The Regenerative Medicine Group was started with the appointment in September 2007 of Professor Cosimo De Bari, a clinically active rheumatologist with expertise in stem cell research for musculoskeletal repair, regenerative medicine and tissue engineering. Since then, the Group has been rapidly expanding and currently consists of 4 post-docs, 6 PhD students and adequate technical support. A non-clinical lecturer and 3 additional post-docs are being recruited.
The Group has access to dedicated, state-of-the-art research facilities within the Institute of Medical Sciences and to in vivo preclinical imaging equipment located in the Medical Research Facility including x-ray and densitometry, optical imaging facilities for fluorescence and bioluminescence, and micro-CT-PET.
The Group relies on winning competitive applications to grant funding bodies such as the Medical Research Council, Technology Strategy Board, Engineering and Physical Sciences Research Council, and Arthritis Research UK. It also relies on support from individual donors, fundraisers and charitable groups.
The Regenerative Medicine Group is also part of the recently established £6 million Arthritis Research UK Tissue Engineering Centre, which is based at four sites: the University of Aberdeen, Newcastle University, Keele University/the Robert Jones and Agnes Hunt Hospital NHS Foundation Trust in Oswestry and the University of York. Funded by a core grant of £2.5 million over five years from Arthritis Research UK with a further £3.4 million pledged by the four participating universities, the Centre brings together leading clinicians, engineers and biologists from research and clinical groups to focus on translating innovative tissue engineering developments directly to patients in order to prevent or treat osteoarthritis, the commonest type of arthritis with as yet no treatment to halt progression of disease towards joint tissue breakdown, ultimately leading to a requirement for prosthetic replacement.
1) Development of stem cell-based tissue engineering bioproducts for cartilage and bone repair
Mesenchymal stem cells (MSCs) can be extensively expanded in culture while maintaining chondro-osteogenic potency. Hence, their use for cartilage and bone repair is intensely sought. We have identified and characterized MSCs from the adult human synovial membrane and periosteum. We have also shown that MSC preparations from different tissue sources possess distinctive biological properties in terms of differentiation and tissue formation. For instance, periosteal MSCs display significantly greater bone-forming potency than synovial MSCs, inherent to the single multipotent MSC.
The variability in the biological properties of MSC preparations is likely to affect the outcome of clinical applications. There is therefore a pressing clinical need to establish MSC preparations with consistent and reproducible biological behaviours, quality-controlled for specific therapeutic applications. Our aims are to identify the best tissue source of MSCs, the most potent MSC sub-populations, and the most effective MSC-scaffold combinations for cartilage and bone repair. We also aim to develop and standardise assays to measure the potency of MSC populations and to monitor the quality of cellular products. This is a crucial requirement for bringing stem cell therapeutic approaches into routine clinical practice.
2) Studies of the native stem cells and their niches in the joint in health and diseases such as osteoarthritis and rheumatoid arthritis
The study of MSCs in their native tissues has been hampered by the lack of specific markers that can identify these cells. To overcome this hurdle, we have recently developed a double-nucleoside analogue labelling method to identify functional MSCs in vivo in the knee joints of mice (Kurth et al., 2011). Our successful labelling approach relied on the slow-cycling nature of MSCs combined with their propensity to undergo rapid proliferation following joint surface injury. We have shown that nucleoside-labelled cells express known MSC markers and undergo ectopic chondrogenic differentiation within synovium in response to articular cartilage injury (Kurth et al., 2011), demonstrating that these cells have ability to function as MSCs in their native environment.
Currently, we are studying the contribution of endogenous MSCs to cartilage repair following injury. We are also studying the roles of native MSCs in the pathogenesis of inflammatory (rheumatoid) arthritis and osteoarthritis. The characterisation of MSC niches and their underlying molecular regulation in joint tissues in health and disease will instruct the development of novel stem cell-based therapies by targeting pharmacologically, using drugs, the native stem cells and their reparative signalling pathways to trigger/enhance tissue repair and modulate disease outcome with the ultimate goal of restoring joint homeostasis.
3) Investigation of the developmental origins of mesenchymal stem cells.
A key question in MSC biology relates to their developmental origins. We are endorsing lineage tracing experiments to determine whether MSCs from different skeletal tissues, i.e. bone marrow, synovium, periosteum, share common developmental origins, or whether there is a divergence in ancestor cell populations early on during embryonic life. Distinct ontogeny paths could imply tissue-specific imprinted embryonic memory which may be reflected in distinct biological properties. These studies will provide a scientific rationale for the choice of the tissue source of MSCs for skeletal tissue repair. Furthermore, lineage tracing studies will offer the prospect of developing novel tools and models to study the function of MSCs in health and disease.