IFN-γ regulates human dental pulp stem cells behavior via NF-κB and MAPK signaling

Abstract

During caries, dental pulp expresses a range of pro-inflammatory cytokines in response to the infectious challenge. Interferon gamma (IFN-γ) is a dimerized soluble cytokine, which is critical for immune responses. Previous study has demonstrated that IFN-γ at relative high concentration (100 ng/mL) treatment improved the impaired dentinogenic and immunosuppressive regulatory functions of disease-derived dental pulp stem cells (DPSCs). However, little is known about the regulatory effects of IFN-γ at relative low concentration on healthy DPSC behavior (including proliferation, migration, and multiple-potential differentiation). Here we demonstrate that IFN-γ at relatively low concentrations (0.5 ng/mL) promoted the proliferation and migration of DPSCs, but abrogated odonto/osteogenic differentiation. Additionally, we identified that NF-κB and MAPK signaling pathways are both involved in the process of IFN-γ-regulated odonto/osteogenic differentiation of DPSCs. DPSCs treated with IFN-γ and supplemented with pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) or SB203580 (a MAPK inhibitor) showed significantly improved potential for odonto/osteogenic differentiation of DPSCs both in vivo and in vitro. These data provide important insight into the regulatory effects of IFN-γ on the biological behavior of DPSCs and indicate a promising therapeutic strategy for dentin/pulp tissue engineering in future endodontic treatment.

Mesenchymal Stem Cells from Human Exfoliated Deciduous Teeth and the Orbicularis Oris Muscle: How Do They Behave When Exposed to a Proinflammatory Stimulus?

“…However, varied results have been reported in relation to the effect of proinflammatory stimulation on the proliferative capacity of MSCs. For example, in a study by He et al [27], it was shown that treatment of dental pulp stem cells with IFN-γ at low concentrations (0.05, 0.5, and 5 ng/mL) stimulated the proliferation and migration of this type of stem cell. On the other hand, Chan et al [28] demonstrated that compared with untreated MSCs, MSCs treated with IFN-γ for 8 days had their proliferative capacity reduced by 50%.…”

“…9 Stem Cells International 10 Stem Cells International the proliferative capacity of dental pulp stem cells were reported when these stem cells were treated with the proinflammatory cytokine TNF-α, regardless of the concentration of the cytokine in the culture medium. Regarding the possible mechanism underlying the stimulation of proliferation in MSCs after treatment with IFN-γ, He et al [27] demonstrated the occurrence of increases in PCNA and Ki-67 expression after IFN-γ treatment, indicating a high percentage of cells undergoing division. This study further demonstrated that the expression of cell cycle-promoting proteins such as Cyclin B1, Cyclin D1, and PCNA was increased, whereas the expression of proteins that inhibit cell cycle progression (such as P21) was reduced after stimulation of MSCs with IFN-γ [27].…”

“…Regarding the possible mechanism underlying the stimulation of proliferation in MSCs after treatment with IFN-γ, He et al [27] demonstrated the occurrence of increases in PCNA and Ki-67 expression after IFN-γ treatment, indicating a high percentage of cells undergoing division. This study further demonstrated that the expression of cell cycle-promoting proteins such as Cyclin B1, Cyclin D1, and PCNA was increased, whereas the expression of proteins that inhibit cell cycle progression (such as P21) was reduced after stimulation of MSCs with IFN-γ [27]. Furthermore, Qin et al [30] demonstrated that TNF-α was capable of stimulating the proliferation of human dental pulp stem cells through the Akt/Glycogen Synthase Kinase-3β/Cyclin D1 signaling pathways.…”

Strategies to improve the migration of mesenchymal stromal cells in cell therapy

“…Prestimulation with a cocktail of five cytokines containing fms-like tyrosine kinase 3 (Flt-3) ligand, stem cell factor (SCF), interleukin (IL)-6, HGF, and IL-3 promotes the migration of FLK(+) MSCs to the bone marrow through up-regulation of both cell surface and intracellular CXCR4 [71] . Other factors, such as IGF-1 [72,73] , IL 1β [74] , interferon γ (IFNγ) [4,75] , basic fibroblast growth factor (bFGF), PDGF [41] , nitric oxide donor [76] , or complement 1q (C1q) [77] have also been shown to improve MSC homing in different disease models possibly as a result of increased CXCR4 or MMP expression. Pretreating MSCs with a combination of hematopoietic growth factors erythropoietin (EPO) and granulocyte colony stimulating factor (G-CSF) can enhance their motility by increasing the MMP expression [78] .…”

“…It has been traditionally thought that MSCs reside mainly in bone marrow. However, MSCs have been recently obtained from various tissues including adipose tissue [3] , dental pulp [4] , synovium [5] , Wharton's jelly [6] , hair follicles [7] , and olfactory bulbs [8] .…”