Developing Blood Cell Production Platforms for Therapeutic Applications

Generation and modification of blood cells ex vivo or in vitro harbours a huge potential in cell based therapies and regenerative medicine. An important bottleneck in realising this potential is the difficulty in efficiently producing large amounts of blood products in vitro. One way to address this problem is to find new ways to effectively manipulate blood precursors and progenitors to create cell lines that can be amplified while still retaining their developmental potential. These cells could potentially represent an unlimited source of therapeutically relevant cell products such as modified natural killer cells, chimeric antigen receptor T-Cells, modified red blood cells, platelets or haematopoietic stem cells.

The seminal demonstration that pluripotency can be induced by the ectopic expression of specific transcription factors has instigated a lot of interest in developing new strategies to manipulate the developmental potential of cells. Transcription factor directed reprogramming, trans-differentiation, or induced proliferation have been achieved through ectopic gene expression. Novel non-genetic methods, such as protein transduction or use of chemical compounds, have been demonstrated as potential alternatives to genetic modification producing similar results, establishing a clinical path for new discoveries in gene based cellular modulation strategies.

This PhD project aims to develop new methods to produce large quantities of haematopoietic cells and differentiated haematopoietic progenitor cells through the establishment of novel blood cell lines. The project also aims to establish modified blood cell platforms for applications in advanced cellular therapies. An ideal target to induce proliferation of is the haemogenic endothelium (HE), which is a rare transient cell population generated during embryonic development, and the precursor to all adult blood cells including haematopoietic stem cells (HSCs). A HE cell line would be a powerful platform for the production of any adult blood lineage including HSCs and provide a tool for investigating the molecular pathways that drive and direct blood formation. The project aims to induce extensive proliferation of HE cells though ectopic gene expression, while maintaining the ability for these cells to transition from endothelial lineage cells to HSCs and their progeny. The potential of modifying these HE and blood cell lines to produce customized blood cell products will be explored with the ultimate goal of developing new potential cellular immunotherapies for the treatment of cancer and autoimmune diseases.