Gingival-derived mesenchymal stem cells alleviate allergic asthma inflammation via HGF in animal models.

Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.

miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.

Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.

Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis.

Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively correlates with RA disease severity as does lipid hyperoxidation of focal monocyte/macrophages. Further study reveals high susceptibility to iron induced ferroptosis of the anti-inflammatory macrophages M2, while pro-inflammatory M1 are less affected. Distinct glutathione peroxidase 4 (GPX4) degradation depending on p62/SQSTM1 in the two cell types make great contribution mechanically. Of note, ferroptosis inhibitor liproxstatin-1 (LPX-1) can alleviate the progression of K/BxN serum-transfer induced arthritis (STIA) mice accompanied with increasing M2 macrophages proportion. We thus propose that the heterogeneous ferroptosis susceptibility of macrophage subtypes as well as consequent inflammation and immune disorders are potential biomarkers and therapeutic targets in RA.