Chronic Inflammation-Induced Senescence Impairs Immunomodulatory Properties of Synovial Fluid Mesenchymal Stem Cells in Rheumatoid Arthritis

Abstract

BackgroundAlthough immunomodulation properties of mesenchymal stem cells (MSCs) has been highlighted as a new therapy for autoimmune diseases, including rheumatoid arthritis (RA), the alteration of disease-specific characteristics of MSCs derived from elderly RA patients are not well understood. MethodsWe established the MSCs derived from synovial fluid (SF) from age-matched early (average duration of disease: 1.7 years) and long-standing (average duration of disease: 13.8 years) RA patients (E-/L-SF-MSCs) and then comparatively analyzed the characteristics of MSCs such as stemness, proliferation, cellular senescence, in vitro differentiation and in vivo immunomodulation properties.ResultsThe presence of MSC populations in the SF from RA patients was identified and we found that L-SF-MSCs exhibited impaired proliferation, intensified cellular senescence, reduced immunomodulation properties and attenuation of anti-arthritic capacity in an RA animal model than E-SF-MSCs. In particular, E-SF-MSCs demonstrated cellular senescence progression and attenuation of immunomodulation properties at similar levels to that of L-SF-MSCs in an RA joint mimicking milieu due to hypoxia and pro-inflammatory cytokine exposure. Due to long-term exposure to the chronic inflammation milieu, the progression of cellular senescence, attenuation of immunomodulation properties and loss of anti-arthritic potentials are more often identified in SF-MSCs of long-standing RA than early RA. ConclusionWe conclude that a chronic RA inflammation milieu affected the potential of MSCs; therefore, this work addresses the importance of understanding MSC characteristics during disease states prior to their application in patients.