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.