Effects of Hypoxia on the Immunomodulatory Properties of Human Gingiva–Derived Mesenchymal Stem Cells

Abstract

The environment of bone marrow mesenchymal stem cells (MSCs) is hypoxic, which plays an important role in maintaining their self-renewal potential and undifferentiated state. MSCs have been proven to possess immunomodulatory properties and have been used clinically to treat autoimmune diseases. Here, we tested the effects of hypoxia on the immunomodulatory properties of MSCs and examined its possible underlying mechanisms. We found that hypoxic stimulation promoted the immunomodulatory properties of human gingiva-derived mesenchymal stem cells (hGMSCs) by enhancing the suppressive effects of hGMSCs on peripheral blood mononuclear cells (PBMCs). The proliferation of PBMCs was significantly inhibited, while the apoptosis of PBMCs was increased, which was associated with the Fas ligand (FasL) expression of hGMSCs. The in vivo study showed that systemically infused hGMSCs could enhance skin wound repair, and 24-h hypoxic stimulation significantly promoted the reparative capacity of hGMSCs. For mechanism, hGMSC treatment inhibited the local inflammation of injured skin by suppressing the inflammatory cells, reducing the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α), and increasing anti-inflammatory cytokine interleukin-10 (IL-10), which was promoted by hypoxia. Hypoxia preconditioning may be a good optimizing method to promote the potential of MSCs for the future cell-based therapy.

Hypoxia‐inducible factor‐1α inhibits interleukin‐6 and ‐8 production in gingival epithelial cells during hypoxia

“…As described previously, hypoxia stimulates the differentiation of dental stem cells . Hypoxia has also been reported to stimulate the immunosuppressive functions of gingival stem cells . This study demonstrates that the inflammatory response in gingival epithelial cells is under regulation by hypoxia‐induced HIF‐1α.…”

Immunomodulatory Properties of PDLSC and Relevance to Periodontal Regeneration

“…Thus, GMSCs can be easily expanded ex vivo for cell-based clinical applications but may be restricted in their applications. Furthermore, GMSCs have also been reported to possess immunomodulatory capabilities, comparable to other MSC-like populations [37,52]. GMSCs suppressed PBMNC proliferation and enhanced the expression of IL-10, IDO, inducible nitric oxide synthase, and cyclooxygenase 2, all of which are immunosuppressive factors, in response to stimulation with the inflammatory cytokine, IFN-γ.…”

“…Systemic infusion of GMSCs into an experimental colitis mouse model significantly ameliorated both the clinical and histopathological severity of the colonic inflammation mediated by the suppression of inflammatory infiltrates and inflammatory cytokine expression and inhibited regulatory T cell infiltration and IL-10 expression at the colonic sites [37]. Another study revealed that systemic infusion of hypoxiastimulated GMSCs into an excisional skin-wound-healing mouse model enhanced wound repair mediated by the suppression of inflammatory cells and pro-inflammatory cytokine expression, and an increase in IL-10 expression [52]. Although further studies are needed, GMSCs could be an attractive cell source for promoting tissue regeneration and recovery in autoimmune and inflammatory diseases.…”

Mesenchymal Stem Cells Improve Healing of Diabetic Foot Ulcer

“…This mechanism also existed in the hypoxic environment [102]. In addition, human GMSCs have elicited M2 polarization of macrophages, which may contribute to rapid reepithelialization, improvement of angiogenesis, and tissue remodeling of skin wound [101].…”