Accumulating evidence has shown that systemic infusion of BMMSCs induced significant immunomodulatory effects in inflammatory and autoimmune diseases. These effects include inhibiting proliferation of immune system cells, such as dendritic cells (DCs), T cells, plus natural killer (NK) cells, promoting Foxp3

+

regulatory T (Treg) cells in both function and proliferation [

14

16

]. The particular immunomodulatory properties of MSCs are further associated with cell-cell contact

via

Fas/FasL apoptosis pathways or the creation of a variety of cytokines and chemokines, such as interleukin (IL)-10, nitric oxide (NO), tumor necrosis factor-inducible gene six (TSG-6), prostaglandin E2 (PGE2), and transforming growth element (TGF)-β [

14

,

17

19

]. These ‘ immunologically privileged’ craniofacial MSCs possess immunomodulatory properties that are comparable or better than those of bone marrow counterparts

via

different systems (Fig.  

1

), which make them promising alternative cell resources for immunotherapy.

Fig. 1

Immunomodulatory properties of craniofacial MSCs. Craniofacial MSCs target many subsets of innate and adaptive immune cells, which includes helper T-lymphocytes (Ths), CD8 + T cells, dentritic cells (DCs), macrophages, mast cells, and regulatory T-lymphocytes (Treg). These effects might be mediated by soluble factors secreted by MSCs, for example prostaglandin E2 ( PGE2 ), transforming growth factor-β 1 ( TGF-β ), nitric oxide ( SIMPLY NO ), and indoleamine 2, 3-dioxygenase ( IDO ), or in a cell-cell contact-dependent manner, inducing T-cell apoptosis through the Fas/FasL pathway. GM-CSF granulocyte-macrophage colony exciting factor, IFN interferon, IL interleukin

Dental pulp stem cells

Since Gronthos et al. 1st identified DPSCs in 2000, experimental and clinical proof has shown that DPSCs are able to regenerate a dentin/pulp-like complicated and bone tissue, and display strong immunosuppressive capability [ 5 ]. DPSCs inhibit proliferation of T tissue more effectively than BMMSCs [ 20 ]. Moreover, DPSCs prevent peripheral blood mononuclear cell (PBMC) proliferation in an allogeneic mixed lymphocyte reaction (MLR) via secreting soluble aspects such as TGF-β, hepatocyte growth factor (HGF), and indoleamine 2, 3-dioxygenase (IDO) [ 21 ]. This immunosuppressive action makes DPSCs better candidates for suppression of To cell-mediated reactions in allogeneic bone marrow transplantation. Additionally , DPSCs induced activated T-cell apoptosis in vitro with the Fas/FasL pathway and ameliorated inflammatory injuries when systemically infused into a murine colitis model.

Gingiva-derived MSCs

Zhang ou al. isolated and identified a distinct population of MSCs from gingiva (GMSCs) which can be conveniently acquired from thrown away gingiva samples [ 9 ]. In addition to higher proliferation plus regeneration capacities than BMMSCs, the immunomodulatory abilities associated with GMSCs have attracted extensive attention [ 9 ]. A number of studies have investigated the immunomodulatory effects of GMSCs and their particular interplay with innate and adaptive immune cells. GMSCs display suppressive effects on proliferation and activation associated with PBMCs in a cell-cell contact-independent manner, apparently mediated through IDO, whereas interferon (IFN)-γ or co-culture with turned on T cells leads to upregulation of IDO [ 22 ]. Similar immunosuppressive effects on PBMCs stimulated by allogeneic lymphocytes in MLRs have been reported [ 23 ]. Additionally , GMSCs inhibit Th17 cell differentiation and promote Treg cell expansion [ 9 , 23 , 24 ]. The immunomodulation on To cells make GMSCs a promising alternative source of cells regarding treating inflammation and immune diseases. Systemic infusion associated with GMSCs has been shown to attenuate the dextran sulfate salt (DSS)-induced murine colitis phenotype, producing beneficiary effects like reversing body weight loss, improving overall colitis score, plus rescuing intestinal architecture. Mechanically, GMSC treatment reduced infiltration of CD4 + IFN-γ + (Th1) and CD4 + IL-17 + (Th17) cells with reduction of the inflammatory cytokines IL-17, IL-6, and IFN-γ, whereas it increased recruitment of Treg cells with increased IL-10 [ 9 ]. In addition , GMSC infusion exhibited remarkable immune tolerance and promoted the success of skin allografts through increased infiltration of Tregs [ 23 ].

Interestingly, GMSCs also exhibit immunomodulatory effects on inborn immune cells, particularly DCs, macrophages, and mast cellular material [ 24 , 25 ]. For instance, GMSCs were reported to prevent the maturation and activation of DCs via manufacturing of PGE2, which contributes to the therapeutic effect of GMSCs on hapten (oxazolone)-induced murine contact hypersensitivity (CHS). Furthermore, GMSCs also inhibit infiltration of CD8 + T cells, Th17, and mast tissues, decrease inflammatory cytokines, and induce a reciprocal improved infiltration of Treg cells via the cyclooxygenase 2 (COX2)/PGE2 axis [ 24 ]. Similar to BMMSCs, GMSCs were proved to be capable of polarizing macrophages into the M2 phenotype, which is regarded as anti-inflammatory, via enhanced secretion of IL-6 and granulocyte-macrophage colony stimulating factor (GM-CSF). Consistently, GMSCs enhance epidermis wound healing by electing polarization of macrophages to the M2 phenotype, indicating that GMSCs prepare an unique microenvironment meant for tissue repair and remodeling [ 25 ]. These results highlight the immunomodulatory functions of GMSCs on adaptive and innate immune cells and their potential program in cell-based therapy for inflammatory diseases.

Gum ligament stem cells

The periodontal ligament is a connective tissue that will connects the cementum to alveolar bone, supporting tooth in the alveolar socket and contributing to tooth nutrition plus homeostasis [ 26 ]. In 2004, Seo et ‘s. first identified PDLSCs, which can generate a cementum/periodontal ligament-like complex [ 7 ]. PDLSCs also exhibit inhibitory results on PBMC proliferation through suppressing cell division or even secreting TGF-β and HGF, but do not induce PBMC apoptosis [ 21 ]. In a co-culture system, PDLSCs had been shown to induce Treg cells, while suppressing Th17 cellular differentiation [ 27 ]. Similar to BMMSCs, PDLSCs possess reduced immunogenicity, and are negative for human leukocyte antigen (HLA)-II DR and co-stimulatory molecules. In the miniature pig periodontitis model, an allogeneic PDLSC sheet was shown to remedy periodontitis, perhaps due to low immunogenicity and secretion associated with PGE2 [ 3 ].

Stem cells from apical papilla

Originate cells from the root apical papilla (SCAP) are remote from the dental papilla located at the apex of building human permanent teeth. SCAP can form cell clusters plus undergo multilineage differentiation [ 20 ]. SCAP possess lower immunogenicity and inhibit T-cell proliferation stimulated by PHA in MLRs perhaps via soluble factors [ 20 ]. However , the immunological features of SCAP remain elusive.

Stem cells from exfoliated deciduous teeth

Miura et al. first of all isolated stem cells from human exfoliated deciduous tooth (SHED), a kind of naturally replaced tissue [ 6 ]. Along with their great capacities to proliferate and differentiate directly into osteogenic cells, adipogenic cells, and odontogenic cells, GET RID OF show remarkable immunosuppressive effects [ 4 ]. SHED screen profound capacity to inhibit Th17 cell differentiation, that might contribute to the therapeutic effects of SHED on systemic lupus erythematosus (SLE) in mice [ 4 ]. More recently, research showed that systemic infusion of SHED ameliorated the particular ovariectomy (OVX)-induced osteopenia phenotype in mice by decreasing the numbers of Th1 and Th17 cells. Mechanistically, DROP transplantation induces activated T-cell apoptosis via Wnt-β -catenin-Fas/FasL-mediated apoptosis pathways and leads to upregulation of Treg tissue and downregulation of Th1 and Th17 cells. Furthermore, the immunomodulatory capacity of SHED can be enhanced simply by acetylsalicylic acid treatment. ASA treatment elevated TERT/FASL signaling in SHED, improving the capacity of SHED-inducing T-cell apoptosis and ameliorating the DSS-induced colitis phenotype in rodents [ 28 ].

Stem cells from dental hair follicle

Stem tissue isolated from the dental follicle surrounding the developing teeth show the ability to form colonies, to express differentiated tissue guns, including nestin and Notch1, and to form periodontal ligament-like structures [ 29 ]. Stem cells from the dental hair follicle also suppress the proliferation of PBMCs, which is controlled by Toll-like receptor 4 (TLR4) agonists [ 29 ]. Further studies on the immunomodulatory properties of this cell human population are still in urgent demand.

Bone marrow come cells derived from jaw bone

Akintoye et al. compared bone marrow stem cells isolated from orofacial (maxilla and mandible) and axial (iliac crest) regions and found that will orofacial MSCs proliferate more rapidly, have delayed senescence along with higher expression level of alkaline phosphatase (ALP), and display more calcium accumulation in vitro [ 30 ]. Yamaza et al. isolated and expanded orofacial MSCs through mice and found that these orofacial MSCs showed more powerful immunosuppressive effects than BMMSCs by inhibiting T-cell expansion [ 8 ]; orofacial MSCs producing more NO might be one of the contributing factors [ 8 , 30 ].

These studies reiterate that craniofacial stem cells have a higher immunomodulation capacity than BMMSCs, indicating that they may be excellent cell sources for infectious plus inflammatory diseases. However , the mechanism underlying this unique home needs to be further investigated.