Tumor necrosis factor receptor 1 is required for human umbilical cord-derived mesenchymal stem cell-mediated rheumatoid arthritis therapy

Abstract

Abstract Background Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) can relieve the symptoms of rheumatoid arthritis. However, we did not know whether TNFR1 expressed by hUC-MSCs contributes to therapy as a neutralizer of TNF-α or whether TNFR1 has more roles. This study aimed to explore the functions of TNFR1 in hUC-MSC-mediated RA therapy. Methods We knocked down TNFR1 in hUC-MSCs and compared the ability of MSCs to inhibit TNF-α production by PBMCs. hUC-MSCs with or without TNFR1 knockdown were infused into collagen-induced arthritis mice to compare RA therapeutic effects. The inflammatory cytokine levels at different timepoints after cell treatment were measured, and hematoxylin and eosin (H&E) staining was performed to observe the pathological differences. After confirming the importance of TNFR1 in RA treatment, we stimulated hUC-MSCs with different inflammatory cytokines to observe how TNFR1 responds and compare whether any genes were influenced by the presence or absence of TNFR1. Results In vitro PMBC experiments showed that the inhibition of TNF-α production was dependent on TNFR1 expression. hUC-MSCs could relieve symptoms of RA in animals in a TNFR1-dependent manner. Inflammatory cytokine simulation revealed that TNFR1 was reduced after 24 h of stimulation in hUC-MSCs, while siTNFR1-MSCs showed upregulation of TNFR1 after the same treatment. In addition, impairment of TNFR1 expression led to different expression levels of p65, TLR2, HGF, and KGF in MSCs. Conclusions Reduced TNFR1 alters gene expression and leads to the loss of therapeutic effects.