Tim Hardingham, BSc PhD DSc
Articular cartilage is an important biomechanical tissue that we rely on, indeed we all walk on, all our lives. Joint diseases such as Osteoarthritis (OA) greatly impact on personal mobility and independence and short of joint replacement there are few treatments that are effective. A key feature of OA is the damage and loss of articular cartilage and to tackle the problem we are using cartilage from individual patients for a broad study to identify subsets of OA that share different pathways to damage. In this study in collaboration with Ray Boot-Handford and Jean Marc Schwartz, we are using deep sequencing by RNAseq to identify the patterns of genes expressed by patient cartilage chondrocytes and age-matched non-OA controls. These are analysed by a Systems Biology approach to identify active pathways in each patient. The intention here is to stratify OA based on disease mechanisms. This will enable the selection of process markers that may be used to identify disease subsets and to reveal new strategies for targeted intervention.
Work on cartilage regeneration in collaboration with Prof Sue Kimber is centred round the targeted differentiation of human embryonic stem cells to chondrocytes (Oldershaw et al 2010), which we showed to promote cartilage repair in immuno-compromised rats (Cheng et al 2014). This work is being extended in two directions; a) to develop GMP procedures for generating human ES cell derived-chondroprogenitors for translational experiments in focal defects in sheep joints leading towards clinical applications; b) towards the generation of human induced pluripotent stem cells-derived chondroprogenitors, as an alternative more versatile source of cells for cartilage repair. Chondrogenic iPS cells are also being developed as part of the large European FP7 programme SYBIL to generate model systems of joint disease relating mechanisms in monogenic conditions (e.g. chondrodysplasias) to complex polygenic conditions such as OA.
Recent key publications
Cheng, A., Hardingham, T.E. and Kimber, S.J. (2014). Generating cartilage repair from pluripotent stem cells. Tissue Eng Part B Rev. 20, 257-66. PubMed
Cheng, A., Kapacee, Z., Peng, J., Lu, S., Lucas, R.J., Hardingham, T.E. and Kimber, S.J. (2014). Cartilage Repair Using Human Embryonic Stem Cell-Derived Chondroprogenitors. Stem Cells Transl Med. 3, 1287-94. PubMed
Dunn, S.L., Soul, J., Anand, S., Schwartz, J-M., Boot-Handford, R.P. and Hardingham, T.E. (2016). Gene Expression Changes in Damaged Osteoarthritic Cartilage Identify a Signature of Non-chondrogenic and Mechanical Responses. Osteoarthritis Cartilage (in press) 10.1016/j.joca.2016.03.007