HUMAN UMBILICAL CORD MESENCHYMAL STROMAL CELLS AS AN INJECTABLE FOR OSTEOARTHRITIS

Claire Mennan, Jade Perry, Karina Wright, Charlotte Hulme, Jamie McDonald, Emma Rand (York), Paul Genever (York), Karin Newall (Cambridge), Fran Henson (Cambridge) Martyn Snow, and Sally Roberts

Funded by the Orthopaedic Institute

At the RJAH we have been characterising mesenchymal stromal or stem cells (MSCs) from human umbilical cords (UC-MSCs) (see picture below) as a potential therapy for OA for the past 10 years. These are an attractive source of cells for regenerative medicine as they grow well and have anti[1]inflammatory properties and have been used in humans in many clinical trials around the world. We have been working with collaborators at Cambridge University to see if these cells could delay osteoarthritis (OA) in their early-stage pre-clinical OA model. We used this model to examine the effect of a single injection of human UC-MSCs to see if they can help repair or regenerate damaged joints and whether the cells reduce joint inflammation and pain. Results showed that there was significantly less OA observed on X-rays when UC-MSCs were used as a treatment. The data from these studies show that UC-MSCs could be an excellent ‘off the-shelf’ source of cells for the treatment of OA in the clinic, especially for patients with very early OA or an injured knee joint, which is likely to lead to OA in the future.

We have identified a group of patients who we feel would benefit greatly from treatment with these cells, those that have suffered an injury to the Anterior Cruciate Ligament (ACL). However, within this large group of often younger patients, there is a further subgroup for whom UCMSC therapy would be best suited to. The knee joint in these patients often has a lot of inflammation, both from the injury itself and sometimes from the surgery to treat it. Some of these patients have inflammation that never resolves and who may need extra help in the form of a cell therapy. Our studies indicate that an injection of UCMSCs into the joint may reduce inflammation and aid cartilage repair, thereby breaking the vicious cycle of joint damage that can lead to OA. We feel that now is the time to prepare for using these cells in a clinical trial in patients. Changing from growing UCMSCs in a research laboratory, such as we have done, to a ‘clean’ lab for treating patients requires a lot of additional but often unseen work. For example, some of the reagents which we have used to date come from animals (e.g. cattle) or are not approved for use in humans by the Regulatory Authorities.

To date we have recruited 15 out of our 30 planned ACLR patients as part of our current funding and we have also retested our existing banked samples of synovial fluid from ACI patients for 4 markers indicative of inflammation and cartilage breakdown. Results from this will help us with the ACLR cohort analysis as the ACI group of patients can be studied as an injury model due to the stage 1 and stage 2 procedures involved. We have added Shrewsbury and Telford Hospitals (SaTH) to our existing ethics studies on umbilical cord and to our Orthopaedic Tissues for Research (OTFR) as a sample collection site. This will allow us to collect many more samples for our research, from the maternity unit at Telford and from the acute knee injury clinic at Shrewsbury which will benefit this project and others greatly.

We have successfully used RNA-sequencing analysis in collaboration with York university to assess the potency of cells isolated from different donors’ umbilical cords. This analysis revealed large donor variation in response to priming with pro-inflammatory cytokines (to simulate the inflammatory joint environment) and also likely predicted biological pathways of disease disruption from the UC-MSCs (see picture insert). Priming hUC-MSCs with pro-inflammatory cytokines induced the up-regulation of genes of biological pathways primarily involved in the regulation of immune response, including lymphocyte proliferation and regulation of T-cell cytokine production. This may help to elucidate the mechanisms of action of UC-MSC transplantation for prevention of OA or its early treatment.