Infusion of GMSCs relieves autoimmune arthritis by suppressing the externalization of neutrophil extracellular traps via PGE2-PKA-ERK axis.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone destruction. Accumulating evidence has shown that neutrophil extracellular traps (NETs) released by activated neutrophils are important for initiating and perpetuating synovial inflammation and thereby could be a promising therapeutic target for RA. K/B × N serum transfer-induced arthritis (STIA) is a rapidly developed joint inflammatory model that somehow mimics the inflammatory response in patients with RA. Human gingival-derived mesenchymal stem cells (GMSCs) have been previously shown to possess immunosuppressive effects in arthritis and humanized animal models. However, it is unknown whether GMSCs can manage neutrophils in autoimmune arthritis. OBJECTIVES: To evaluate whether infusion of GMSCs can alleviate RA by regulating neutrophils and NETs formation. If this is so, we will explore the underlying mechanism(s) in an animal model of inflammatory arthritis. METHODS: The effects of GMSCs on RA were assessed by comparing the symptoms of the K/B × N serum transfer-induced arthritis (STIA) model administered either with GMSCs or with control cells. Phenotypes examined included clinical scores, rear ankle thickness, paw swelling, inflammation, synovial cell proliferation, and immune cell frequency. The regulation of GMSCs on NETs was examined through immunofluorescence and immunoblotting in GMSCs-infused STIA mice and in an in vitro co-culture system of neutrophils with GMSCs. The molecular mechanism(s) by which GMSCs regulate NETs was explored both in vitro and in vivo by silencing experiments. RESULTS: We found in this study that adoptive transfer of GMSCs into STIA mice significantly ameliorated experimental arthritis and reduced neutrophil infiltration and NET formation. In vitro studies also showed that GMSCs inhibited the generation of NETs in neutrophils. Subsequent investigations revealed that GMSCs secreted prostaglandin E2 (PGE2) to activate protein kinase A (PKA), which ultimately inhibited the downstream extracellular signal-regulated kinase (ERK) pathway that is essential for NET formation. CONCLUSION: Our results demonstrate that infusion of GMSCs can ameliorate inflammatory arthritis mainly by suppressing NET formation via the PGE2-PKA-ERK signaling pathway. These findings further support the notion that the manipulation of GMSCs is a promising stem cell-based therapy for patients with RA and other autoimmune and inflammatory 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.

Erratum: Human gingiva tissue-derived MSC ameliorates immune-mediated bone marrow failure of aplastic anemia via suppression of Th1 and Th17 cells and enhancement of CD4+Foxp3+ regulatory T cells differentiation.

[This corrects the article on p. 7627 in vol. 11, PMID: 31934306.].

Human gingiva tissue-derived MSC ameliorates immune-mediated bone marrow failure of aplastic anemia via suppression of Th1 and Th17 cells and enhancement of CD4+Foxp3+ regulatory T cells differentiation.

Accumulating evidence has revealed that human gingiva-derived mesenchymal stem cells (GMSCs) are emerging as a new line of mesenchymal stem cells and may have the potential to control or even treat autoimmune diseases through maintaining the balance between Th and Treg cells. Given that GMSCs have a robust immune regulatory function and regenerative ability, we investigated the effect of GMSCs on preventing T cell-mediated bone marrow failure (BMF) in a mouse model. We observed that GMSCs markedly improved mice survival and attenuated histological bone marrow (BM) damage. Moreover, we found GMSCs significantly reduced cell infiltration of CD8+ cells, Th1 and Th17 cells, whereas increased CD4+Foxp3+ regulatory T cells (Tregs) differentiation in lymph nodes. GMSCs also suppressed the levels of TNF-α, IFN-γ, IL-17A and IL-6, but IL-10 was increased in serum. The live in vivo imaging identified that GMSCs can home into inflammatory location on BM. Our results demonstrate that GMSCs attenuate T cell-mediated BMF through regulating the balance of Th1, Th17 and Tregs, implicating that application of GMSCs may provide a promising approach in prevention and treatment of patients with aplastic anemia.