The functional role and therapeutic potential of vascular niches in bone

Bone disorders affect almost one in every two individuals posing a major health burden on people, health systems and the Government. Aging is associated with a loss of bone density, which increases risk of fractures and poor fracture repair, as well as other musculoskeletal disorders. Bone loss is also common after ablation of the bone marrow compartment in bone marrow transplantation and cancer therapy. Understanding regulation of bone turnover and how the bone marrow microenvironment can be re-established may lead to new strategies to treat bone-loss and associated bone disorders, which pose a major challenge with increasing life expectancy in the general population

Blood vessels - collectively referred to as the vasculature - supply bone with oxygen and nutrients and provide cell surface or secreted signals that regulate skeletal tissue. The bone vasculature interacts with nearby 'mesenchymal' stem progenitor cells that can give rise to bone, fat cells (adipocytes) and cartilage. Vascular cells and mesenchymal stem cells interact to support bone growth and create a nurturing environment for blood stem cells. In aging and bone loss-related disorders, an increase in the number of adipocytes in bone interferes with beneficial interactions and may lead to further age-related blood and bone diseases.

A certain type of blood vessel in bone called "type H" is essential for bone formation and is a key regulator of developmental bone growth. These type H blood vessels decline during aging and are further reduced in osteoporosis. Certain experimental procedures that activate the vasculature lead to an increase in mesenchymal stem progenitor cell numbers. This raises the exciting possibility of targeting the bone vasculature to stimulate mesenchymal cells and to stimulate regenerative and therapeutic processes in the bone.

In the proposed study, I will interrogate the contribution of blood vessels in bone repair, with a particular focus on the crosstalk between the vasculature and the activity and potential of mesenchymal stem cells to give rise to bone versus fat cells. These studies will provide the first insight into the cell types and signals that control production of bone cells and fat cells by mesenchymal stem cells, and how this impacts bone development and repair. This will break new ground by revealing strategies to manipulate the vasculature for bone regeneration, and may also identify novel strategies for managing bone pathologies. To achieve my goals, I will combine cutting-edge techniques like advanced high-resolution imaging, sophisticated inducible cell-type specific mouse models available within my host Institute (The Kennedy Institute of Rheumatology), and exploit my proven expertise in bone vascularization and bone imaging in an unprecedented manner to push the limits of our understanding. In addition to state-of-the-art facilities (e.g. advanced imaging, flow cytometry) host Institute provides indispensable local collaborations (e.g. Prof. Jagdeep Nanchahal - for fracture models, Dr. Stephen Sansom -computational biology), access to human samples (Arthritis Research UK Osteoarthritis Centre and Nuffield Orthopaedic Centre) to enable future translation to humans and the availability of mentoring and career development training, and access to Oxford University infrastructure offer an ideal environment.

Taken together, this interdisciplinary project on the frontiers of regenerative medicine, bone and vascular biology will make a significant contribution towards the establishment of my independent career, allowing me to stay at the forefront of the field, and develop my own scientific niche.

The skeleton and the bone endothelium form a functional unit with great relevance in health, ageing and disease. The skeletal vasculature provides nurturing niches for bone and blood-forming stem cells and regulates osteogenesis and hematopoiesis. Thereby, the endothelium plays a key role in maintaining the skeletal health, and a dysregulation of the vasculature is speculated for several bone diseases. Increasing occurrence of bone disorders pose a major burden on people, health systems and the Government. I identified a specialized blood vessel subtype termed 'type H' that generates an active niche for osteoprogenitor cells. The abundance of type H endothelium declines in ageing, and reactivation of type H endothelium in aged mice leads to increased osteoprogenitor numbers and improved bone mass, indicative of their therapeutic potential. My preliminary data suggests that distinct blood vessel subtypes support specific mesenchymal stem/progenitor cell (MSPC) subsets in bone. Here, I will characterize the regenerative niches in bone and will define the role of the endothelium and associated MSPCs in bone repair by using irradiation and fracture models. Further, I will demarcate the role of distinct endothelial cell populations in regulating the MSPCs quiescence and fate determination towards osteogenic versus adipogenic lineages in development and repair. Finally, I will elucidate endothelial-mesenchymal regulatory signalling pathways in MSPC differentiation, using transcript profiling, computational biology, in vitro 3D cultures and genetic mouse models. The study will not only elucidate regenerative niches and regulatory angiocrine signaling networks in bone repair but will it will also break new ground by illustrating the vascular control of MSPC quiescence, fate and differentiation, and may identify novel strategies for managing bone pathologies.

Health benefits. Musculoskeletal disorders affect almost one in every two individuals posing a major burden on people, health systems and the Government. With increasing life expectancy, ageing populations are more severely affected and fracture repair remains a major challenge. The proposed study, will interrogate the contribution of blood vessels in bone repair and understand the vascular control of MSPCs fate and differentiation during bone developmental and repair. Therefore, the study may identify novel strategies for managing bone pathologies and age-related bone diseases.
Academic benefits. I will bring a new experimental system (bone vasculature) to an already multidisciplinary unit, thereby increasing the broad expertise of my host. Additionally, my expertise in novel imaging techniques and mouse genetics will contribute to the research excellence of my host. The proposed research will result in high quality scientific publications as well as oral and poster communications at international scientific meetings. We will particularly aim to publish in Nature journals, and attend conference like Gordon Conference: Bone and Teeth. Many of the findings and reagents resulting from this study will become available resources for the wider research community. My research interests and expertise in bone vasculature will provide ample opportunities for scientific collaborations within the Kennedy Institute of Rheumatology (KIR) and the Botnar Research Centre, University of Oxford and across the UK. Being one of the pioneers in the field, my expertise will be beneficial to different scientific communities such as musculoskeletal, vascular and regenerative biology. The proposed research has potential to support future PhD and postdoctoral scientists with high quality research projects thereby providing opportunities for training and fostering early career scientists in a wide range of experimental approaches.
Public Engagement. The research team and NDORMS and KIR are committed to creating high quality opportunities for the public and patients to engage with its research, supported by a dedicated Communications team.
Throughout the duration of funding, I will develop tailored events to engage with the public and to explain how my research contributes towards a better understanding of age-associated bone diseases. I plan to be involved in a wide-range of science festivals such as the British Science Festival, MRC Festival of Medical Research (annually in June), the Big Bang Fair, Oxfordshire Science Festival and Cheltenham Science Festival.
Given that my work is of immediate relevance to bone diseases, I will seek to engage with patient groups through e.g. the National Osteoporosis Society. The NOS has initiated an All-Party Parliamentary Osteoporosis Group (APPOG) and as a public-funded researcher, I am very keen to inform and engage parliamentarians in the challenges age-related bone diseases pose to constituents and the NHS as a whole.
Sharing my work with school children I wish to inspire the next generation of scientists: I will engage with pupils through hosting Nuffield research placements in my group and through teaching school children regularly at the in-house Microscopy Workshops or visiting local schools. I will be fully supported in my outreach and engagement work by the Communications Team at NDORMS.
Media and social media. Together with the Communications Team, I will explore engagement through social media, such as Twitter Q+A and a departmental blog platform, as well as make use of short videos and written opinion/editorial content in high quality news outlets (e.g. The Conversation, Oxford University Science blog) to further disseminate our research. The Communications Team will issue press releases on relevant results arising from this project to local, national and international media, supported by the Press Office at the University of Oxford.