Abstract
Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent progenitor cells which reside in bone marrow (BM), support homing of hematopoietic stem cells (HSCs) and self-renewal in the BM. These cells have the potential to differentiate into tissues of mesenchymal origin, such as fibroblasts, adipocytes, cardiomyocytes, and stromal cells. MSCs can express surface molecules like CD13, CD29, CD44, CD73, CD90, CD166, CXCL12 and toll-like receptors (TLRs). Different factors, such as TGF-β, IL-10, IDO, PGE-2, sHLA-G5, HO, and Galectin-3, secreted by MSCs, induce interaction in cell to cell immunomodulatory effects on innate and adaptive cells of the immune system. Furthermore, these cells can stimulate and increase the TH2 and regulatory T-cells through inhibitory effects on the immune system. MSCs originate from the BM and other tissues including the brain, adipose tissue, peripheral blood, cornea, thymus, spleen, fallopian tube, placenta, Wharton's jelly and umbilical cord blood. Many studies have focused on two significant features of MSC therapy: (I) MSCs can modulate T-cell-mediated immunological responses, and (II) systemically administered MSCs home in to sites of ischemia or injury. In this review, we describe the known mechanisms of immunomodulation and homing of MSCs. As a result, this review emphasizes the functional role of MSCs in modulating immune responses, their capability in homing to injured tissue, and their clinical therapeutic potential.
Introduction
Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent progenitor cells, which exist in the bone marrow (BM)(CitationBen-Ami et al. 2011). They are responsible for the homing of hematopoietic stem cells (HSCs) and their self-renewal in the BM(CitationMaitra et al. 2004). These cells are capable of differentiating in vitro and in vivo into more cells of mesenchymal lineage, as well as adipocytes, chondrocytes, osteocytes, tenocytes, fibroblasts, cartilage, bone, cardiomyocytes, skeletal myocytes, visceral cells, mesoderm, ectodermal cells (e.g. neurons), endodermal cells (e.g. hepatocytes), and stromal cells(CitationKrampera et al. 2006a, CitationGebler et al. 2012, CitationWang et al. 2009).
In addition, MSCs have been found to supply cytokine and growth factor support for expansion of hematopoietic and embryonic stem cells(CitationAggarwal and Pittenger 2005). These cells, which are also well known as multipotent stromal or mesenchymal cells, were discovered by Friedenstein and his colleagues in 1970. MSCs are capable of dividing up to 50 times in about 10 weeks, in vitro(CitationLotfinegad 2014). The presence of non-hematopoietic stem cells in the bone marrow was first revealed by the observation of the German pathologist Cohnheim, 130 years ago(CitationChamberlain et al. 2007). This class of the multipotent progenitors were spindle-shaped, plastic-adherent, and non-phagocytic, with fibroblast-like morphology(CitationMohammadian and Shamsasenjan 2013).
MSCs are well-known for the expression of surface markers such as:
CD105 (SH2), CD73 (SH3, SH4), stromal antigen-1, CD90, CD44, CD166 (VCAM), CD54, CD102 (ICAM-2), and CD49 (VLA) (CitationVolarevic et al. 2011). Conversely, MSCs are distinguished from HSCs in that they lack the cell surface markers, CD11b, CD11c, CD14, CD19, CD31, CD34, CD45, CD79a, and the HLA-DR, lymphocyte function-associated antigen1(LFA1), erythrocytes (glycophorin A), platelet and endothelial cell markers. The commonly known phenotypes and markers are listed in (CitationVolarevic et al. 2011, CitationGhannam et al. 2010a, CitationShi et al. 2011). ().
Table I. Phenotypes, lineage-specific and functional markers of MSCs (Krampera et al. 2006, CitationPountos et al. 2007, CitationBühring et al. 2007, CitationDeans and Moseley 2000, CitationDevine et al. 2002, CitationFickert et al. 2004, CitationJorgensen et al. 2004, CitationOtto and Rao 2004, CitationPittenger and Martin 2004, CitationSimmons and Torok-Storb 1991, CitationBarry et al. 2001, CitationTse et al. 2003, CitationLe Blanc et al. 2003, CitationXu et al. 2004, CitationVogel et al. 2003, CitationMajumdar et al. 2003, CitationBruder et al. 1998, CitationGronthos et al. 1994, CitationPotian et al. 2003).
It is believed that MSCs are remnants of embryonic stem cells which remain in the adult human body, and express embryonic stem cell markers including: HOX, SSEA-1, Nanong, Oct-4, Rex-1 and GATA-4(CitationKrampera et al. 2006b, CitationLotfinegad 2014). In addition to the BM, MSCs originate from other sources, including the liver, lung, brain, adipose tissue, peripheral blood, cornea, synovium, thymus, dental pulp, periosteum, tendon, spleen, fallopian tube, placenta, amniotic fluid, Wharton's jelly and umbilical cord blood(CitationLotfinegad 2014). In vitro and in vivo, MSCs release IL-6, IL-7, IL-8, IL-10, IL-11, IL-12, IL-14, IL-15, sHLA-G5, PGE2, M-CSF, IDO,TGF-β, hepatocyte growth factor (HGF), inducible nitric oxide synthase (iNOS), Galectin-3, and hemooxygenase (HO). The potential for self-renewal and multipotency are the hallmarks of MSCs (CitationMohammadian and Shamsasenjan 2013, CitationShi et al. 2011, CitationMoriscot et al. 2005). Pevsner-Fischer et al. displayed that cultured MSCs express toll-like receptor (TLR) molecules 1 to 9. Activation of MSCs by TLR ligands provoked IL-6 secretion and NF-kB nuclear translocation(CitationYagi et al. 2010, CitationPevsner-Fischer et al. 2007).
It has been identified that TLRs mediate responses of bone marrow-derived progenitor cells. A new study has described the significance of TLRs in migration and immune regulation of MSCs(CitationYagi et al. 2010, CitationPevsner-Fischer et al. 2007, CitationNagai et al. 2006, CitationRyan et al. 2007). It is predicted that MSCs constitute about 0.001% of mononucleotide cells in the BM, while their proportion declines with age(CitationMohammadian and Shamsasenjan 2013, CitationKitoh et al. 2004, CitationMueller and Glowacki 2001).
This review presents the immunomodulatory mechanism of MSCs on immune cells. In addition, homing of MSCs and the current uses of these cells in medicine are discussed briefly.
Immunomodulatory effects of MSCs on immune cells
It has been agreed that the potential of MSCs to modulate immune responses is due to both cell-cell interactions and paracrine effects(CitationLotfinegad 2014). MSCs can down-regulate the strength of an immune response by influencing both natural and adaptive immunity(CitationBen-Ami et al. 2011). MSCs can inhibit innate immune system cells (DCs, NK, monocyte and neutrophil) and adaptive immune system cells (B, TH1 and T-CTL). MSCs also induce stimulation of the TH2 and regulatory T-cells by the inflammatory microenvironment.
Innate immune system cells
Natural killer cells
Natural killer cells (NK cells) are the main effector cells in inherent immunity, and are commonly thought to play a basic role in antiviral responses(CitationYagi et al. 2010). MSCs hinder the proliferation of IL-2-induced NK cells, which is mostly mediated by the soluble immunosuppressive factors, transforming growth factor-ß (TGF-ß), soluble human leukocyte antigen-G (sHLA-G), prostaglandin E2 (PGE2) and indoleamine2,3-dioxygenase, in addition to cell-cell contact(CitationBen-Ami et al. 2011, CitationGebler et al. 2012, CitationLotfinegad 2014, CitationYagi et al. 2010, CitationSpaggiari et al. 2008, CitationGonen-Gross et al. 2010, CitationAbdi et al. 2008). MSCs can exert more influence on innate immunity during their inhibition of the cytotoxicity of NK cells by down-regulating the expression of NKp30, NKp44, NKG2D and DNAM-1-activating receptors on these cells, and also by inhibiting proliferation and inducing suppression of IFN-γ(CitationBen-Ami et al. 2011, CitationSpaggiari et al. 2008, CitationSpaggiari et al. 2006). Several studies have demonstrated that MSCs suppress NK cell proliferation and IFN-ɤ production driven by IL-2 or IL-15, but only partially inhibit the proliferation of activated NK cells(CitationAggarwal and Pittenger 2005, CitationShi et al. 2011, CitationRyan et al. 2007, CitationSotiropoulou et al. 2006, CitationRasmusson et al. 2003, CitationMaccario et al. 2005). In contrast, Krampera et al. described that NK cells cultured for 4–5 days with IL-2 in the presence of MSCs showed reduced cytolytic potential against K562 cells, and this suppressive effect might be attributed to the IFN-γ produced by NK cells(CitationShi et al. 2011). Recently, Prigione et al. discovered that the inhibitory effect of MSCs on the proliferation of invariant NK T (iNKT, Vα24 + Vß11+) and γδT(Vδ2+) cells in the peripheral blood is mediated by secreting prostaglandin E2 (PGE2), before IDO and TGF-β1. On the other hand, cytokine production and cytotoxic activity of the cells were only moderately affected by MSCs. Vδ2 + cells also function as expert antigen-presenting cells for naive CD4+ T cell response, and MSCs do not restrain antigen processing/presentation of activated Vδ2 + Tcells to CD4+ T-cells. ()(CitationShi et al. 2011, CitationPrigione et al. 2009).
Figure 1. Effects of Mesenchymal stem cells (MSCs) on the innate immune system. MSCs exert an influence on a variety of cells of the immune system. Mechanisms governing these interactions include secretion of soluble paracrine factors by MSCs and direct cell–cell contact between MSCs and innate immune cells. Abbreviations: IFN gamma (interferon γ), IDO (indoleamine 2,3-dioxygenase), IL-2 (interleukin 2), IL-6 (interleukin 6), prostaglandin E2 (PGE2), transforming growth factor beta (TGFβ) TNF-α (tumor necrosis factor α), soluble human leukocyte antigen-G5 (sHLA-G5) M-CSF (monocyte-colony stimulating factor), MHC (major histocompatibility complex), KIR (killer inhibitory receptor), NK(natural killer cell), PD-1(programmed death 1), PD-L1(programmed death ligand1).
Dendritic cells
Dendritic Cells (DCs) participate with a key function in the beginning of primary immune responses, which depend on the maturation and activation steps of DCs. Immature DCs function as guards in peripheral tissues, by increased antigen uptake and processing, with low capability to stimulate T-cells(CitationYagi et al. 2010, CitationBanchereau and Steinman 1998, CitationMellman and Steinman 2001). In the past, MSCs hampered the in vitro maturation of monocytes and hematopoietic progenitor cells into DCs, in addition to down-regulating the cell surface expression of MHC class II, CD11c, CD83 and co-stimulatory molecules on mature DCs(CitationBen-Ami et al. 2011, CitationJiang et al. 2005).
MSCs may also regulate immune reaction during interaction with DCs. MSCs could inhibit differentiation of monocytes into DCs; however, they could also inhibit the maturation of DCs, giving rise to immature DCs that could consequently render T-cells anergic. MSCs have also been shown to modify the cytokine secretion profile of DCs to up-regulate regulatory cytokines, for example IL-10, and down-regulate inflammatory cytokines like IFN-ɤ, IL-12, and TNF-α, and induce further anti-inflammatory effect or tolerant DC-phenotypes(CitationAbdi et al. 2008, CitationRyan et al. 2005, CitationNauta et al. 2006). Spaggiari et al. confirmed that MSCs powerfully inhibit the maturation and functioning of immunomodulators of mesenchymal stem cell monocyte-derived DCs, by interfering selectively on the generation of immature DCs by means of inhibitory mediator MSC-derived PGE2, but not IL-6. On the other hand, the fundamental mechanism in the up-regulation of PGE2 in monocyte–MSC co-cultures remains unclear. Ramasamy et al. showed that the cell cycle in DCs was arrested in the G0/G1 phase upon contact with MSCs. A new study has reported that MSCs isolated from human adipose tissue are more potent immunomodulators for the differentiation of human DCs than MSCs derived from the BM (CitationShi et al. 2011, CitationSpaggiari et al. 2009, CitationRamasamy et al. 2007, CitationIvanova-Todorova et al. 2009). One more MSC-secreted factor, IL-6, has been reported to be involved in the inhibition of the differentiation of monocytes to DCs, diminishing their stimulatory capacity on T-cells(CitationGhannam et al. 2010b, CitationJiang et al. 2005, CitationDjouad et al. 2007).
Myeloid DCs are the main potent antigen-presenting cells, important in the induction of immunity and tolerance. Through maturation, immature DCs acquire the expression of co-stimulatory molecules and up-regulate the expression of MHC class I and class II molecules collectively, with further cell surface markers such as CD11c, CD80, CD83 and CD86. In vitro, MSCs inhibit the maturation of monocytes and the development of CD34+ hematopoietic progenitor cells into DCs, as shown by a decline in cell surface expression of MHC class II and co-stimulatory molecules, in addition to a reduced production of IL-12 and TNFα. This outcome is at least partly mediated through the production of IL-6 by activated MSCs or PGE-2, which are directly responsible for blocking DC maturation. These results propose that MSCs might regulate DC maturation to an anti-inflammatory or regulatory phenotype responsible for a satisfactory T-cell response(CitationAggarwal and Pittenger 2005, CitationGhannam et al. 2010a, CitationJiang et al. 2005, CitationSpaggiari et al. 2009, CitationDjouad et al. 2007). The effect of MSCs is controlled toward primary phases of DC maturation, as verified by alterations in the expression of the DC surface markers CD80, CD86, CD83, and the secretion of the polarizing cytokine IL-12. DCs which are produced in the presence of MSCs secrete low levels of IL-12 and TNF-α, but elevated levels of IL-1β, IL-10; in addition, they express low levels of MHC class II surface antigens. Most recent studies propose that antigen processing and presentation by MHC class II surface antigens are impaired(CitationGebler et al. 2012, CitationNauta et al. 2006, CitationZhang et al. 2004). For the first time, Di Nicola et al. showed the repression of cell-mediated immune connections by co-culturing DCs, irradiated allogenic lymphocytes or phytohemaglutinin (PHA)-stimulated T-cells with irradiated MSCs, in a mixed lymphocyte reaction (MLR)(CitationLotfinegad 2014). They found that MSCs delayed the up-regulation of CD1A, CD40, CD80 (B7-1), CD86 (B7-2) and HLA-DR through DC maturation, even as CD83 increased. Significantly, DCs isolated from cultures that were co-cultured with MSCs showed a decreased potential to activate CD4+ cells in the presence of MLCs(CitationAggarwal and Pittenger 2005, CitationMaccario et al. 2005, CitationJiang et al. 2005, CitationZhang et al. 2004, CitationLe Blanc and Ringden 2007, CitationBeyth et al. 2005). In the presence of MSCs, IL-10-secreting plasmacytoid DCs, characterized by the expression of the BDCA4 antigen, increased after stimulation by lipopolysaccharide(CitationAggarwal and Pittenger 2005, CitationLe Blanc and Ringden 2007). CD14+ monocytes activate MSCs to secrete soluble factors as well as IL-1β that inhibit alloreactive T-cells. () (CitationLe Blanc and Ringden 2007, CitationGroh et al. 2005).
Neutrophils
Neutrophils are the first cells that arrive at inflammatory tissue, and these cells secrete cytokines. One more MSC-produced factor, IL-6, has been shown to be engaged in the inhibition of monocyte differentiation to DCs, diminishing their stimulation capacity on T-cells. Similarly, the production of IL-6 by MSCs has also been reported toward stoppage of apoptosis of lymphocytes and neutrophils(CitationGhannam et al. 2010b, CitationJiang et al. 2005, CitationDjouad et al. 2007, CitationRaffaghello et al. 2008, CitationXu et al. 2007). MSCs greatly inhibit the in vitro secretion of hydrogen peroxide in activated neutrophils, therefore these stem cells can potentially control the intensity of a respiratory burst upon inflammatory stimulation(CitationBen-Ami et al. 2011, CitationRaffaghello et al. 2008). With respect to cells of the inherent immune system, MSCs can significantly decrease the power of the respiratory burst and apoptosis, which is a vital factor of the phagocytic role of neutrophils. This can be a serious process whereby MSCs can control the intensity of tissue injury following ischemic and ischemia/reperfusion damage(CitationMazaheri et al. 2012, CitationHirata et al. 1993). Hyperactivated T-lymphocyte helper 1 (Th1) produces proinflammatory cytokines such as IL-2, IL-6, IL-8, IL-17, TNF-α and IFN-γ. These cytokines stimulate neutrophils and activate monocytes. Activated monocytes stimulate Th1 differentiation by secreting IL-12, and the hyperfunction of neutrophils causes a tissue wound. Altogether, the connection between APCs, hypersensitivity of T-lymphocytes, and hyperactivity of neutrophils, might be the major cause for immune responses in Behcet's disease (BD). () (CitationMazaheri et al. 2012, CitationTürsen 2012, CitationKapsimali et al. 2010, CitationTursen 2009, CitationHirohata and Kikuchi 2003).
Adaptive immune system cells
B-cells
MSCs are capable of modulating the immune response of B-cells. It has been demonstrated that in a co-culture method of stimulated B-cells and MSCs, the proliferation of B-cells as well as the secretion of antibodies (IgA, IgG, and IgM) were inhibited in plasma cells(CitationLotfinegad 2014, CitationCorcione et al. 2006). In murine studies, MSCs have been stated to inhibit the proliferation of B-cells, stimulated through anti-CD40L and IL-4, or by pokeweed mitogen and protein A, as in Staphylococcus aureus(CitationNauta and Fibbe 2007, Schwartz et al. 2007, CitationGlennie et al. 2005, CitationZhang et al. 2005, CitationTögel et al. 2005, CitationLe Blanc et al. 2004a, CitationBreitbach et al. 2007). Allogeneic MSCs have been revealed to restrain the proliferation, activation and IgG secretion of B-cells, as shown in BXSB mice that were utilized as an investigational model for human systemic lupus erythematous(CitationNauta and Fibbe 2007, CitationAugello et al. 2005, CitationDeng et al. 2005). Krampera et al. demonstrated that MSCs only decreased the proliferation of B cells in the presence of IFN-γ. The suppressive effect of IFN-ɤ was probably attributed to its capacity to stimulate the secretion of IDO by MSCs, which in turn suppresses the proliferative response of effector cells during the tryptophan pathway(CitationNauta and Fibbe 2007, CitationKrampera et al. 2006a). Due to the fact that B-cell activation is mostly T-cell dependent, the influence of MSCs on the activity of T-cells might also not directly suppress B-cell functions. Additionally, MSCs have been shown to apply a direct influence on B-cells through cell to cell contact and during secretion of paracrine molecules(CitationCorcione et al. 2006, CitationAugello et al. 2005, CitationWeil et al. 2011, CitationGerdoni et al. 2007). MSCs arrest B-cells in the G0/G1 phase of the cell cycle, without apoptosis(CitationMohammadian and Shamsasenjan 2013, CitationCampagnoli et al. 2001). MSCs down-regulate the expression of the chemokine receptors CXCR4 and CXCR5, in addition to CCR7B, as well as lead to chemotaxis of CXCL12, the CXCR4 ligand, CXCL13 and CXCR5 ligand, suggesting that elevated numbers of MSCs influence the chemotactic properties of B-cells(CitationChamberlain et al. 2007, CitationVolarevic et al. 2011, CitationShi et al. 2011, CitationAbdi et al. 2008, CitationLe Blanc and Ringden 2007, CitationCorcione et al. 2006, CitationDeng et al. 2005). These findings cannot support the potential therapeutic utilization of MSCs in autoimmune diseases, where the B-cells play a major role ()(CitationLe Blanc and Ringden 2007). Also, MSCs were observed to increase the CD40 expression and the ectopic hyperexpression of the CD40 ligand on the B-cells of BXSB mice(CitationShi et al. 2011, CitationDeng et al. 2005).
Figure 2. Effects of Mesenchymal stem cells (MSCs) on the adaptive immune system. These effects promote an overall anti-inflammatory and immunosuppressive state. Abbreviations: IFN gamma (interferon γ), IDO (indoleamine 2,3-dioxygenase), IL-2(interleukin 2), IL-4 (interleukin 4) IL-10 (interleukin 10), IL-6 (interleukin 6), IL-12 (interleukin 12), IL-17 (interleukin17),prostaglandin E2(PGE2), transforming growth factor beta (TGFβ), hepatocyte growth factor (HGF), induced nitric oxide synthases (iNOS), soluble human leukocyte antigen-G5 (sHLA-G5), ICAM 1(Intercellular adhesion molecule 1), LFA 1(Lymphocyte function-associated antigen-1), TH 2 (T helper 1), Treg (T regulatory).
T-cells
Mesenchymal stem cells are immunosuppressive by inhibiting the response of naive and memory T-cells in MLC, which are made by mitogens. Repression is MHC-free and mainly manifests if MSCs are added on the earliest day of the 6-day culture. The amount of restraint is dosage- dependent(CitationPevsner-Fischer et al. 2007, CitationTse et al. 2003, CitationLe Blanc et al. 2003, CitationPotian et al. 2003, CitationLe Blanc and Ringden 2007). Manifest reserve is detected when more numbers of MSCs are present (MSC/lymphocyte ratio > 1/10). In distinction, the adding of MSCs at a low ratio (1/100–1/10 000) frequently increases proliferation(CitationPotian et al. 2003, CitationLe Blanc and Ringden 2007, CitationLe Blanc et al. 2003, CitationLiu et al. 2004). Tse et al. demonstrated that nearness to MSCs was significant in suppressing T-cell responsiveness and recommended that direct interaction between lymphocytes and MSCs was more significant than soluble mediators in the immunosuppressive function of MSCs(CitationYagi et al. 2010, CitationTse et al. 2003). Krampera et al. stated that inhibition needs the presence of MSCs and MSC-T-cell interaction in culture(CitationYagi et al. 2010, CitationKrampera et al. 2003).
Regulatory T cells
Although MSCs powerfully hamper T-cell proliferation, they can protect the role of CD4+ CD25+ CD127–, forkhead box P3 (FoxP3)+ regulatory T cells (Treg)(CitationLe Blanc and Ringden 2007). MSCs raised the amount of CD4+ CD25high, CD4+ CTLA4+ and CD4 + CD25+ CTLA4+ cells in IL-2-motivated lymphocytes and MLC(CitationAggarwal and Pittenger 2005, CitationMaccario et al. 2005, CitationLe Blanc and Ringden 2007). In contrast, the amount of CD25+ and CD38+ cells diminished in the presence of MSCs in mitogen-stimulated lymphocyte cultures ()(CitationLe Blanc and Ringden 2007, CitationGroh et al. 2005). MSCs also generate bone morphogenic protein-2 (BMP-2), which mediates immunosuppression through the production of CD8+ regulatory T cells(CitationLe Blanc and Ringden 2007, CitationDjouad et al. 2003).
T-helper and cytotoxic T-cells
The presence of signals that support the development of the Th1, such as CD3, CD28, IL-4, IL-2 and IL-12 stimulation, cause naive T-cells mature into IFN-γ-secreting cells. If MSCs are present in the culture, IFN-γ secretion is decreased. Hence, MSCs provoke a bias towards Th2 differentiation(CitationAggarwal and Pittenger 2005, CitationLe Blanc and Ringden 2007). Mesenchymal stem cells suppress CD8 + T-cell-mediated lysis if added at the beginning of the MLC (CitationRasmusson et al. 2003, CitationLe Blanc and Ringden 2007). Cytotoxicity was not affected if MSCs were added in the cytotoxic stage(CitationPotian et al. 2003, CitationRasmusson et al. 2003, CitationMaccario et al. 2005, CitationLe Blanc and Ringden 2007, CitationAngoulvant et al. 2004). Lysis was partly abrogated by the addition of IL-2. MSCs might hinder the afferent stage of alloreactivity and stop the growth of cytotoxic T-cells. When cytotoxic T-cells are activated, MSCs are not effective. In vivo studies are essential to clarify this point(CitationLe Blanc and Ringden 2007, CitationAngoulvant et al. 2004). Human MSCs limit the structure of CD4+ and CD8+ T cells by soluble factors(CitationTse et al. 2003, CitationPotian et al. 2003, CitationLe Blanc and Ringden 2007, CitationCorcione et al. 2006, CitationDi Nicola et al. 2002). The suppressive factor is not constitutively produced by MSCs, since cell culture supernatants do not suppress T-cell proliferation(CitationMaitra et al. 2004, CitationPotian et al. 2003, CitationLe Blanc and Ringden 2007, CitationAugello et al. 2005, CitationLe Blanc et al. 2004b). This result may be characteristic of the inhibition of cell division, which is supported through the gathering of cells in the G0/G1 phase of the cell cycle. At the molecular level, cyclin D2 expression is down-regulated, whereas p27 expression is up-regulated; this might clarify why T-cell proliferation, before activation, and IFN-γ secretion, are affected with MSC(CitationShi et al. 2011, CitationGlennie et al. 2005). Liu et al. clarified that the addition of antibodies specific to FasL and TGF-β1 satisfied suppression by MSCs in concanavalin A-stimulated MLC in a dose-dependent style, other than anti-IL-10, had no effect(CitationLe Blanc and Ringden 2007, CitationLiu et al. 2004). Mesenchymal stem cells may inhibit T-cell proliferation through the secretion of indoleamine 2, 3-dioxygenase (IDO). IDO is induced via IFN-γ, catalyzes the alteration of tryptophan to kynurenine, and inhibits T-cell responses through tryptophan diminution(CitationLe Blanc and Ringden 2007, CitationMunn et al. 1998).
Meisel et al., using the Western blotting technique, revealed that human MSCs do not constitutively express IDO, but the expression is provoked by IFN-γ. IFN-γ also aroused IDO enzyme activity in dose-dependent behavior. Important IDO activity was detected in T-cells stimulated with mitomycin C-treated PBMC, in the presence of MSCs(CitationLe Blanc and Ringden 2007, CitationMeisel et al. 2004). PGE2, which is produced by cyclooxygenase (COX) enzymes, induces regulatory T-cells. (15-750). MSCs constitutively express COX-1 and COX-2 (CitationAggarwal and Pittenger 2005, CitationLe Blanc and Ringden 2007, CitationArikawa et al. 2004) together. While purified T-cells were co-cultured by MSCs, both COX-2 and PGE2 production were boosted(CitationAggarwal and Pittenger 2005, CitationTse et al. 2003, CitationLe Blanc and Ringden 2007). Inhibitors of PGE2 synthesis restored the majority of the proliferation of phytohemaglutinin-activated (PHA) lymphocytes co-cultured with MSCs. Tse et al. studied alloreactive lymphocytes in contrast to mitogen-stimulated cultures. They set up that neither MSC production of IL-10, TGFb1, and PGE2, nor tryptophan reduction, was responsible for the suppression in MLC(CitationAggarwal and Pittenger 2005, CitationTse et al. 2003). Di Nicola et al. recommended that HGF worked synergistically through TGF-β1, to challenge T-cell detection by simultaneous neutralization of HGF and TGF-β1 in the later study restoring T-cell proliferation(CitationYagi et al. 2010, CitationDi Nicola et al. 2002). One more statement exhibited that quantitative real-time PCR confirmed important HGF mRNA up-regulated by IFN-γ and TNFα(CitationYagi et al. 2010, CitationEnglish et al. 2007). NO (nitric oxide) stops the proliferation of T-cells by suppressing the phosphorylation of signal transducer and activator of transcription-5 (STAT5), a transcription factor vital for T-cell activation and proliferation(CitationShi et al. 2011, CitationBingisser et al. 1998). Ding et al. reported that matrix metalloproteinases (MMPs), in particular MMP-2 and MMP-9, produced by MSCs, mediate the suppressive activity of MSCs through diminution of CD25 expression on responding T-cells within a model of allogeneic islet transplant(CitationDing et al. 2009). In an experimental model of arthritis, MSCs reduced antigen-specific Th1/Th17 cell expansion and reduced the production of cytokines released via Th1/Th17 cells, for example IFN-γ and IL-17, and caused the Th2 cells to raise production of IL-4 and IL-10 in lymph node joints(CitationAggarwal and Pittenger 2005, CitationShi et al. 2011, CitationKrampera et al. 2003, CitationZappia et al. 2005). Conversely, a new study reported that MSCs might provoke apoptosis in activated T-cells[CD3+ and bromodeoxyuridine BrdU+], but not in the resting T-cells[CD3+ and BrdU–]; this leads to clear reduction of delayed-type hypersensitivity (DTH) response in vivo with inducing NO production(CitationLim et al. 2010). A recent study demonstrated that the negative co-stimulatory molecule B7-H4 was involved in the immunosuppressive effect of MSCs on T-cell activation and proliferation by the generation of cell cycle arrest and the inhibition of nuclear translocation of the nuclear factor (NF)-kappa B(CitationSensebe et al. 2010). MSCs inhibit Th17 differentiation from naive T-cells. MSCs can also decrease the expression of major histocompatibility complex class E (MHC class E)(CitationMazaheri et al. 2012, CitationGhannam et al. 2010b). Conversely, in one study, it was found that CD25 and CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) surface expression, and Foxp3 mRNA levels, were not dependent on whether CD4+ T-cells were cultured in the presence of MSCs(CitationKrampera et al. 2006b). Furthermore, MSCs have also been reported to influence the cytokine secretion profile of the different T-cell subsets, since their addition to an in vitro activated T-cell culture leads to reduced production of the pro-inflammatory cytokines: IFN-γ, TNF-α, IL-6, IL-17, and enhanced levels of anti-inflammatory cytokines, for example IL-4 and IL-10. On the whole, these outcomes could show a probable MSC-mediated alteration in Th1/Th2 balance(CitationZappia et al. 2005, CitationKong et al. 2009). MSCs can hamper T-cell proliferation by engaging the inhibitory molecule programmed death 1(PD-1) to its ligands PD-L1 and PD-L2, thus producing soluble factors that suppress T-cell proliferation (such as TGF-β or IL-10) and during interaction through DCs(CitationVolarevic et al. 2011, CitationNauta and Fibbe 2007, CitationVolarevic et al. 2009). MSCs increase Th2 and IL-4 production, regulatory T-cell response and decrease activation by foreign antigen, cytotoxic T-cells and IFN-γ production(CitationWeil et al. 2011). The generation of HLA-G5 by MSCs has more lately been revealed to suppress T-cell proliferation, in addition to cytotoxicity of NK cells T-cells, and to increase the generation of regulatory T (Treg) cells. Cell contact between MSCs and activated T-cells stimulated IL-10 production, which was necessary to induce the release of soluble HLA-G5. () (CitationGhannam et al. 2010a, CitationSelmani et al. 2008, CitationNasef et al. 2009).
Homing of MSCs
Homing is the procedure by which cells migrate to, and engraft within, the tissue in which they are able to apply local, efficient effects. While the homing of leukocytes to places of inflammation is well studied, the methods of progenitor cell homing to places of ischemia or damage are weakly recognized(CitationImhof and Aurrand-Lions 2004, CitationLuster et al. 2005). Homing engages a cascade of incidents begun with shear-resistant adhesive interactions between flowing cells and the vascular endothelium at the target tissue (Stage I). This procedure is mediated via ‘homing receptors’ expressed on circulating cells that involve related endothelial co-receptors, causing in cell-tethering and rolling contacts on the endothelial surface. This is characteristically pursued via chemokine-generated activation of integrin adhesiveness (Stage II), hard adhesion (Stage III) and extravasation (Stage IV)(CitationYagi et al. 2010, CitationSackstein 2005). MSCs expressed chemokine receptors for homing of immune cells such as: CCR1, CCR2, CCR3, CCR4, CCR7, CCR8, CCR10, CCL2, CCL3, CCL4, CCL5, CCL7, CCL20, CCL26, CX3CL1, CXCL1, CXCL2, CXCL3, CXCL5, CXCL8, CXCL10, CXCL11 and CXCL12, but not CXCR4, suggesting that CXCR4 can simply be significant for the trafficking of mature stem cell populations and receptor tyrosine kinase growth factor receptors such as platelet-derived growth factor (PDGF) and insulin-like growth factor1(IGF-1)(CitationLotfinegad 2014, CitationYagi et al. 2010, CitationMcTaggart and Atkinson 2007, CitationHoogduijn et al. 2010). Integrins have been identified to play a significant role in cell adhesion, migration, and chemotaxis(CitationRidger et al. 2001, CitationWerr et al. 1998). Integrin α4/β1-VCAM contact has been known to regulate T-cell and NK trafficking(CitationWoodside et al. 2006). Integrin β1 engages cell to-cell adhesion, which can be essential for the anchorage of the engrafted cells. As expected, blockade of integrin β1 reduces neutrophil migration to the lung through inflammation(CitationYagi et al. 2010, CitationRidger et al. 2001). Ruster et al. explained that MSCs react in an organized style through endothelial cells, not only through integrin α4/β1-VCAM-1 interaction or integrin β1, but also via the endothelial phenotype, P-selectin, MMP-2 production, and cytokines(CitationRüster et al. 2006).
Fibronectin attaches extracellular matrix constituents like collagen, fibrin and heparan sulfate proteoglycans. It plays a significant role in cell adhesion, growth, migration, as well as differentiation, and it is significant for the injury healing processes. Records of previous studies show that contact between integrin α4 and β1-fibronectin plays a significant role in transmigration of MSCs into the extracellular matrix(CitationRuoslahti 1984, CitationValenick et al. 2005). Stromal cell-derived factor 1 (SDF-1), which is formally identified as chemokine (C-X-C motif) ligand 12 (CXCL12), is a minute chemotactic cytokine that activates leukocytes and is frequently stimulated through proinflammatory stimuli like TNF-α or IL-1(CitationFedyk et al. 2001). The receptor for this chemokine is CXCR4 and the SDF-1-CXCR4 communication is regarded to be private (CitationMa et al. 1998).
Interaction between SDF-1 and its ligand CXCR4 co-operates a significant function in homing, bone marrow retention and mobilization, as shown in studies on engraftment of hematopoietic stem/progenitor cells(CitationChamberlain et al. 2007, CitationPeled et al. 1999). MSCs migrated considerably in response to SDF-1 and CX3CL, consistent with their corresponding expression of chemokine receptors CXCR4 or CX3CR1. Unexpectedly, Basic Fibroblast Growth Factor (bFGF) might have contrasting effects on MSC migration, depending on the concentration(CitationYagi et al. 2010). MSCs have an important role in co-transplantation by hematopoietic stem cells, by producing SDF-1, Flt-3 ligand and stem cell factor, together with expressing extra-cellular matrix proteins including fibronectin, laminin and vimentin, which have a critical function in HSC homing in the bone marrow niche(CitationMohammadian and Shamsasenjan 2013, CitationHorwitz et al. 2011, CitationDelalat et al. 2009, CitationAkbari et al. 2007).
Medical applications of MSCs
Stem cells in general and MSCs in particular, by their adaptable increase and differentiation potential, are considered perfect candidates for utilization in regenerative medical procedures(CitationMcTaggart and Atkinson 2007). One of the most significant properties that make MSCs a special device for cell-based therapeutic approaches, is their capability to escape from immune refusal; therefore, HLA-matching is not of much significance for their implant and HLA-mismatched donors can also be selected (CitationSiegel et al. 2009, CitationDazzi and Marelli Berg 2008). Major roles of MSCs are correlated to their diverse therapeutic properties, like their anti-inflammatory and immunomodulatory effects, the secretion of mediators that initiate or support tissue renovation and tissue substitution with the potential of multipotent differentiation (CitationCaplan and Dennis 2006, CitationWaszak et al. 2012, CitationDu et al. 2013). The major significant therapeutic areas comprise ischemic cardiac disease, graft-versus-host disease (GVHD), chronic obstructive pulmonary disease, Crohn's and Behcet's disease(CitationMazaheri et al. 2012, CitationDu et al. 2013). MSCs infusion can also be very useful in cord blood transplantation where the restricted amount of stem cells delays engraftment and favors graft rejection. The cell therapy approach has also been utilized as prophylaxis in GVHD in HSC transplantation. The therapeutic efficiency was related to reduced antigen-specific Th1/Th17 cell expansion, increased production of IL-10 and generation of CD4+,CD25+,FoxP3 +Treg cells via the ability to suppress self-reactive T-effector responses(CitationGhannam et al. 2010a, CitationGonzález et al. 2009). Growth of autoimmune diabetes results from immune cell dysfunction to maintain peripheral and central tolerance. MSCs can be useful in regulating Treg/auto reactive T-cell balance. The earliest proposed function of MSCs was the stimulation of the regeneration of endogenous insulin-secreting cells, and next, inhibition of the T-cell-mediated immune responses against newly produced beta cells(CitationUrban et al. 2008). MSCs have been brought into clinical therapy for numerous reasons: to differentiate and repair injured tissues, to increase hematopoietic engraftment following transplant through the production of growth factors, and for immunosuppressant function in GVHD. Since the immunomodulatory methods vary between murine and human MSCs, animal forms cannot mimic the medical position(CitationLazarus et al. 1995, CitationKoç et al. 2000). Recently studies in pathological models have also revealed that MSC can home in to damaged kidneys and make simple renovations(CitationMcTaggart and Atkinson 2007). The proof-of-principle essential to utilize of MSCs in vivo has been shown in a series of trials:(I) MSCs might engraft into mouse tissues after infusion and use a site-specific differentiation, which is due to their exclusive immunological properties that permit engraftment with no rejection; (II) in humans, autologous enlarged MSCs in vitro could be infused intravenously with no toxicity; (III) transplantation of autologous MSCs in arrangement by HSCs lead to improved HSC engraftment; and(IV) allogeneic transplantation of MSCs decreased the frequency and intensity of acute and chronic GVHD (CitationGebler et al. 2012, CitationSato et al. 2010, CitationTolar et al. 2010). Additionally, MSCs have been used for the conduct of different autoimmune diseases leading to the stimulation of T-cell tolerance and damaged pathogenic T and B cell responses. BM-derived MSCs can also suppress the proliferation of PBMCs, independent of their supply (autologous or allogeneic), subtype of autoimmune disease and form of conduct(CitationMacDonald et al. 2011). In the case of tissue renovation, the anti-inflammatory activity of MSCs resulted in the production of anti-inflammatory macrophages, which were important for increasing tissue repair(CitationKim and Hematti 2009). Moreover, MSCs also have therapeutic potential in treating pulmonary fibrosis, acute renal nephropathy, and in inhibiting the progress of diabetes. MSC transplantation promotes the extension and growth of B-cells and renal glomeruli as well as decreasing collagen expression and inflammation in fibrosis(CitationLee et al. 2009, CitationVija et al. 2009). MSCs express high levels of arylsulfatase A and α-l-iduronidase. The absence of these enzymes cause breakdown to hydrolyze a different substrate, leading to its accumulation and the dysfunction of several organs, the most severe being mental retardation. The lack of arylsulfatase A is the cause of metachromatic leukodystrophy, and the deficit of α-l-iduronidase is the cause of Hurler's disease, disorders that can possibly be prevented via allogeneic hematopoietic stem cell transplantation (HSCT), which is just potential therapy(CitationGroth and Ringdén 1984, CitationKrivit et al. 1999). MSCs can be exploited to treat bone disorders (e.g., osteogenesis imperfecta). Five patients with osteogenesis imperfecta, treated with bone marrow transplantation, had donor osteoblast engraftment, novel dense bone shape, an augmentation in complete bone mineral content, increase in development rate and decreased frequencies of bone cracks. This proposes that HSCT leads to engraftment of practical MSCs. Gene-marked MSCs, to recognize the cells after infusion, were given to six children who had undergone HSCT for severe osteogenesis imperfecta(CitationSillence et al. 1978, CitationHorwitz et al. 1999, CitationHorwitz et al. 2001, CitationHorwitz et al. 2002). A bone marrow biopsy demonstrated 0.3%–7.4% Y-chromosome-positive cells by fluorescent in situ hybridization (FISH),signifying engraftment of the donor MSCs. Lee et al. stated the case of a patient with acute leukemia, who accepted a peripheral blood stem cell graft collectively via MSCs since her HLA-haploidentical father was treated by regular immunosuppression(CitationLe Blanc and Ringden 2007, CitationLee et al. 2002).
Conclusion
Mesenchymal Stem Cells (MSCs) have a capacity to home in and integrate into damaged tissues. MSCs provide immunomodulatory effects by paracrine and/or cell-cell contact that inhibit innate immune system cells (DCs, NK cells, monocytes and neutrophils) and adaptive immune system cells (B, TH1 and T CTL). Also, MSCs stimulate Th2 and regulatory T-cells by the inflammatory microenvironment. Therefore, the use of MSCs could lead to various therapeutic possibilities such as supporting tissue regeneration and correcting inherited disorders. A rational understanding of the mechanisms of action of MSCs allows the translation of our basic knowledge of MSC biology into the design of new clinical therapies .The potential antiproliferative and immunomodulatory function of MSCs is being intensely studied by various groups, with the hope that MSCs may be developed as a therapeutic strategy for autoimmune disease, HSCT, BMT(Bone marrow Transplantation) and as a useful tool for cell-based therapy. Autologous transplantation of MSCs has a high ability to produce the desired results in clinical therapies, but it could induce tumors, because MSCs can undergo spontaneous transformation exhibiting a tumorigenic potential with immunosuppression effects. Also, allogeneic MSCs might have a potential risk of infections obtained from donors. The opportunity exists to utilize genetic engineering of MSCs to state particular factors for homing and therapy. Finally, clinical trials with MSCs will afford a rich resource of information that can be studied widely in the laboratory and will play an important role in clinical therapy. In the present review, the comprehensive definition, sources, markers, and receptors of MSCs, as well as the immunomodulatory effect of these cells on innate and adaptive immune system cells, homing to the damaged tissues and therapeutic aspects in a variety diseases, have been reviewed. We hope that using MSCs in the treatment of autoimmune diseases, BMT, HSCT and cell-based therapy will be investigated more in the near future.
Authors’ contributions
AA, AR, and FSTM conceived of the study and participated in its design and coordination. AM, K S, SK, Mt, AS, VZ, and MGG participated in the sequence alignment and drafted the manuscript. All authors read and approved the final manuscript.
Acknowledgements
The authors thank Department of Hematology, Faculty of Medicine, Tabriz University of Medical Sciences for all supports provided.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.
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