1. Introduction
Bone marrow is a complex tissue containing hematopoietic cell progenitors and their progeny integrated within a connective-tissue network of mesenchymal-derived cells known as the stroma (1). The stroma cells, or Mesenchymal stem cells (MSCs), are multi-potent progenitor cells that constitute a minute proportion of the bone marrow, represented as a rare population of cells that makes up 0.001 to 0.01% of the total nucleated cells. They represent 10-fold less abundance than the haematopoietic stem cells (2), which contributes to the organization of the microenvironment supporting the differentiation of hematopoietic cells (3). MSC are present in tissues of young, as well as, adult individuals (4, 5), including the adipose tissue, umbilical cord blood, amniotic fluid and even peripheral blood (1, 6-8). MSCs were characterized over thirty years ago as fibroblast-like cells with adhesive properties in culture (9, 10). The term MSC has become the predominant term in the literature since the early 90s (11), after which their research field has grown rapidly due to the promising therapeutic potential, resulting in an increased frequency of clinical trials in the new millennium at an explosive rate.
As data accumulated, there was a need to establish a consensus on the proper definition of the MSCs. The International Society for Cellular Therapy has recommended the minimum criteria for defining multi-potent human MSCs (12, 13). The criteria included: (i) cells being adherent to plastic under standard culture conditions; (ii) MSC being positive for the expression of CD105, CD73 and CD90 and negative for expression of the haematopoietic cell surface markers CD34, CD45, CD11a, CD19 or CD79a, CD14 or CD11b and histocompatibility locus antigen (HLA)-DR; (iii) under a specific stimulus, MSC differentiate into osteocytes, adipocytes and chondrocytes
All cells have half-lives and their natural expiration must be matched by their replacement; MSCs, by proliferating and differentiating, can be the proposed source of these new replacement cells as characterized in their differentiation capacity. This replacement hypothesis mimics the known sequence of events involved in the turnover and maintenance of blood cells that are formed from haematopoietic stem cells (HSCs) (18). Unlike HSCs, MSCs can be culture-expanded
2. Effect of Mesenchymal Stem Cells on Immune cells
Mesenchymal Stem Cells have been shown to possess immunomodulatory characteristics, as described through the inhibition of T-cell proliferation
3. Immunomodulatory effect of mesenchymal stem cells in innate immunity
Dendritic cells have the elementary role of antigen presentation to naïve T cells upon maturation, which in turn induce the proinflammatory cytokines. Immature DCs acquire the expression of co-stimulatory molecules and upregulate expression of MHC-I and II, as well as, other cell-surface markers (CD11c and CD83). Mesenchymal stem cells have profound effect on the development of DC, where in the presence of MSC, the percentage of DC with conventional phenotype is reduced, while that of plasmacytoid DC is increased, therefore biasing the immune system toward Th2 and away from Th1 responses in a PGE-2 dependent mechanism (37). Furthermore, MSCs inhibit the up-regulation of CD1a, CD40, CD80, CD86, and HLA-DR during DC differentiation and prevent an increase of CD40, CD86, and CD83 expression during DC maturation (38). When mature DCs are incubated with MSCs they have a decreased cell-surface expression of MHC class II molecules, CD11c, CD83 and co-stimulatory molecules, as well as, decreased interleukin-12 (Il-12) production, thereby impairing the antigen-presenting function of the DCs (Fig 1) (39, 40). MSCs can also decrease the pro-inflammatory potential of DCs by inhibiting their production of tumour-necrosis factor α (TNF-α) (40). Furthermore, plasmacytoid DCs (pDCs), which are specialized cells for the production of high levels of type-I IFN in response to microbial stimuli, upregulate production of the anti-inflammatory cytokine IL-10 after incubation with MSCs (34). These observations indicate a potent anti-inflammatory and immunoregulatory effect for MSC
Natural killer (NK) cells are key effector cells of the innate immunity in anti-viral and anti-tumor immune responses through their Granzyme B mediated cytotoxicity and the production of pro-inflammatory cytokines (41). NK-mediated target cell lysis results from an antigen-ligand interaction realized by activating NK-cell receptors, and associated with reduced or absent MHC-I expression by the target cell (42). MSCs can inhibit the cytotoxic activity of resting NK cells by down-regulating expression of NKp30 and natural-killer group 2, member D (NKG2D), which are activating receptors involved in NK-cell activation and target-cell killing (Fig 1) (43). Resting NK cells proliferate and acquire strong cytotoxic activity when cultured with IL-2 or IL-15, but when incubated with MSC in the presence of these cytokines, resting NK-cell, as well as, pre-activated NK cell proliferation and IFN-γ production are almost completely abrogated (44, 45). It is worth noting that although the susceptibility of NK cells to MSC mediated inhibition is potent, the pre-activated NK cells showed more resistance to the immunosuppressive effect of MSC compared to resting NK cells (43). The susceptibility of human MSCs to NK-cell-mediated cytotoxicity depends on the low level of cell-surface expression of MHC class I molecules by MSCs and the expression of several ligands, that are recognized by activating NK-cell receptors. Autologous and allogeneic MSC were susceptible to lysis by NK cells (43), where NK cell-mediated lysis was inversely correlated with the expression of HLA class I on MSC (46). Incubation of MSCs with IFN-γ partially protected them from NK-cell-mediated cytotoxicity, through the up-regulation of expression of MHC-I molecules on MSCs (43). Taken together, a possible dynamic interaction between NK cells and MSC
Neutrophils play a major role in innate immunity during the course of bacterial infections, where they are activated to kill foreign infectious agents and accordingly undergo a respiratory burst. MSCs have been shown to dampen the respiratory burst and to delay the spontaneous apoptosis of resting and activated neutrophils through an IL-6-dependent mechanism (47). MSC had no effect on neutrophil phagocytosis, expression of adhesion molecules, and chemotaxis in response to IL-8, f-MLP, or C5a (47). Stimulation with bacterial endotoxin induces chemokine receptor expression and mobility of MSCs, which secrete large amounts of inflammatory cytokines and recruit neutrophils in an IL-8 and MIF-dependent manner. Recruited and activated neutrophils showed a prolonged lifespan, an increased expression of inflammatory chemokines, and an enhanced responsiveness toward subsequent challenge with LPS, which suggest a role for MSCs in the early phases of pathogen challenge, when classical immune cells have not been recruited yet (48). Furthermore, MSC have shown the capability to mediate the preservation of resting neutrophils, a phenomenon that might be important in those anatomical sites, where large numbers of mature and functional neutrophils are stored, such as the bone marrow and lungs (49).
4. Immunomodulatory effect of mesenchymal stem cells in adaptive immunity
T-cells are major players of the adaptive immune response. After T-cell receptor (TCR) engagement, T cells proliferate and undergo numerous effector functions, including cytokine release and, in the case of CD8+ T cells (CTL), cytotoxicity. Abundant reports have shown that T-cell proliferation stimulated with polyclonal mitogens, allogeneic cells or specific antigen is inhibited by MSCs (28, 29, 50-56). The observation that MSCs can reduce T cell proliferation
MSC inhibition of T-cell proliferation is not MHC restricted, since it can be mediated by both autologous and allogeneic MSCs and depends on the arrest of T-cells in the G0/G1 phase of the cell cycle (55, 57). Thus, MSCs do not promote T-cell apoptosis, but instead maintain T cell survival upon subjection to overstimulation through the TCR and upon commitment to undergo CD95–CD95-ligand-dependent activation-induced cell death (57). MSC effects on T cell proliferation
Regulatory T cells (Tregs), a subpopulation of T cells, are vital to keep the immune system in check, help avoid immune-mediated pathology and contain unrestricted expansion of effector T-cell populations, which results in maintaining homeostasis and tolerance to self antigens. Tregs are currently identified by co-expression of CD4 and CD25, expression of the transcription factor FoxP3, production of regulatory cytokines IL-10 and TGF-β, and ability to suppress proliferation of activated CD4+CD25+ T cells in co-culture experiments. Differential expression of CD127 (α-chain of the IL-7 receptor) enable flow cytometry-based separation of human Tregs from CD127+ non-regulatory T-cells (61). MSCs have been reported to induce the production of IL-10 by pDCs, which, in turn, trigger the generation of regulatory T cells (Fig 1) (34, 40). Furthermore, Tregs secrete TGF-β and when used
Antibody producing B-cells constitute the second main cell type involved in adaptive immunity. Interactions between MSCs and B-cells have produced controversial results attributable to the inconsistent experimental conditions used (31, 55, 64). Initial reports on mice suggested that MSC exercise a dampening effect on the proliferation of B-cells (64), which is in concordance with most published works to date (31, 55, 64). Furthermore, MSCs can also inhibit B-cell differentiation and constitutive expression of chemokine receptors via the release of soluble factors and cell-cell contact mediated possibly by the Programmed Cell Death 1 (PD-1) and its ligand (31, 64). The addition of MSCs, at the beginning of a mixed lymphocyte reaction (MLC), considerably inhibited immunoglobulin production in standard MLC, irrespective of the MSC dose employed, which suggests that third-party MSC are able to suppress allo-specific antibody production, consequently, overcoming a positive cross-match in sensitized transplant recipients (65). However, other
Low concentrations of IFN-γ upregulate the expression of MHC-II molecules by MSCs, which indicates that they could act as antigen presenting cells (APCs) early in an immune response, when the level of IFN-γ are low (68, 69). However, this process of MHC-II expression by MSCs, along with the potential APC characteristics, was reversed as IFN-γ concentrations increased. These observations could suggest that MSCs function as conditional APC in the early phase of an immune response, while later switch into an immunosuppressive function (68). Since bone marrow might be a site for the induction of T-cell responses to blood-borne antigens (70), and since MSC are derived from the stromal progenitor cells that reside in the bone marrow, therefore, MSC express a yet unidentified role in the control of the immune response physiology of the bone marrow. Dendritic cells are the main APC for T-cell responses, and MSC-mediated suppression of DC maturation would prohibit efficient antigen presentation and thus, the clonal expansion of T-cells. Direct interactions of MSCs with T-cells
The
Although many of the studies use MSC-conditioned medium, both contact-dependent and -independent mechanisms are probably invoked in the therapeutic use of MSCs (20, 71). In addition to cytokines, the network of costimulatory molecules is hypothesized to play a prominent role in modulating tolerance and inflammation. MSCs down-regulate the expression of costimulatory molecules (30, 72, 73). The discovery of new functions for B7 family members, together with the identification of additional B7 and CD28 family members, is revealing new ways in which the B7:CD28 family may regulate T-cell activation and tolerance. Not only do CD80/86:CD28 interactions promote initial T-cell activation, they also regulate self-tolerance by supporting CD4+CD25+ Treg homeostasis (74-76). Cytotoxic T-lymphocyte antigen 4 (CTLA-4) can exert inhibitory effects in both B7-1/B7-2–dependent and –independent fashions. B7-1 and B7-2 can signal bi-directionally through engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells (77). The B7 family members—inducible co-stimulator (ICOS) ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1)—are expressed on professional APC cells, while B7-H4 and B7-H1 are expressed on
5. Mesenchymal Stem Cells escape the immune system in vitro
Studies have shown that MSCs escape the immune system, and this makes them a potential therapeutic tool for various transplantation procedures. MSCs express intermediate levels of HLA major histocompatibility complex (MHC) class I molecules (16, 50, 82, 83), while they do not express HLA class II antigens of the cell surface. However, HLA class II is readily detectable by Western blot on whole-cell lysates of unstimulated adult MSCs, thus suggesting that MSCs contain intracellular deposits of HLA class II allo-antigens (83). Cell-surface expression can be induced by treatment of the cells with IFN-γ for 1 or 2 days. Unlike adult MSCs, the fetal liver– derived cells have no intracellular nor cell surface HLA class II expression (84), but incubation with IFN-γ initiated their intracellular expression followed by surface expression. Differentiation of MSCs into their mesodermal lineages of bone, cartilage, or adipose tissue, both in adult and fetal MSCs continued to express HLA-I, but not class II (84). Undifferentiated MSCs
Although MSCs are transplantable across allogeneic barriers, a delayed type hypersensitivity reaction can lead to rejection in xenogenic models of human MSCs injected into immunocompetent rats (91). In this study, MSCs were identified in the heart muscle of severe compromised immune deficiency rats, in contrast to that of immunocompetent rats. In the latter group, peripheral blood lymphocytes proliferated after re-stimulation with human MSCs
6. Mechanisms of immunosuppression by Mesenchymal Stem Cells
Several studies have acknowledged the immunosuppressive activities of MSCs, but the underlying mechanisms are far from being fully characterized. The initial step in the interaction between MSCs and their target cells involves cell–cell contact mediated by adhesion molecules, in concordance with studies showing the dependence of T-cell proliferation on the engagement of PD-1 by its ligand (31). Several soluble immunosuppressive factors, either produced constitutively by MSCs or released following cross-talk with target cells have been reported, including nitric oxide and indoleamine 2,3-dioxygenase (IDO), which are only released by MSC after IFN-γ stimulation with target cells (92, 93), and thus not in a constitutive manner. IDO induces the depletion of tryptophan from the local environment, which is an essential amino acid for lymphocyte proliferation. MSC-derived IDO was reported as a requirement to inhibit the proliferation of IFN-γ-producing TH1 cells (92) and together with prostaglandin E2 (PGE-2) to block NK-cell activity (Fig 1) (44). In addition, IFN-γ, alone or in combination with TNF-α, IL-1α or IL-1β, stimulates the production of chemokines by mouse MSCs that attract T-cells and stimulate the production of inducible nitric-oxide synthase (iNOS), which in turn inhibits T-cell activation through the production of nitric oxide (56). It is worth noting that MSCs from IFN-γ receptor (IFN-γ-R1) deficient mice do not have immunosuppressive activity, which highlights the vital role of IFN-γ in the immunosuppressive function of MSC (56).
Additional soluble factors, such as transforming growth factor-β1 (TGF-β1), hepatocyte growth factor (HGF), IL-10, PGE-2, haem-oxygenase-1 (HO1), IL-6 and soluble HLA-G5, are constitutively produced by MSCs (28, 34, 51, 63, 94) or secreted in response to cytokines released by target cells upon interacting with MSC. TNF-α and IFN-γ have been shown to stimulate the production of PGE-2 by MSCs above constitutive level (34). Furthermore, IL-6 was shown to dampen the respiratory burst and to delay the apoptosis of human neutrophils by inducing phosphorylation of the transcription factor signal transducer and activator of transcription 3 (47), and to inhibit the differentiation of bone-marrow progenitor cells into DCs (95).
The failure to reverse suppression, when neutralizing antibodies against IL-10, TGF-β and IGF were added to MLR reactions does point to the possibility that MSC may secrete as yet uncharacterized immunosuppressive factors (93). Galectin-1 and Galectin-3, newly characterized lectins, are constitutively expressed and secreted by human bone marrow MSC. Inhibition of galectin-1 and galectin-3 gene expression with small interfering RNAs abrogated the suppressive effect of MSC on allogeneic T-cells (Fig 1) (96). The restoration of T-cell proliferation in the presence of β- lactose indicates that the carbohydrate-recognition domain of galectins is responsible for the immunosuppression of T-cells and highlights an extracellular mechanism of action for the MSC-secreted galectins. In this respect, the inhibition of T-cell proliferation could result from either direct effects of galectin-1 and galectin-3 on T cells and/or through a direct or an indirect on effect on dendritic cells (97).
HLA-G5 represents another important molecule involved in MSC mediated regulation of the immune response, where its production has been shown to suppress T-cell proliferation, as well as NK-cell and T-cell cytotoxicity, while promoting the generation of Tregs (63, 98). HLA-G protein expression is constitutive and the level is not modified upon stimulation by allogeneic lymphocytes in MSC/MLR. HLA-G5 is detected on MSCs by real-time reverse-phase polymerase chain reaction, immune-fluorescence, flow cytometry and enzyme-linked immunosorbent assay in the supernatant (99). Cell contact between MSCs and activated T-cells induces IL-10 production, which, in turn, stimulates the release of soluble HLA-G5 by MSCs (63). It is worth nothing that none of these molecules have an exclusive role and that MSC-mediated immune-regulation is a redundant system that is mediated by several molecules.
7. Mesenchymal Stem Cells in response to injury
One important characteristic of
Nitric Oxide (NO) mediate its effect partly through phosphorylation of Stat-5, which results in suppression of T- cell proliferation, partly through the inhibition of NO synthase or the inhibition of prostaglandin synthesis. This reveals the MSC-dependent effects on proliferation. Although indoleamine-2, 3-dioxygenase (IDO) has been hypothesized to be critical in mediating the effect of NO, neutralizing IDO by using a blocking antibody did not interfere with NO’s suppressive effects (93, 110).
Within an
8. Mesenchymal Stem Cell clinical applications
The clinical experience with and the safety of MSCs is of utmost interest for their wide therapeutic applications. The pioneering
The perspective role of adult stem cells in degenerative disease conditions, where there is progressive tissue damage and an inability to repair, possibly due to the depletion of stem cell populations or functional alteration, has been considered. In cases of osteoarthritis, a disease of the joints where there is progressive and irreversible loss of cartilage characterized by changes in the underlying bone, Murphy et al showed that the proliferative capacity of the MSC was substantially reduced, and this was independent of the harvest site from patients with end-stage OA undergoing joint replacement surgery (118). In this study the marrow samples were harvested both from the site of surgery (either the hip or the knee) and also from the iliac crest. These effects were apparently disease-related, and not age-related. However, the data suggest that susceptibility to OA and perhaps other degenerative diseases may be due to the reduced mobilization or proliferation of stem cells. In addition, successfully recruited cells may have a limited capacity to differentiate, leading to defective tissue repair. Alternatively, the altered stem cell activity may be in response to the elevated levels of inflammatory cytokines seen in OA, which was confirmed by several other investigators (119, 120).
Similarly, the functional impairment of the anti-proliferative effect of MSCs derived from patients with aplastic anaemia (121) or multiple myeloma (122) might be resulting from an intrinsic abnormality in the microenvironment of the bone marrow, which is consistent with the possible use of autologous MSC for therapeutic purposes.
With the knowledge of the homing capacity of MSC and their capacity to engraft into the recipient’s bone after systemic administration, MSCs have been utilized to treat children with severe osteogenesis imperfecta, leading to improved parameters of increased growth velocity and total body mineral content associated with fewer fractures (123). Systemic infusion of allogeneic MSCs also led to encouraging bone marrow recovery in patients with tumors following chemotherapy (123). The immunosuppressive effect of infused MSCs has been successfully shown in acute, severe graft-versus-host disease (GvHD) (32). The probable effect of MSC was the inhibition of donor T-cell reactivity to histocompatibility antigens of the recipient tissue. Currently, there is no successful therapy for steroid-refractory acute GVHD. The possible role of MSCs in this context is therefore of potential interest. Le Blanc et al reported a case of grade IV acute GVHD of the gut and liver in a patient who had undergone ASCT with cells from an unrelated female donor (32). The patient was unresponsive to all types of immunosuppression drugs. When the patient was infused with 2x 106 MSCs per kilogram from his HLA-haploidentical mother, his GVHD responded with a decline in bilirubin and normalization of stools. After the MSC infusion, DNA analysis of his bone marrow showed the presence of minimal residual disease (124). When immunosuppression was discontinued, the patient again developed severe acute GVHD, with its associated symptoms within a few weeks.
Modulation of host allo-reactivity led to accelerated bone-marrow recovery in patients co-transplanted with MSCs and haplo-identical HSCs (125). Clinical trials are being conducted on the immunomodulatory potential of MSCs in the treatment of Crohn’s disease, with the potential for those cells to contribute to the regeneration of gastrointestinal epithelial cells (126).
As described previously, MSCs are characterized by their hypoimmunogenicity. In 2000, data from several research groups demonstrated long-term allo-MSC engraftment in a variety of non-cardiac tissues in the absence of immunosuppression (88, 90). On the basis of these observations, investigators began to look into the possibility of allo-MSCs engraftment into affected myocardium in rats, and later in swine, where allo-MSCs were found to readily engraft in necrotic myocardium and favorably alter ventricular function (2). The allo-MSC engraftment occurred without evidence of immunologic rejection or lymphocytic infiltration in the absence of assisted immunosuppressive therapy emphasizing some of the apparent advantages of these cells over other cell populations for cellular cardiomyoplasty. The immunologically privileged status of MSCs was also observed in xenogeneic setting, where Saito et al injected MSC intravenously from C57BL/6 mice into immunocompetent adult Lewis rats (127). When these animals were later subjected to MIs, murine MSCs could be identified in the region of necrosis, and these cells expressed muscle specific proteins not present before coronary ligation.
9. Animal models
Consistent with results from
In experiments designed to study the trafficking of
MSC’s immunological properties appeared to have potential therapeutic advantages in other forms of autoimmune diseases, especially in type 1 diabetes. In NOD mouse model, several physiological defects that aim to maintain peripheral and central tolerance contribute to the development of autoimmune diabetes. These defects are summed up as a combination of immune cell dysfunction (including T-cell, NK cells, B-cells, and dendritic cells), associated with the presence of inflammatory cytokine milieu (134). MSCs possess specific immunomodulatory properties capable of halting autoimmunity through immunomodulation processes described in this chapter. The processes might be through a direct effect via the presentation of differential levels of negative costimulatory molecules and the secretion of regulatory cytokines that affect regulatory T-cells/autoreactive T-cells. Furthermore, MSCs could modulate the immunological dysregulation observed in antibody producing B-cells and cytotoxic NK cells. Dendritic cells have been shown to be defective in NOD mice characterized by higher levels of costimulation with a potential capability to shift to a TH-1 type of immune response.
In an experimental mouse model of diabetes induced by streptozotocin, it was observed that MSCs promoted the endogenous repair of pancreatic islets and renal glomeruli (109). Similarly, co-infusion of MSCs and bone-marrow cells inhibited the proliferation of β-cell-specific T-cells isolated from the pancreas of diabetic mice and restored insulin and glucose levels through the induction of recipient-derived pancreatic β-cell regeneration in the absence of trans-differentiation of MSCs (135). These studies show that the
The timing of MSC infusion seems to be a critical parameter in their therapeutic efficacy. In the EAE mouse model of multiple sclerosis, MSC systematically injected at disease onset ameliorated myelin oligodendrocyte glycoprotein (MOG)-induced EAE and further decreased the infiltration T-cells, B-cells and macrophages into the central nervous system (CNS). Furthermore, T cells isolated from the lymph nodes of MSC-treated mice did not proliferate after
Several other studies have provided insights into the effects of MSCs mediated by cytokines. In a model of acute renal failure, the administration of MSCs increased the recovery of renal function through the inhibition of production of proinflammatory cytokines, such as Il-1β, TNF and IFNγ, and through an anti-apoptotic effect on target cells (140). Along the same line, the anti-inflammatory activity of MSCs was revealed in a mouse model of lung fibrosis, where they inhibited the effects of IL-1α-producing T cells and TNF-producing macrophages through the release of IL-1 receptor antagonist (IL-1RA) (141). The release of trophic factors such as the WNT-associated molecule secreted frizzled-related protein 2 (SFRp2), which leads to the rescue of ischemic cardiomyocytes and the restoration of ventricular functions represent another important function for MSC (142).
With all the promising therapeutic potential of MSC, there seems to be a growing concern about their association with tumors. The immunoregulatory and anti-proliferative effects of MSCs led to several studies investigating the inhibitory effect of MSCs on tumor growth. Inhibition or, more frequently, stimulation of tumor-cell proliferation
10. Conclusion
As a whole, the data accumulated from preclinical and clinical data indicate that bone marrow-derived MSCs have, in addition to their therapeutic purposes in regenerative medicine, effects that can result from other characteristics, such as their anti-proliferative and anti-inflammatory properties. The immuno suppressive activity of MSCs provides means for inducing peripheral tolerance following systemic injection mediated through the inhibition of cell division, thereby preventing their responsiveness to antigenic triggers while maintaining them in a quiescent state. In addition, the clinical efficacy of MSCs in different experimental model seems to occur almost only during the acute phase of disease associated with limited trans-differentiation, which indicates that the therapeutic effectiveness of MSCs relies heavily on their ability to modify microenvironments. These modifications occur through the release of anti-inflammatory cytokines, and anti-apoptotic and trophic molecules that promote the repair and protection of damaged tissues, as well as, maintain the integrity of the immune cells.
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