The role of pro-inflammatory mesenchymal stem cells in rheumatoid arthritis

Rheumatoid arthritis (RA) is a common form of arthritis affecting about 1 in 100 people at some stage in their life. Rheumatoid arthritis causes inflammation, pain, and swelling of joints. It is a persistent disease and over time can damage affected joints with a severity from mild to severe. There is no cure for RA, but treatments can reduce symptoms. Treatments include disease-modifying medicines to suppress inflammation. They usually need to be taken indefinitely and may have side-effects. If disease modifying medicines do not work the alternative is biological medicine such as anti-TNF, which blocks the inflammatory response. Problem with biological medicines includes that they need to be given by injection and they are expensive. Therefore they are only given if a patient has not responded to other treatment for at least 6 months, during which time, the joint can be severely damaged. Therefore new treatments are required.
Recently a new treatment involving transplantation of stem cells has been proposed as a cure for RA. The stem cells are called mesenchymal stem cells (MSC) and and are thought to be able to stop inflammation permanently. They are taken from the bone marrow of patients or healthy volunteers, treated in the laboratory and given to the patient to stop inflammation. So far this has worked on occasion but not in all patients and not indefinitely. The same results are seen when the procedure is tested in animal models of RA. Here we want to understand why that is and determine whether we can improve this procedure to permanently stop inflammation and cure RA.
Recently scientists have discovered that there are two types of mesenchymal stem cells, ones that increase inflammation, called MSC1 and ones that stop it, called MSC2. We want to test whether with RA the number of MSC1 stem cells is greater than MSC2, and whether patients who are not responsive to current therapies have the greatest numbers of MSC1 compared to MSC2. We also want to test whether we can find ways to treat MSC1 cells in the laboratory and make them become MSC2 cells so that inflammation can be stopped when they are given to the patient. We want to test this hypothesis in animals and verify some of our findings in patients affected by RA. This will allow us to think of new ways to make transplantation of MSC in patients affected by RA more effective.

Rheumatoid arthritis (RA) is the commonest chronic inflammatory joint disease and has a prevalence of 1%. RA affects individual still in their working age and often leaves them unable to work or absent for long periods of time. Treatments are not curative and rely on disease modifying anti-rheumatic drugs (DMARDs). In UK, only if these fail the use of inhibitors of tumour necrosis factor and other biological DMARDS can be considered due to higher acquisition costs. This leaves the patient at risk of developing permanent joint damage with poor quality of life. Treatment of RA is long term with side effects due to prolonged immune-suppression and, together with the absence from work, results in high societal costs. Treating the condition early and permanently can prevent disability and cut the large cost to the economy. Mesenchymal stem cell (MSC) transplantation has been proposed as an option to overcome some of these issues. In principle, as bone stem cells MSC have the ability to repair damaged bone/joint tissue, they can migrate to the sites of inflammation and suppress immune responses in situ. MSC can do this for prolonged periods of time. However, data from experimental models and clinical case studies on efficacy have shown contrasting results. A better understanding of how MSC deliver immunosuppressive responses is needed. Recently MSC have been shown to be able to display both a pro-inflammatory (MSC1) and anti-inflammatory (MSC2) phenotype. It is unknown what MSC phenotype is predominant in RA and whether transplantation of MSC2 is more efficacious. We will address these questions both in an experimental model of RA and in RA patients. We will take advantage of novel markers to isolate MSC allowing their study directly from the tissues without the need of in vitro culture. The research will be performed by a team with unique and complementary expertise in stem cells biology, both in animal models and clinical transplantation, immunology and rheumatology.

Who will benefit from this research and how?
Rheumatoid arthritis affects approximately 1% of the population and no curative treatment is available. Despite important progress having been made it remains a chronic disease with severe morbidity and high costs to the health system and society as a whole. Stem cell treatment has high promise for the treatment of this disease. However, an understanding of the biology of mesenchymal stem cells (MSC) especially in relation to their immunological features in rheumatoid arthritis is required if protocols for transplantation are to be optimised to achieve long term efficacy. This project will benefit different groups:

1. Clinicians
Small pilot clinical trials are ongoing using mesenchymal stem cells transplantation in autoimmune diseases. These protocols are designed by trial and error rather approaches than having an understanding of the disease and what processes occur during transplantation of MSC. This research project will start to unravel some of the mechanisms.of action. A fuller understanding of whether pro-inflammatory MSC1 are involved in the development of RA or MSC2 can dampen immune responses will lead to new protocols for the expansion of MSC to obtain pure population of MSC2 before transplant and possibly conditioning regimens that will ensure this phenotype is maintained once the cells have been transplanted. This will lead to clinical trials that are better designed and therefore more informative.

2. Industrial partners
a) This project will benefit industrial partners with interests in cellular therapy as it will provide protocols for the isolation and expansion of MSC for best efficacy upon transplantation. LS has already filed patents describing protocols for isolation of MSC. He has close collaborative links with industrial partners such as Beike Biotechnology, China's leading biotechnology company on the development and commercialization of adult stem cell therapies.
b) Follow on programs based on the knowledge developed by this proposal will focus on whether it is possible to identify molecular targets able to switch from MSC1 to MSC2 directly in vivo using small molecules. Although we expect this to happen 3-5 years time, identification of novel target for pharmacological intervention will open up new markets. The applicants have experience of interacting with industrial partners, for example IB is actively involved in a new program of academic-industrial networking in Sheffield (InKForge) to enhance interactions with industrial partners and collaborations. This will be the first route to liaise with industrial partners on new candidate molecules. AGW has extensive links with pharma such as GSK and UCB.
c) The medical student in Sheffield will be encouraged to attend the workshop "commercial skills for life scientists", and the "Biotechnology Yes" competition to foster entrepreneurial skills and will be involved in all collaborative activity with industry in line with the RCUK impact strategy on training people according to the employers' needs.

3. Patients affected by RA
This project will not directly benefit patients affected by RA during the duration of this grant. However, we are committed to ensure our research is appropriately disseminated to the potential users and they are given the opportunity to express their opinion on the potential impact to their wellbeing. In Sheffield we have the Lay advisory panel for bone research, which assess research proposals and give feedback to the investigators. We will meet with them once during the duration of thios project and to discuss follow on proposals.

Funding request
In this application, we request funding for results dissemination via peer-reviewed, open access publication (£ 2,000) and expenses to cover 1 information session with the lay panel (£500)