Human cell therapies in preclinical and clinical studies of cartilage repair

Abstract

Cell therapy offers potential to repair and regenerate damaged tissues. An established example of its use in the clinic is for treating cartilage defects. This thesis addresses this topic, both studying the use of imaging in such patients having had cell therapy and assessing a potential future development of an improved allogeneic cell therapy in preclinical models of cartilage/joint injury. Osteoarthritis (OA) is a complex degenerative joint disease, characterised by pain, articular cartilage degradation, joint space narrowing, and often subchondral bone changes. Currently, there are no effective pharmaceutical or non-surgical therapies to reverse osteoarthritis. Focal chondral or osteochondral lesions commonly progress to OA and recently NICE recommended autologous chondrocyte implantation (ACI) for the treatment of such defects. Autologous cell therapy products are much more restrictive in terms of production costs, logistics and donor site morbidity than an allogeneic cell therapy product. Hence, development of an allogeneic treatment could have many advantages, with cells sourced from tissues earlier in development having potential advantages over those obtained from more mature individuals. In this thesis, human mesenchymal stromal cells (MSCs) sourced from umbilical cords (hUC-MSCs) have been used in two pre-clinical murine models, one representing end stage OA (the partial medical meniscectomy model (PMM)) and the other a ‘focal’ chondral defect, (the joint surface injury model (JSI)); the latter is akin to defects which ACI was developed to treat. Human bone marrow MSCs (hBMMSCs) were used as the “gold standard” in the JSI model to compare the effects of the hUCMSCs as they are already used in therapeutic applications.
Individual donor hUC-MSCs were used in the PMM model, whereas 3 donors’ MSCs were pooled in the JSI model prior to transplantation. Histology and imaging (via microcomputerised tomography (CT)) were the main means of assessments used. Neither hUCMSCs nor hBM-MSCs, elicited an inflammatory response in vivo in the murine pre clinical models as assessed by histology or inflammatory marker analysis. Both populations of hMSCs significantly improved cartilage repair in the JSI model when compared to no cell controls, whereas in the more severe PMM model, the transplanted hUC-MSCs did not result in less joint damage histologically.
Imaging studies are crucial for the correct diagnosis, treatment and monitoring of joint disease. High resolution micro-CT was employed in the PMM model to determine if the implanted hUC-MSCs affected joint degeneration associated with OA. A beneficial change (reduced joint space narrowing) was seen with only one population of hUC-MSCs, indicating the importance of donor cell characterisation for allogeneic cell therapies and also that cell therapy is not appropriate for severely osteoarthritic joints.
Clinical imaging, specifically Magnetic Resonance Imaging (MRI) and CT, are used to help surgeons decide the best course of treatment for patients with articular cartilage (AC) defects or early OA in the knee and to follow NICE guidelines. One of these is that ACI is appropriate for treating defects greater than 2cm2 in size. Hence an accurate estimate of the area of the defect to be treated is important both clinically and financially (for reimbursement reasons). This thesis delved into the accuracy of pre-operative MR imaging at predicting cartilage defect sizes at the time of surgical intervention post debridement (removal of damaged AC tissue). Taking the whole abnormal cartilage region into account, rather than just the full thickness component of the AC defect, better estimates the actual defect size for treatment.
At present, despite the recent emergence of CT as a method of OA imaging, MRI remains the pre-eminent technique for assessing damage to the joint’s components. Therefore, this thesis aimed to determine whether using CT could provide additional information for appropriate treatment selection and monitoring of patients with chondral/osteochondral lesions and OA, as well as developing and assessing a semi-quantitative score. Results indicate that while MRI is best for assessing changes in articular cartilage, CT is best for alterations in the bone, such as subarticular cysts and osteophytes. Hence employing both imaging modalities provides a greater insight into the biological processes throughout the joint. Furthermore, when MRI is not available, CT can be used to provide a reliable and cheaper semi-quantitative score relating to the health of the patient’s knee joint.