Scaling Up Mesenchymal Stromal Cell Extracellular Vesicle Production for Therapeutic Application in Rheumatoid Arthritis
Rebecca Davies, Claire Mennan, Karina Wright, Charlotte Hulme, Mark Platt†, Oksana Kehoe
†Loughborough University
Funded by the Orthopaedic Institute James Richardson Studentship, Keele University and EPSRC/MRC Centre for Doctoral Training in Regenerative Medicine
We work with the goal of finding effective therapies for rheumatoid arthritis (RA), hoping to combat the inappropriate activation of the immune system at its root. One potential therapy involves the use of a certain type of cell, mesenchymal stromal cells (MSCs), that show great promise in restoring balance to a wayward immune system. Unfortunately, cell therapy is not as straight forward as we could hope. It is not a simple process to store the cells, something which could impact their immune restoring potential, and they are highly receptive to their environment, meaning they could be influenced by a rheumatic joint and end up adding to the problem.
Our solution is extracellular vesicles (EVs) – see Figure 1. These are very small particles that all cells use to talk with each other. Therefore, they contain information which reflects the abilities of their parental cells – kind of like biological Royal Mail – see Figure 2. This means that EVs isolated from MSCs could restore balance to the immune system without injecting the cell itself. Moving towards with the goal of making MSC-EVs available to patients, we have been studying them to understand their contents, find ways to increase their production to make treating patients with them feasible and testing whether they would truly be effective in treating RA.
We have now thoroughly characterised our EVs and found promising ways to increase their production, predominantly by combining MSCs from different people, which encourages the cells to ‘talk’ to each other and increase EV yields. This method of production also seemed to have promising effects when introduced in pre-clinical models of RA, significantly decreasing the swelling and signs of an overactive immune system in the joints – see Figure 3. This is now being translated to patients as we begin to test the effectiveness of MSC EVs when added to the immune cells isolated from patients with RA.
It is our hope that MSC EVs could provide a promising new treatment to the field of RA, that which is effective but lacks the disadvantages of current medications. For example, EVs could replace the use of steroids during joint flares, which are associated with certain side effects such as high blood pressure or increased infection rates. Nonetheless, it is our hope that this work contributes to the wider knowledge of this field, bringing us one step closer to EV therapies for the future benefit of all patients with immune based disorders.
Figure 1. Images of mesenchymal stromal cells in cell culture (A), versus their isolated extracellular vesicles (B)
Figure 2. EV-Press Mail: a visual representation of the structure of extracellular vesicles and their ability to act as ‘letters’ to neighbouring cells, depicted in a format submitted for the purposes of communicating science in an engaging manner
Figure 3. The results of studies involving pre-clinical model of arthritis in which swelling was highly decreased when combining cells from many people and isolating their extracellular vesicles (pooled EVs, orange) to treat the rheumatic joint (A) as well as lessening the amount of immune cells (immune cell infiltration), inappropriate cell growth (synovial thickening) and cartilage damage in the joint (B)