4. Analysis of factors influencing the function of GMSC

Only well preserved the comprehensive and stable features, GMSCs can be an alternative cell therapy to autoimmune and inflammation-related diseases. Many factors can disturb the functions of GMSCs. Su et al. reported disturbed oral microbiome weakened the wound healing of GMSCs through miR-21/Sp1/telomerase reverse transcriptase pathway [66]. The physical condition of donors is a key factor to properties of GMSCs. Assem et al. revealed that GMSCs exhibited a greater proliferation rate and higher surviving in normal individuals than the diabetic patients [67]. Moreover, GMSCs exosome from diabetic mice showed reduced IL-1RA and decreased Fas expression when compared to WT GMSCs [40]. Different culture techniques of GMSCs have a profound effect on their biological functions. Subbarayan et al. showed that GMSCs derived spheroids enhanced abilities of viability, pluripotency and multi-lineages and maintained the properties of stem cells convincingly than conventional culture methods [68]. Zhang et al. have confirmed that spheroid-derived GMSCs possessed better therapeutic efficacy than their adherent counterpart [69]. The spheroid-derived GMSCs also had a greater homing ability to mucositis sites and underwent a higher mesenchymal-epithelial transformation compared to conventional culture GMSC in murine model of chemotherapy-induced oral mucositis [69]. Although normal and inflammatory GMSCs similarly expressed mesenchymal stem cells markers and proliferation ability, inflammatory microenvironments indeed reduced differentiation potentials of GMSCs [70]. Zhang et al. demonstrated that initial inflammatory stimuli of IL-1 and TNF-α appeared essential for GMSCs proliferation and tissue regeneration, while with inflammatory persistence, this effect turned to osteogenesis followed by a short-term stimulatory [71]. However, Apatzidou et al. demonstrated that GMSCs from periodontal granulation tissue possessed similar immunophenotype and regeneration feature to those in healthy periodontal tissue [72]. Many studies have also demonstrated that other elements also affect the biological characteristics of GMSCs, for instance, Lee et al. reported that dexamethasone accelerated the aging of GMSCs through downregulating SIRT1 and IL6 and upregulating EDN1 genes via the AGE/RAGE pathway [73]. In addition, hypoxic enhanced the suppressive effects of GMSCs on peripheral blood mononuclear cells and inhibited the local inflammation of injured skin by suppressing the inflammatory cells, accompanying with reduction of TNF-α and increase of IL-10 [74].
