Department of Veterinary Clinical Pathology, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, 1 Kangwondaehak-gil, Chuncheon, Gangwon-do, 24341, Republic of Korea.
Bioanalysis Center, GenNBio Inc., 700, Daewangpangyo-ro, Bundang-guGyeonggi-do, Seongnam-si, 13488, Republic of Korea.
Stem Cell Res Ther. 2023 Oct 4;14(1):283. doi: 10.1186/s13287-023-03523-0.
Rheumatoid arthritis (RA) is a chronic and systemic autoimmune disease characterized by synovial inflammation-mediated progressive destruction of the cartilage and bone, resulting in reduced quality of life. We primed human telomerase reverse transcriptase-overexpressing immortalized human adipose tissue-derived mesenchymal stem cells (iMSCs) with serum derived from a non-human primate RA model and studied the immunomodulatory ability of exosomes obtained from primed iMSCs.
After immunophenotyping, nanoparticle tracking analysis, and in vitro functional tests, Dulbecco's phosphate-buffered saline (dPBS, Group C), exosomes derived from the supernatant of iMSCs (Exo-FBS, Group E), exosomes derived from the supernatant of iMSCs primed with RA serum (Exo-RA, Group F), and methotrexate (Group M) were administered in collagen-induced arthritis (CIA) model mice. dPBS was administered to the normal (N) group for comparison (n = 10/group).
Exo-RA had a significantly higher number of exosomes compared to Exo-FBS when measured with nanoparticle tracking analysis or exosome marker CD81, and Transforming growth factor-β1 amounts were significantly higher in Exo-RA than in Exo-FBS. When Exo-FBS or Exo-RA was administered to the collagen-induced arthritis model, serum interleukin (IL)-4 and the proportion of Th2 (CD4+CD25+GATA3+) and M2 (CD11c - CD206+ of CD45+CD64+) cells were significantly increased compared to the control group. Furthermore, Exo-RA could alleviate cartilage damage by significantly lowering the concentrations of proinflammatory cytokines such as tumor necrosis factor-α, keratinocyte chemoattractant, and IL-12p70.
Exosomes derived from disease-condition-serum-primed iMSCs ameliorated cartilage damage in a RA model by enhancing TGF-β1 production, inducing Th2 and M2 polarization and lowering proinflammatory cytokines, TNF-α, KC, and IL-12p70 in the host. Patient-derived serum can be used as an iMSC priming strategy in iMSC-derived exosome treatment of RA.
类风湿关节炎（RA）是一种慢性和系统性自身免疫性疾病，其特征为滑膜炎症介导的软骨和骨进行性破坏，导致生活质量下降。我们用来源于非人灵长类 RA 模型的血清对人端粒酶逆转录酶过表达的永生化人脂肪组织源性间充质干细胞（iMSC）进行预刺激，研究了预刺激 iMSC 来源的外泌体的免疫调节能力。
在免疫表型分析、纳米颗粒跟踪分析和体外功能测试后，用磷酸盐缓冲液（Dulbecco's phosphate-buffered saline，D-PBS，C 组）、iMSC 上清液来源的外泌体（Exo-FBS，E 组）、iMSC 上清液来源的 RA 血清预刺激的外泌体（Exo-RA，F 组）和甲氨蝶呤（M 组）处理胶原诱导性关节炎（CIA）模型小鼠。用 D-PBS 处理正常（N）组作为对照（每组 n=10）。
与 Exo-FBS 相比，用纳米颗粒跟踪分析或外泌体标记物 CD81 测量时，Exo-RA 中的外泌体数量明显更多，并且 Exo-RA 中的转化生长因子-β1 含量明显高于 Exo-FBS。当将 Exo-FBS 或 Exo-RA 给予胶原诱导性关节炎模型时，与对照组相比，血清白细胞介素（IL）-4 和 Th2（CD4+CD25+GATA3+）和 M2（CD11c−CD206+CD45+CD64+）细胞的比例明显增加。此外，Exo-RA 可通过显著降低促炎细胞因子（如肿瘤坏死因子-α、角质细胞趋化因子和 IL-12p70）的浓度来减轻软骨损伤。
来源于疾病条件-血清-预刺激 iMSC 的外泌体通过增强 TGF-β1 的产生、诱导 Th2 和 M2 极化以及降低宿主中的促炎细胞因子 TNF-α、KC 和 IL-12p70，改善了 RA 模型中的软骨损伤。患者来源的血清可用作 iMSC 衍生外泌体治疗 RA 中的 iMSC 预刺激策略。
