis. The cancerous cells can also metastasise to the spleen and liver. Myeloid leukaemias are difficult to treat with current therapies and research is ongoing to understand how the cancerous cells alter the bone marrow niche. In vitro models currently do not represent the entire process of myeloid leukaemia development and the haematological system, limiting their potential to replace in vivo models. Patient-derived xenograft mouse models are the current ‘gold standard’ for studying myeloid leukaemia. These experiments are classified as moderate severity under the UK’s Animals (Scientific Procedures) Act 1986 due to the level of suffering caused by the growth of the tumour. However, the rate of implantation can be variable and subcutaneous implantations mean the tumour microenvironment is not accurately replicated in the mouse.

Professor Helen Wheadon and colleagues have developed a 3D artificial haematopoietic system using hydrogels designed to mimic the bone marrow structure. The system contains niches, to model both the bone marrow and splenic microenvironment, and microfluidics to mimic blood flow. Helen will use the system to compare the behaviour of normal HSCs and leukaemic stem cells and how each cell type influences the different niches. Helen will then validate the model by comparing results from patient cells in the in vitro system to the same cells in xenograft models, using data already generated in her laboratory.