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Blood regeneration: de novo development of human hematopoietic stem cells (DENOVOHSC)
Start date: Jan 1, 2015, End date: Dec 31, 2019 PROJECT  ONGOING 

Hematopoietic stem cells (HSC) are used in clinical therapies for leukemia and blood-related genetic disorders. Whereasthe number of patients requiring treatment continues to increase, HSC transplantations are limited due to insufficientpatient-matched donor HSCs. The current challenge is to create more matched HSCs. As evidenced by the Nobel Prizeaward this year, reprogramming of somatic cells to pluripotent stem cells (iPS) is one of the most important breakthroughsof recent times. This innovative advance contributes to our ability to reprogram patient-specific cells not only to pluripotency, but also to directly program them to other desired cell lineages. The study of healthy and diseased patient cells in this context will have huge impact on the development of new drug and cell-based treatments. My research is uniquely positioned at the interface of fundamental and translational research at the University of Edinburgh Centre for Inflammation Research and Centre for Regenerative Medicine. Through more than a decade of HSC developmental research, my group has shown that HSCs arise from endothelial cells in a natural reprogramming event. We are one of the few groups worldwide that can isolate these special endothelial cells and show that they yield robust transplantable HSCs (the gold-standard for clinically relevant HSCs). Using our unique expertise I aim to foster new translational strategies to de novo generate human HSCs from patient somatic cells. My aims are to 1) mark and manipulate the program for HSC generation during the endothelial to HSC transition (EHT); 2) define extrinsic molecules affecting EHT and engineer novel niches; 3) reprogram human somatic cells or endothelial derived iPS cells directly to HSCs. These aims will be realized through novel multi-color reporter mouse and ES/iPS lines indicating EHT in real-time, allowing for the isolation and functional validation of de novo HSC generation. These novel models and cultures will significantly advance research and technology, to have major impact on the field.

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