Mechanisms of adhesion-dependent haematopoietic transdetermination
Lead Research Organisation:
University of Cambridge
Department Name: Physiology Development and Neuroscience
Abstract
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.
Technical Summary
The proposed research explores the pathway that links mechanosensing and cell fate decisions. Integrin extracellular matrix receptors are key players in mechanosensing, with contrasting roles in survival and proliferation. However, identification of a consensus pathway for the signals sensed by integrin adhesion complexes has remained elusive. We propose to use Drosophila haematopoiesis as a model system to elucidate this pathway. We have discovered a physiological cell fate change that relies on integrin mechanosensing, which is the natural reprogramming step that converts mature plasmatocytes to crystal cells. Preliminary data has shown that two integrin associated proteins are essential for the formation of crystal cells, and the number of crystal cells is easy to assay in live animals. We propose to exploit this powerful new assay to elucidate the signalling pathway linking integrins to transdetermination of cell fate. We will combine live imaging, genetics and genomics to characterize how mechanotransduction contributes to crystal cell transdetermination, and discover the different components in this integrin signalling pathway. This project will provide insights into how mechanical changes transmitted to cells orchestrate cell fate decisions, and how mechanical signals contribute to modulating immune function. The molecular mechanism of crystal cell fate determination shares conserved pathways and transcription factors with the process of haematopoietic stem cell fate acquisition in humans. Therefore, elucidating how integrin signalling intersects with these factors may aid the production of haematopoietic stem cells for therapeutic purposes.
Planned Impact
The beneficiaries of this study will be:
1.Pharmaceutical industries. We have identified a role of integrin mediated mechanosensing in a cell fate decision involving the RUNK family transcription factor, Lozenge. Deregulation of RUNX1 is associated with lymphoid leukaemia and acute lymphoid leukaemia. Our identification of the pathway between integrins and transcriptional control will produce new potential drug targets, benefiting the economy of the UK and strengthen our position as a world leader in drug development. (5-10 years)
2. Patients suffering from leukaemia and genetic disorders of the blood that require treatment by transplantation of haematopoietic stem cells (HSCs). Our improved understanding of the transcriptional programmes involved in haematopoiesis, in particular transdetermination between differentiated cells, and the role of mechanical inputs in the niche can be used to develop ways to produce and/or expand HSCs in culture. This will improve the availability of HSCs for transplantation, and permit the repair of genetic disorders prior to transplantation. (10-15 years)
3. Patients suffering from cancer. A vast majority of cancer deaths are caused by metastasis, the process by which cancer cells spread within the body. The invasive behavior of cancer cells is critically regulated by mechanosensing. Our improved understanding of mechanosensing mechanisms will be exploited to design ways of inhibiting the metastatic capability of cancer cells. Particularly our work will be relevant to patients suffering from myeloid leukemia/acute myeloid leukemia, as we have identified mechanosensing as a regulator of RUNX factors associated with these diseases. (10-15 years)
4. Those wishing to develop high levels of fitness and longevity. The mechanisms of mechanotransduction are an essential part of how the body ensures that tissues can withstand the forces produced by everyday and strenuous activity. For example, increasing levels of the mechanoeffector vinculin in the heart of the model organism Drosophila extends its lifespan 150%. The improved understanding of the beneficial activities of vinculin in regulating cell fate and immune function will aid in developing fitness regimes and promoting healthy ageing. (10-15 years)
5. Organizations and Companies recruiting scientifically trained staff, including both public and private sectors. The postdoctoral researcher funded by this work will develop their training and expertise, as well as supervising A-level, undergraduate and postgraduate students. Thus, the work will benefit a new generation of scientists. After the completion of the work, the researchers will be able to contribute to the scientific economy of the UK by applying the skills gained in the project, whether in public or private sectors.
6. The general public. Through engagement with the public through talks, websites, social media and general audience publications we seek to communicate the excitement and beauty of scientific research. Our work will involve a substantial amount of compelling images that serve as an important starting point for public engagement with biomedicine. We will submit such images to competitions (e.g. Nikon/Welcome Trust) to reach the widest audience.
1.Pharmaceutical industries. We have identified a role of integrin mediated mechanosensing in a cell fate decision involving the RUNK family transcription factor, Lozenge. Deregulation of RUNX1 is associated with lymphoid leukaemia and acute lymphoid leukaemia. Our identification of the pathway between integrins and transcriptional control will produce new potential drug targets, benefiting the economy of the UK and strengthen our position as a world leader in drug development. (5-10 years)
2. Patients suffering from leukaemia and genetic disorders of the blood that require treatment by transplantation of haematopoietic stem cells (HSCs). Our improved understanding of the transcriptional programmes involved in haematopoiesis, in particular transdetermination between differentiated cells, and the role of mechanical inputs in the niche can be used to develop ways to produce and/or expand HSCs in culture. This will improve the availability of HSCs for transplantation, and permit the repair of genetic disorders prior to transplantation. (10-15 years)
3. Patients suffering from cancer. A vast majority of cancer deaths are caused by metastasis, the process by which cancer cells spread within the body. The invasive behavior of cancer cells is critically regulated by mechanosensing. Our improved understanding of mechanosensing mechanisms will be exploited to design ways of inhibiting the metastatic capability of cancer cells. Particularly our work will be relevant to patients suffering from myeloid leukemia/acute myeloid leukemia, as we have identified mechanosensing as a regulator of RUNX factors associated with these diseases. (10-15 years)
4. Those wishing to develop high levels of fitness and longevity. The mechanisms of mechanotransduction are an essential part of how the body ensures that tissues can withstand the forces produced by everyday and strenuous activity. For example, increasing levels of the mechanoeffector vinculin in the heart of the model organism Drosophila extends its lifespan 150%. The improved understanding of the beneficial activities of vinculin in regulating cell fate and immune function will aid in developing fitness regimes and promoting healthy ageing. (10-15 years)
5. Organizations and Companies recruiting scientifically trained staff, including both public and private sectors. The postdoctoral researcher funded by this work will develop their training and expertise, as well as supervising A-level, undergraduate and postgraduate students. Thus, the work will benefit a new generation of scientists. After the completion of the work, the researchers will be able to contribute to the scientific economy of the UK by applying the skills gained in the project, whether in public or private sectors.
6. The general public. Through engagement with the public through talks, websites, social media and general audience publications we seek to communicate the excitement and beauty of scientific research. Our work will involve a substantial amount of compelling images that serve as an important starting point for public engagement with biomedicine. We will submit such images to competitions (e.g. Nikon/Welcome Trust) to reach the widest audience.
