Liu Guangyang, Wang Herui, Zhang Chenliang, Li Xin, Mi Yi, Chen Yaoyao, Xu Liqiang, Miao Li, Long Haomiao, Liu Yongjun
Stem Cell Biology and Regenerative Medicine Institution, Yi-Chuang Institute of Bio-Industry, Beijing, China.
Cell Transplant. 2025 Jan-Dec;34:9636897241301703. doi: 10.1177/09636897241301703.
Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease characterized by altered levels of inflammatory cytokines. One of the key cytokines involved in the pathogenesis of RA is tumor necrosis factor α (TNF-α), which plays a crucial role in the differentiation of T cells and B cells and serves as a primary trigger of inflammation and joint damage in RA. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have shown potential in alleviating the symptoms of RA. Previous studies indicate that TNF-α secreted by T cells can activate NF-κB in human MSCs, thereby triggering the immunoregulatory capacity of MSCs in a manner dependent on tumor necrosis factor receptor 1 (TNFR1). Inspired by these findings, we aimed to evaluate whether TNFR1 determine the therapeutic effects of hUC-MSCs on RA. First, we investigated whether TNFR1 is necessary for hUC-MSCs to inhibit TNF-α production of PBMCs, a source of elevated TNF-α in patients. Through coculture experiment, we confirmed that this inhibition was dependent on TNFR1. Subsequently, we administered hUC-MSCs or siTNFR1-MSCs to DBA/1J male mice with collagen-induced arthritis. The results indicated that hUC-MSCs significantly alleviated the pathological features of RA and suppressed the inflammatory cytokines IFN-γ, TNF-α, and IL-6 in peripheral blood, also in a manner dependent on TNFR1 either. Given the dramatic pathologic differences between hUC-MSCs and siTNFR1-MSCs treatments, we questioned whether production of growth factors and chemokines was significantly influenced by TNFR1. Consequently, we stimulated hUC-MSCs or siTNFR1-MSCs through IFN-γ, TNF-α, and IL-6, and profiled growth factors and chemokines in serum, which revealed significant changes of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF), as well as chemokines CXCL9, CXCL10, IL-8, and RANTES. In summary, our findings suggest that TNFR1 may determine whether hUC-MSCs will gain abilities of anti-inflammation and tissue regeneration.
类风湿性关节炎（RA）是一种全身性慢性炎症性疾病，其特征在于炎症细胞因子水平的改变。参与RA发病机制的关键细胞因子之一是肿瘤坏死因子α（TNF-α），它在T细胞和B细胞的分化中起关键作用，并作为RA炎症和关节损伤的主要触发因素。人脐带间充质干细胞（hUC-MSCs）已显示出缓解RA症状的潜力。先前的研究表明，T细胞分泌的TNF-α可激活人骨髓间充质干细胞中的NF-κB，从而以依赖肿瘤坏死因子受体1（TNFR1）的方式触发骨髓间充质干细胞的免疫调节能力。受这些发现的启发，我们旨在评估TNFR1是否决定hUC-MSCs对RA的治疗效果。首先，我们研究了TNFR1对于hUC-MSCs抑制PBMCs（患者体内TNF-α升高的来源）产生TNF-α是否必要。通过共培养实验，我们证实这种抑制作用依赖于TNFR1。随后，我们将hUC-MSCs或siTNFR1-MSCs给予患有胶原诱导性关节炎的DBA/1J雄性小鼠。结果表明，hUC-MSCs显著减轻了RA的病理特征，并抑制了外周血中的炎症细胞因子IFN-γ、TNF-α和IL-6，同样也是以依赖TNFR1的方式。鉴于hUC-MSCs和siTNFR1-MSCs治疗之间存在显著的病理差异，我们质疑生长因子和趋化因子的产生是否受到TNFR1的显著影响。因此，我们通过IFN-γ、TNF-α和IL-6刺激hUC-MSCs或siTNFR1-MSCs，并分析血清中的生长因子和趋化因子，结果显示肝细胞生长因子（HGF）、角质形成细胞生长因子（KGF）以及趋化因子CXCL9、CXCL10、IL-8和RANTES有显著变化。总之，我们的研究结果表明，TNFR1可能决定hUC-MSCs是否具有抗炎和组织再生能力。
