Mesenchymal Stromal Cells Improve Salivary Function and Reduce Lymphocytic Infiltrates in Mice with Sjögren's-Like Disease

Abstract

BackgroundNon-obese diabetic (NOD) mice develop Sjögren's-like disease (SS-like) with loss of saliva flow and increased lymphocytic infiltrates in salivary glands (SGs). There are recent reports using multipotent mesenchymal stromal cells (MSCs) as a therapeutic strategy for autoimmune diseases due to their anti-inflammatory and immunomodulatory capabilities. This paper proposed a combined immuno- and cell-based therapy consisting of: A) an injection of complete Freund's adjuvant (CFA) to eradicate autoreactive T lymphocytes, and B) transplantations of MSCs to reselect lymphocytes. The objective of this was to test the effectiveness of CD45−/TER119− cells (MSCs) in re-establishing salivary function and in reducing the number of lymphocytic infiltrates (foci) in SGs. The second objective was to study if the mechanisms underlying a decrease in inflammation (focus score) was due to CFA, MSCs, or CFA+MSCs combined.Methodology/Principal FindingsDonor MSCs were isolated from bones of male transgenic eGFP mice. Eight week-old female NOD mice received one of the following treatments: insulin, CFA, MSC, or CFA+MSC (combined therapy). Mice were followed for 14 weeks post-therapy. CD45−/TER119− cells demonstrated characteristics of MSCs as they were positive for Sca-1, CD106, CD105, CD73, CD29, CD44, negative for CD45, TER119, CD11b, had high number of CFU-F, and differentiated into osteocytes, chondrocytes and adipocytes. Both MSC and MSC+CFA groups prevented loss of saliva flow and reduced lymphocytic infiltrations in SGs. Moreover, the influx of T and B cells decreased in all foci in MSC and MSC+CFA groups, while the frequency of Foxp3+ (Treg) cell was increased. MSC-therapy alone reduced inflammation (TNF-α, TGF-β), but the combination of MSC+CFA reduced inflammation and increased the regenerative potential of SGs (FGF-2, EGF).Conclusions/SignificanceThe combined use of MSC+CFA was effective in both preventing saliva secretion loss and reducing lymphocytic influx in salivary glands.

Inflammation in Post-Traumatic Stress Disorder (PTSD): A Review of Potential Correlates of PTSD with a Neurological Perspective

“…Although there had been no associations found between levels of IL-1β, IL-6, and TNF-α and amygdala activity as measured by FDG signal, findings from the study by Toczek and colleagues (2019) reported a significant correlation among FDG signal in the amygdala, spleen and bone marrow [92]. The spleen and bone marrow are closely related organs that are also described as lymphoid organs [96,97] and have been previously described as key factors in the immune system as immune cells migrate across the spleen [97], while the bone marrow is the production site for lymphocytes [98]. As such, while proinflammatory cytokine levels did not alter in association with FDG signal of the amygdala in this study, correlation between FDG signals within lymphoid organs and the amygdala in individuals with PTSD may implicate inflammatory responses within the brain that results from trauma.…”

Mesenchymal Stromal Cells to Halt the Progression of Type 1 Diabetes?

“…MSCs may in this manner promote tissue repair and provide immunosuppressive or immunomodulatory changes. Signals of injury in tissues e.g., cytokines such as tumor necrosis factor-α, interleukin-1, interferon-γ, and hypoxia trigger a variety of growth and angiogenetic factors secreted from the MSCs, including epidermal growth factor [31][32][33], platelet-derived growth factor [34], fibroblast growth factor [32,35], transforming growth factor-β [36], vascular endothelial growth factor [37,38], hepatocyte growth factor [39], insulin-like growth factor-1 [32], angiopoietin-1 [40], erythropoietin [41], glial cell line-derived neurotrophic factor [42], stem cell-derived factor-1 [43], and interleukin-8 [32]. All these paracrine factors orchestrate wound healing, angiogenesis, and tissue repair irrespective of the cause of tissue injury, including those forms not directly immune cell related e.g., recovery from myocardial infarction [44,45].…”

Sjögren’s syndrome versus IgG4-related diseases – classification difficulties and treatment progress

“…A reduction in inflammation in the salivary glands was noted, demonstrated by a decrease in TNF-α and TGF-β concentrations. Regeneration of the salivary glands was also observed, evidenced by an increase in FGF (fibroblast growth factor) and EGF (epidermal growth factor) concentrations [54]. Another study showed that both mice and human subjects had reduced inflammatory infiltration in the salivary glands, increased saliva output, a reduction in disease activity assessed by means of the SSDAI scale (Sjögren's syndrome disease activity index) and a reduction in the level of anti-Ro/SSA antibodies [55].…”