Chronic inflammation-induced senescence impairs immunomodulatory properties of synovial fluid mesenchymal stem cells in rheumatoid arthritis
Hyeon‐Jeong Lee, Won‐Jae Lee, Sun‐Chul Hwang, Yong‐Ho Choe, Saet-Byul Kim, Eun‐Yeong Bok, Sang-Yeob Lee, Seung-Joon Kim, Hyun Ok Kim, Sun‐A Ock, Hae-Sook Noh, Gyu‐Jin Rho, Gyu-Jin Rho, Sung‐Lim Lee, Sang-Yeob Lee, Sung‐Lim Lee, Sung‐Lim Lee
Abstract
BACKGROUND: Although the immunomodulatory properties of mesenchymal stem cells (MSCs) have been highlighted as a new therapy for autoimmune diseases, including rheumatoid arthritis (RA), the disease-specific characteristics of MSCs derived from elderly RA patients are not well understood. METHODS: We established MSCs derived from synovial fluid (SF) from age-matched early (average duration of the disease: 1.7 years) and long-standing (average duration of the disease: 13.8 years) RA patients (E-/L-SF-MSCs) and then analyzed the MSC characteristics such as stemness, proliferation, cellular senescence, in vitro differentiation, and in vivo immunomodulatory properties. RESULTS: The presence of MSC populations in the SF from RA patients was identified. We found that L-SF-MSCs exhibited impaired proliferation, intensified cellular senescence, reduced immunomodulatory properties, and attenuated anti-arthritic capacity in an RA animal model. In particular, E-SF-MSCs demonstrated cellular senescence progression and attenuated immunomodulatory properties similar to those of L-SF-MSC in an RA joint-mimetic milieu due to hypoxia and pro-inflammatory cytokine exposure. Due to a long-term exposure to the chronic inflammatory milieu, cellular senescence, attenuated immunomodulatory properties, and the loss of anti-arthritic potentials were more often identified in SF-MSCs in a long-term RA than early RA. CONCLUSION: We conclude that a chronic RA inflammatory milieu affects the MSC potential. Therefore, this work addresses the importance of understanding MSC characteristics during disease states prior to their application in patients.