Analysis of Stem Cell Populations in Juvenile Arthritis - Version 1
Research type
Research Study
Full title
Analysis of Stem Cell Populations in Juvenile Idiopathic Arthritis (JIA) - Version 1
IRAS ID
177467
Contact name
Eileen Baildam
Contact email
Duration of Study in the UK
3 years, 11 months, 30 days
Research summary
Research Summary
Juvenile Idiopathic Arthritis (JIA) is the collective term for arthritis of unknown cause, occurring before the 17th birthday and lasting more than 6 weeks. It is the most common rheumatic disease to occur in childhood. JIA has significant long-term effects on the child’s physical and psychological health. Major implications include chronic disease, advanced joint damage, growth impairment, impaired physical activity and absence from education.
Effective management of JIA relies on early and aggressive intervention to prevent long-term tissue damage and morbidity. Significant advances using bio-pharmaceutical interventions have been made but are expensive and require long-term treatment regimens without long-term safety data. Furthermore, variations in response to treatment have been reported. For children who do not respond to treatment, hematopoietic stem cell transplant is the last resort for achieving disease regression.
Further understanding of JIA and sJIA biology will enable 1) greater understanding of the cause of disease, 2) identification of molecules that will allow for earlier diagnosis and 3) identification of biological targets for developing more permanent and cost-effective therapeutics.
Mesenchymal stem cells (MSCs) can be isolated from diverse mesenchymal tissues and have been shown to regenerate damaged tissues. MSCs are also able to control immune reactions using a number of different mechanisms. It is known from other studies that MSCs of patients with underlying chronic pathologies (e.g. rheumatoid arthritis, heart disease and diabetes) have impaired MSC function. It is therefore likely that there is a relationship between MSCs and the onset and progression of JIA.
Our study will employ a series of laboratory techniques to characterise JIA-MSC populations in comparison to those from normal tissues in order to investigate the hypothesis that JIA-MSCs have reduced stem cell properties and impaired immunomodulatory function contributing to the onset and progression of JIA.
Summary of Results
Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatic disease of childhood, characterised by progressive joint destruction with a loss of function and severe systemic complications. Despite improvements in the clinical management of JIA, a further scientific understanding of JIA pathogenesis is required to improve diagnostic techniques and advance treatment options. Complex interactions between immune cell populations trigger the disease cascade in JIA, but there is little information regarding the contribution made by mesenchymal stem cells (MSCs). MSCs are able to modulate immune response and maintenance of self-tolerance, which alongside their regenerative properties makes them potential candidates for clinical application as immunosuppressants in treatment of autoimmune diseases. Current research provided findings that can help in understanding the mechanistic pathways of JIA and involvement of MSCs in immunopathogenesis of the disease.
This study aimed to investigate the role of MSCs in the pathogenesis of JIA. MSCs were isolated from peripheral blood and synovial fluid of JIA patients and healthy controls and populations characterised for proliferation kinetics, immunophenotype, stem cell phenotype, metabolic activity, and reactive oxygen species (ROS) production. Immunomodulatory properties of MSCs were determined by measurement of pro- and anti-inflammatory gene and protein expression and in vitro mixed lymphocyte reactions (MLRs) to quantify immune response suppression. Finally, mechanisms contributing to MSC dysfunction in JIA were investigated.
MSCs isolated from clinical tissue samples confirmed expression of cell surface antigens and stem cell transcription factors, consistent with MSC phenotype. Comparative analyses of MSCs populations showed differences between those isolated from JIA and healthy controls and between tissues. JIA-MSC colony-forming unit fibroblasts (CFU-Fs) were fewer and appeared disorganised with large cytoplasmic protrusions in contrast to the classical fibroblastic morphology of control MSCs. JIA-MSCs had a lower cell proliferation rate, impaired metabolic activity and overproduction of ROS. Gene expression analysis revealed both pro-inflammatory and anti-inflammatory genes were upregulated in JIA-MSCs. Moreover, pro-inflammatory cytokine expression was higher in plasma and synovial fluid of JIA patients. In parallel, immunoregulatory genes were overexpressed in JIA-MSCs compared to control populations. Analysis of MLR results showed that control bone marrow-derived (BM)-MSCs inhibited the proliferation of activated T-helper cells, T-suppressor cells, B-cells and natural killer cells proliferation, whereas JIA-MSCs did not. Evidence of premature cell ageing in JIA-MSCs was shown .
Taken together the results demonstrated that within the pro-inflammatory environment, JIA-MSCs experience oxidative stress and impairment of metabolic activity with overproduction of ROS, acquiring a senescencent phenotype with the upregulation of pro-inflammatory, anti-inflammatory and regulatory genes, reduction of cell proliferation and, finally, loss of the immune regulation.REC name
Wales REC 4
REC reference
15/WA/0319
Date of REC Opinion
17 Dec 2015
REC opinion
Further Information Favourable Opinion