Mechanisms of adhesion-dependent haematopoietic transdetermination

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Current treatments for leukemia and other blood disorders involve the transplantation of the stem cells that reside in our bone marrow and give rise to all types of blood cells. However, the availability of healthy stem cells for transplantation is limited, reducing the effectiveness of this treatment. If we are to increase the number of these cells that can be used for treatment, we need to discover more about how the stem cells arise and proliferate so that we can grow them in culture. Our research suggests that what may be preventing the successful culture of these cells at present is the absence of the appropriate mechanical signals from the surrounding environment. The tissues and organs in our body are made up of cells that need to stick to each other and the material that surrounds the cells, the extracellular matrix. By sticking to the extracellular matrix, the integrin receptors can sense when physical forces push or pull on cells. This helps explain how the physical surroundings of cells can affect what kind of cell they become. This proposal arose from our discovery that changes between types of cells within the blood of the model organism Drosophila are regulated by these mechanical pathways. This discovery provides us with a new easy way to discover how integrins can communicate to the nucleus to change cells from one type to another. The ability to grow large numbers of Drosophila and examine them for changes in their blood cell number means that we can identify the machinery of this pathway more easily than in mammals. Nonetheless, due to the high level of conservation of basic cellular mechanism between Drosophila and mammals, we expect that most of the machinery that we discover will have an equivalent in humans. Thus, our research will aid in treating diseases where cellular responses to mechanical signals goes awry. In addition to elucidating this integrin signalling pathway, we will also find out more about the process of changing cell fates, which will be of value for those aiming to reprogramme cells for therapeutic treatments.