InTechOpen uses cookies to offer you the best online experience. By continuing to use our site, you agree to our Privacy Policy.

Medicine » Stem Cell Research » "Stem Cells in Clinic and Research", book edited by Ali Gholamrezanezhad, ISBN 978-953-307-797-0, Published: August 23, 2011 under CC BY-NC-SA 3.0 license. © The Author(s).

Chapter 3

Mesenchymal Stem Cells: Immunology and Therapeutic Benefits

By Najib El Haddad
DOI: 10.5772/21933

Article top


Potential mechanisms of the MSC interactions with immune cells. Mesenchymal stem cells (MSCs) can inhibit both the proliferation and cytotoxicity of resting natural killer (NK) cells, as well as, their cytokine production by releasing prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO) and soluble HLA-G5 (sHLA-G5). Killing of MSCs by cytokine-activated NK cells involves the engagement of cell-surface receptors (Thick blue line) expressed by NK cells with its ligands expressed on MSCs. MSCs inhibit the differentiation of monocytes to immature myeloid dendritic cells (DCs), bias mature DCs to an immature DC state, inhibit tumour-necrosis factor (TNF) production by DCs and increase interleukin-10 (IL-10) production by plasmacytoid DCs (pDCs). MSC-derived PGE2 is involved in all of these effects. Immature DCs are susceptible to activated NK cell-mediated lysis. MSC Direct inhibition of CD4+ T-cell function depends on their release of several soluble molecules, including PGE2, IDO, transforming growth factor-β1 (TGFβ1), hepatocyte growth factor (HGF), inducible nitric-oxide synthase (iNOS) and haem-oxygenase-1 (HO1). MSC inhibition of CD8+ T-cell cytotoxicity and the differentiation of regulatory T cells mediated directly by MSCs are related to the release of sHLA-G5 by MSCs. In addition, the upregulation of IL-10 production by pDCs results in the increased generation of regulatory T cells through an indirect mechanism. MSC-driven inhibition of B-cell function seems to depend on soluble factors and cell–cell contact. Finally, MSCs dampen the respiratory burst and delay the spontaneous apoptosis of neutrophils by constitutively releasing IL-6.
Figure 1. Potential mechanisms of the MSC interactions with immune cells. Mesenchymal stem cells (MSCs) can inhibit both the proliferation and cytotoxicity of resting natural killer (NK) cells, as well as, their cytokine production by releasing prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO) and soluble HLA-G5 (sHLA-G5). Killing of MSCs by cytokine-activated NK cells involves the engagement of cell-surface receptors (Thick blue line) expressed by NK cells with its ligands expressed on MSCs. MSCs inhibit the differentiation of monocytes to immature myeloid dendritic cells (DCs), bias mature DCs to an immature DC state, inhibit tumour-necrosis factor (TNF) production by DCs and increase interleukin-10 (IL-10) production by plasmacytoid DCs (pDCs). MSC-derived PGE2 is involved in all of these effects. Immature DCs are susceptible to activated NK cell-mediated lysis. MSC Direct inhibition of CD4+ T-cell function depends on their release of several soluble molecules, including PGE2, IDO, transforming growth factor-β1 (TGFβ1), hepatocyte growth factor (HGF), inducible nitric-oxide synthase (iNOS) and haem-oxygenase-1 (HO1). MSC inhibition of CD8+ T-cell cytotoxicity and the differentiation of regulatory T cells mediated directly by MSCs are related to the release of sHLA-G5 by MSCs. In addition, the upregulation of IL-10 production by pDCs results in the increased generation of regulatory T cells through an indirect mechanism. MSC-driven inhibition of B-cell function seems to depend on soluble factors and cell–cell contact. Finally, MSCs dampen the respiratory burst and delay the spontaneous apoptosis of neutrophils by constitutively releasing IL-6.

Mesenchymal Stem Cells: Immunology and Therapeutic Benefits

Najib El Haddad

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 in vitro. These criteria presented properties to purify MSC and to enable their expansion by several-fold in-vitro, without losing their differentiation capacity. When plated at low density, MSCs form small colonies, called colony-forming units of fibroblasts (CFU-f), and which correspond to the progenitors that can differentiate into one of the mesenchymal cell lineages (14, 15). It has been reported lately that MSCs are able to differentiate into both mesenchymal, as well as, non-mesenchymal cell lineages, such as adipocytes, osteoblasts, chondrocytes, tenocytes, skeletal myocytes, neurones and cells of the visceral mesoderm, both in vitro and in vivo (16, 17).

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 ex vivo in up to 40 or 50 cell doublings without differentiation (19). A dramatic decrease in MSC per nucleated marrow cell can be observed when the results are grouped by decade, thus showing a 100-fold decrease from birth to old age. Being pericytes present in all vascularized tissues, the local availability of MSC decreases substantially as the vascular density decreases by one or two orders of magnitude with age (20). In recent years, the discovery of MSCs with properties similar, but not identical, to BM-MSCs has been demonstrated in the stromal fraction of the connective tissue from several organs, including adipose tissue, trabecular bone, derma, liver and muscle (21-24). It is important to note that the origin of MSCs might determine their fate and functional characteristics (25). Studies of human bone marrow have revealed that about one-third of the MSC clones are able to acquire phenotypes of pre-adipocytes, osteocytes and chondrocytes (16). This is in concordance with data showing that 30% of the clones from bone marrow have been found to exhibit a trilineage differentiation potential, whereas the remainder display a bi-lineage (osteo-chondro) or uni-lineage (osteo) potential (26). Moreover, MSC populations derived from adipose tissue and derma present a heterogeneous differentiation potential; indeed, only 1.4% of single cells obtained from adipose-derived adult stem cell (ADAS) populations were tri-potent, the others being bi-potent or unipotent (27).

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 in vitro (28-30). These observations have triggered a huge interest in the immunomodulatory effects of MSCs. The in vitro studies have been complemented in vivo, where both confirmed the immunosuppressive effect of MSC. MSC activating stimuli in vitro, appears to include the secretion of cytokines and the interaction with other immune cells in the presence of proinflammatory cytokines (Fig 1) (31). Primarily, the in vivo effect has been originally shown in a baboon model, in which infusion of ex vivo–expanded matched donor or third-party MSCs delayed the time to rejection of histo-incompatible skin grafts (29). The delay indicated a potential role for MSC in the prevention and treatment of graft-versus-host disease (GVHD) in ASCT, in organ transplantation to prevent rejection, and in autoimmune disorders. Recently, MSCs were used to successfully treat a 9-year-old boy with severe treatment-resistant acute GVHD, further confirming the potent immunosuppressive effect in humans (32). The immunosuppressive potential has no immunologic restriction, whether the MSCs are autologous with the stimulatory or the responder lymphocytes or the MSCs are derived from a third party. The degree of MSC suppression is dose dependent, where high doses of MSC are inhibitory, whereas low doses enhance lymphocyte proliferation in MLCs (33). Broadly, MSC modulate cytokine production by the dendritic and T cell subsets DC/Th1 and DC/Th2 (34), block the antigen presenting cell (APC) maturation and activation (35), and increase the proportion of CD4+CD25+ regulatory cells in a mixed lymphocyte reaction (36).


Figure 1.

Potential mechanisms of the MSC interactions with immune cells. Mesenchymal stem cells (MSCs) can inhibit both the proliferation and cytotoxicity of resting natural killer (NK) cells, as well as, their cytokine production by releasing prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO) and soluble HLA-G5 (sHLA-G5). Killing of MSCs by cytokine-activated NK cells involves the engagement of cell-surface receptors (Thick blue line) expressed by NK cells with its ligands expressed on MSCs. MSCs inhibit the differentiation of monocytes to immature myeloid dendritic cells (DCs), bias mature DCs to an immature DC state, inhibit tumour-necrosis factor (TNF) production by DCs and increase interleukin-10 (IL-10) production by plasmacytoid DCs (pDCs). MSC-derived PGE2 is involved in all of these effects. Immature DCs are susceptible to activated NK cell-mediated lysis. MSC Direct inhibition of CD4+ T-cell function depends on their release of several soluble molecules, including PGE2, IDO, transforming growth factor-β1 (TGFβ1), hepatocyte growth factor (HGF), inducible nitric-oxide synthase (iNOS) and haem-oxygenase-1 (HO1). MSC inhibition of CD8+ T-cell cytotoxicity and the differentiation of regulatory T cells mediated directly by MSCs are related to the release of sHLA-G5 by MSCs. In addition, the upregulation of IL-10 production by pDCs results in the increased generation of regulatory T cells through an indirect mechanism. MSC-driven inhibition of B-cell function seems to depend on soluble factors and cell–cell contact. Finally, MSCs dampen the respiratory burst and delay the spontaneous apoptosis of neutrophils by constitutively releasing IL-6.

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 in vitro and potentially in vivo.

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 in vivo exists, where the latter partially inhibit activated MSC, without compromising their ability to kill MSC, reflecting on an interaction tightly regulated by IFN-γ concentration.

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 in vitro is mirrored by the in vivo finding through infusions of hMSCs that control GVHD following bone marrow transplantation. Nevertheless, there is no demonstrable correlation between the measured effects of MSCs in vitro and their counter effect in vivo due to the lack of universality of methodology correlating the in vitro findings with the in vivo therapeutic potential.

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 in vitro appear to have both contact-dependent and contact-independent components (58). Inhibition of T-cell proliferation by MSCs leads to decreased IFN-γ secretion in vitro and in vivo associated with increased IL-4 production by T helper 2 (TH2) cells (34, 59). Taken together, there is an implication for a shift from a pro-inflammatory state characterized by IFN-γ secretion to an anti-inflammatory state characterized by IL-4 secretion (Fig 1). An imperative role for effector T-cell is the MHC restricted killing of virally-infected or of allogeneic cells mediated via CD8+ CTLs, and which is down-regulated by MSC (60).

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 in vitro, TGF-β in combination with IL-2 directs the differentiation of T-cells into Tregs, while Tregs suppress the proliferation of TCR-dependent proliferation of effector CD25null or CD25low T-cells in a non-autologous fashion. Also TGF-β alters angiogenesis following injury in experiments using MSC (62). In addition, after co-culture with antigen-specific T-cells, MSCs can directly induce the proliferation of regulatory T-cells through release of the immunomodulatory HLA-G isoform HLA-G5 (Fig 1) (63). Taken together, MSCs can modulate the intensity of an immune response by inhibiting antigen-specific T-cell proliferation and cytotoxicity and promoting the generation of regulatory T-cells.

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 in vitro studies have shown that MSCs could support the survival, proliferation and differentiation to antibody-secreting cells of B-cells from normal individuals and from pediatric patients with systemic lupus erythematosus (66, 67). A major mechanism of B-cell suppression was hMSC production of soluble factors, as indicated by transwell experiments, where hMSCs inhibited B-cell differentiation shown as significant impairment of IgM, IgG, and IgA production. CXCR4, CXCR5, and CCR7 B-cell expression, as well as chemotaxis to CXCL12, the CXCR4 ligand, and CXCL13, the CXCR5 ligand, were significantly down-regulated by hMSCs, suggesting that these cells affect chemotactic properties of B-cells (Fig 1). B-cell costimulatory molecule expression and cytokine production were unaffected by hMSCs (64). Regardless of the controversial in vitro effects, B-cell response is mainly a T-cell dependent mechanism, and thus its outcome is significantly influenced by the MSC-mediated inhibition of T-cell functions. More recently, Corcione et al have shown that systemic administration of MSCs to mice affected by experimental autoimmune encephalomyelitis (EAE), a prototypical disease mediated by self-reactive T cells, results in striking disease amelioration mediated by the induction of peripheral tolerance (52). In addition, it has been shown that tolerance induction by MSCs may occur also through the inhibition of dendritic-cell maturation and function (34, 35), thus suggesting that activated T cells are not the only targets of MSCs.

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 in vivo could lead to the arrest of T-cell proliferation, inhibition of CTL-mediated cytotoxicity and generation of CD4+ regulatory T-cells. As a consequence, impaired CD4+ T-cell activation would translate into defective T-cell help for B-cell proliferation and differentiation to antibody-secreting cells.

The hMSCs express few to none of the B7-1/B7-2 (CD80/CD86) costimulatory–type molecules; this appears to contribute, at least in part, to their immune privilege characteristic. Mechanisms that lead to immune tolerance rely on interrelated pathways that involve complex cross talk and cross regulation of T-cells and APCs by one another. Both soluble mediators and modulation exerted via complex networks of cytokines and costimulatory molecules appear to play a role in MSC regulation of T cells, and these mechanisms invoke both contact-dependent and -independent pathways.

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 hMSCs and on cells within non-lymphoid organs. These observations may provide a new means for regulating T-cell activation and tolerance in peripheral tissues (31, 71, 78). ICOS and PD-1 are expressed upon T-cell-induction, and they regulate previously activated T-cells (79). Both the ICOS:ICOSL pathway and the PD-1:PD-L1/PD-L2 pathway play a critical role in regulating T-cell activation and tolerance (79). There is consensus that both CTLA-4 and PD-1 inhibit T-cell and B-cell activation and may play a crucial role in peripheral tolerance (79, 80). Both CTLA-4 and PD-1 functions are associated with Rheumatoid Arthritis (RA) and other autoimmune diseases. PD-1 is over expressed on CD4+ T cells in the synovial fluid of RA patients (81). Whether or not these costimulatory molecules are critical mediators of MSC-mediated immune suppression and/or tolerance in vivo is still under current investigation.

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 in vitro fail to elicit a proliferative response from allogeneic lymphocytes, thus suggesting that the cells are not inherently immunogenic (28, 30, 50). When pre-cultured with IFN-γ for full HLA class II expression, MSCs still escape recognition by allo-reactive T-cells, (83, 84) as is the case with MSCs differentiated adipocytes, osteoblasts, and chondrocytes. Limited in vivo data demonstrate the persistence of allogeneic MSCs into immunocompetent hosts after transplantation. In one patient treated with MSCs, DNA of donor MSC could not be detected in any organ at autopsy few weeks after the infusion, while in another patient receiving MSCs from two donors, the donor DNA from both donors was detected in lymph node and colon, the target organs of GVHD, within weeks after infusion (85). Data from our lab indicated that MSC were undetectable after two weeks in an allogeneic system (86). Therefore, the question of whether MSCs are recognized by an intact allogeneic immune system in vivo remains open, although the in vitro data support the theory that MSCs escape the immune system. MSCs do not express FAS ligand or costimulatory molecules, such as B7-1, B7-2, CD40, or CD40L (50). When costimulation is inadequate, T-cell proliferation can be induced by the addition of exogenous costimulation. However, MSCs differ from other cell types, and no T-cell proliferation can be observed when they are cultured with HLA-mismatched lymphocytes in the presence of a CD28-stimulating antibody (50). However, in agreement with the in vitro data, infusion or implantation of allogeneic and MHC-mismatched MSCs into baboons has been well tolerated (87-89). Unique immunologic properties of MSCs were also suggested by the fact that engraftment of human MSCs occurred after intra-uterine transplantation into sheep, even when the transplantation was performed after the fetuses became immunocompetent (90). MSC mainly fail to activate T-cells and show to be targets for CD8+ T cell-cytotoxicity, althought controversial (60). Phyto-hemagglutinin (PHA) blasts, generated to react against a specific donor, will lyse chromium-labeled mononuclear cells from that individual but it will not lyse MSCs derived from the same donor. Furthermore, killer cell inhibitory receptor (KIR ligand)–mismatched natural killer cells do not lyse MSCs (60). Thus, MSCs, although incompatible at the MHC, tend to escape the immune system.

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 in vitro, thus suggesting cellular immunization. Such a proliferative response in vitro has not been detected in humans treated with intravenous (IV) infusion of allogeneic MSCs (Le Blanc and Ringdén, unpublished data, 2004).

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 hMSCs is their ability to suppress inflammation resulting from injury, as well as, resulting from allogeneic solid organ transplants, and autoimmune disease. Consistent with in vitro studies, murine allogeneic MSCs are effective cellular therapy models in the treatment of murine models of human disease (52, 100-102). Several studies have documented the substantial clinical improvements observed in animal models, when MSC were systemically introduced as a therapy in mouse models of multiple sclerosis (102, 103), inflammatory bowel disease (104-106), infarct, stroke, and other neurologic diseases (107, 108), as well as diabetes (109). These findings strongly suggest that xenogeneic hMSCs are not immunologically recognized by various immunocompetent mouse models of disease and are able to home to sites of inflammation. However, the mechanisms behind the immunosuppressive actions at the site of inflammation and its association with the homing activity have not yet been completely elucidated.

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 in vivo setting, injury, inflammation, and/or foreign cells can lead to T-cell activation, which results in those T-cells producing proinflammatory cytokines including, but not limited to, TNF-α, IFN-γ, IL-1α, and IL-1β. Combinations of cytokines may also induce cell production of chemokines, some of which bind to CXCR3-R expressing cells (including T cells) that co-localize with MSCs. MSCs then produce NO, which inhibits Stat-5 phosphorylation, thereby leading to cell-cycle arrest (and thus halting T cell proliferation) (Fig 1) (110). In addition, iNOS appears to be important in mouse MSC in vivo effects. MSCs from mice that lack iNOS (or IFN-γR1) are unable to suppress GVHD. In contrast to mouse MSCs that use NO in mediating their immune-suppressive effect, hMSCs and MSCs from non-human primates appear to mediate their immune-suppressive effects via IDO (56). There is some controversy about whether the effect of IDO results from local depletion of tryptophan, or from the accumulation of tryptophan metabolites (which is suggested by data showing that use of a tryptophan antagonist, 1-methyl-L tryptophan, restored allo-reactivity that would otherwise have been suppressed by MSCs). In addition to its effect on the JAK-STAT pathway, NO may also influence mitogen activated protein kinase and nuclear factor κB, which would cause a reduction in the gene expression of proinflammatory cytokines.

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 in vivo studies with MSC focused on the engraftment facilitation for the haematopoietic stem cells (111). Further work also focused on the regenerative functions of MSC in terms of functional repair of damaged tissues (112). Hypoimmunogenicity of MSC provided a critical advantage in their use for clinical and therapeutic purposes in vitro (50), followed by pre-clinical studies (29) and reaching the human clinical studies (32) with the use of allogeneic donors. Allogeneic MSC have proved to be an option with major advantages in clinical use, since the use of autologous MSC is hindered by the limited time frame for clonal expansion and the costly in vitro proliferation. However, some sub-acute conditions, such as autoimmune diseases, might allow the use of autologous MSCs and their culture in vitro. It is worth noting that some reports have recently challenged the belief that allogeneic MSCs are poorly immunogenic (113, 114), indicating that in some cases an autologous MSC source could be advantageous. Recent reports have shown that MSCs from patients with autoimmune disease have a normal capability to support hematopoiesis, (115) and to exercise immunomodulatory functions (116), and to show a normal phenotypic characteristics (117).

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 vitro studies, murine allogeneic MSCs are effective in the treatment of murine models of human disease (52, 103, 128). Several studies have reported clinical improvements in mouse models of multiple sclerosis and amyotrophic lateral sclerosis, inflammatory bowel disease, stroke, diabetes, infarct and GVHD using I.V. injected xenogeneic hMSCs rather than allogeneic MSCs (108, 109). A major advantage in using hMSCs in mouse models of human disease is that the possibility of gathering mechanistic data through measuring biomarkers from body fluids or using noninvasive imaging technology, which may prove to be an advantage in clinical studies when applied on humans.

In experiments designed to study the trafficking of hMSCs, investigators used mouse models of severe erosive polyarthritis characterized by an altered transgene allele that results in chronic over-expression of TNF-α and which resemble human RA patients (60, 72). The motive behind utilizing these mice models was to investigate similarities in MSC homing with mouse models of chronic asthma and acute lung injury. Injected hMSC revealed a reduction in ankle arthritis parameters associated with decrease appendage related erythema, possibly due to the MSC localization to ankle joints as revealed by bioluminescence (129). Similar observations for inducing tolerance were made using adipose-derived MSC, where Treg were induced in RA PBMC and in mouse models of arthritis (36, 130). Furthermore, studies of rheumatoid arthritis T-cells showed a down-regulation of effector response using adipose-derived MSCs (131). Variations in this potential described by the capability of MSCs to down-regulate collagen-induced arthritis, and in the ability to induce Tregs, depend on the source of MSC (mouse vs. human) and its characteristics (primary isolate of MSC line), which reflect on difference in function compared to primary expanded MSC (132). Other studies reported that in the collagen-induced model of arthritis, mice infused with MSCs have increased numbers of CD4+CD25+ cells that express FoxP3 and thus reveal a Treg phenotype (20). Recent data on collagen-induced arthritis model, where murine MSCs did not reveal therapeutic benefits against arthritis in vivo, but did show anti-proliferative effect in vitro suggest that there is no appropriate in vitro measures that can be accurately extrapolated into a potential therapeutic utility of MSCs in vivo, and that mouse MSCs show difference in functional characteristics to hMSC in terms of immunoregulatory capacity (133).

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 in vivo administration of MSCs is clinically efficacious through the modulation of pathogenic β- and T-cell responses and through potent bystander effects on the target tissue.

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 in vitro re-challenge with MOG peptide, which is an indication of the induction of T-cell anergy (52). Systematic injection of MSCs was found to inhibit the in vivo production of pathogenic plp-specific antibodies and to suppress the encephalitogenic potential of plp-specific T cells in passive-transfer experiments. In this model, the MSCs migrated to the lymphoid organs, as well as, to the inflamed CNS, where they exercised a protective effect on the neuronal axons in situ (135, 136). In these studies, the therapeutic effect of MSCs depended on the release of anti-apoptotic, anti-inflammatory and trophic molecules, as occurred in the case of stroke in rats (137), and, possibly, on the recruitment of local progenitors and their subsequent induction to differentiate into neural cells (138). As trophic effect, the MSCs appeared to favor oligo-dendrogenisis by neural precursor cells (139).

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 in vitro and/or tumor growth in vivo by MSCs has been reported (143-145). The heterogeneous nature of the MSC populations and the different experimental tumor models used, contribute to the effect of tumors on MSC in which the microenvironment generated by tumors influence the behavior of MSCs (146). Two main mechanisms are probably involved in the enhancement of tumor growth by MSCs. First, the cell-to-cell cross-talk between MSCs and tumor cells contribute to tumor progression, thus integrating within the tumor stroma (147), and second, the suppressive effects of MSCs on the immune system of tumor-bearing hosts might facilitate tumorigenesis, as shown for the inhibition of melanoma rejection, possibly mediated by regulatory CD8+ T cells (144). Irrespective of the possible interactions between cancer cells, immune cells and MSCs, the potential risk of stimulating the growth cancer by MSCs must be considered.

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.


1 - N. J. Zvaifler, L. Marinova-Mutafchieva, G. Adams, C. J. Edwards, J. Moss, J. A. Burger, R. N. Maini, 2000 Mesenchymal precursor cells in the blood of normal individuals. Arthritis Res 2477488
2 - M. F. Pittenger, B. J. Martin, 2004 Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 95920
3 - B. Sacchetti, A. Funari, S. Michienzi, S. Di Cesare, S. Piersanti, I. Saggio, E. Tagliafico, S. Ferrari, P. G. Robey, M. Riminucci, P. Bianco, 2007 Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131324336
4 - J. E. Grove, E. Bruscia, D. S. Krause, 2004 Plasticity of bone marrow-derived stem cells. Stem Cells 22487500
5 - D. J. Prockop, C. A. Gregory, J. L. Spees, 2003 One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues. Proc Natl Acad Sci U S A 100 Suppl 11191711923
6 - S. Gronthos, D. M. Franklin, H. A. Leddy, P. G. Robey, R. W. Storms, J. M. Gimble, 2001Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol 1895463
7 - A. Erices, P. Conget, J. J. Minguell, 2000 Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 109235242
8 - ‘t. In, P. S. Anker, S. A. Scherjon, C. Kleijburg-van, W. A. der Keur, F. H. Noort, R. Claas, W. E. Willemze, Fibbe, H. H. Kanhai, 2003 Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 10215481549
9 - A. J. Friedenstein, K. V. Petrakova, A. I. Kurolesova, G. P. Frolova, 1968 Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6230247
10 - A. J. Friedenstein, 1976 Precursor cells of mechanocytes. Int Rev Cytol 47327359
11 - A. I. Caplan, 1991 Mesenchymal stem cells. J Orthop Res 9641650
12 - E. M. Horwitz, K. Le Blanc, M. Dominici, I. Mueller, I. Slaper-Cortenbach, F. C. Marini, R. J. Deans, D. S. Krause, A. Keating, 2005 Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7393395
13 - M. Dominici, K. Le Blanc, I. Mueller, I. Slaper-Cortenbach, F. Marini, D. Krause, R. Deans, A. Keating, D. Prockop, E. Horwitz, 2006 Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8315317
14 - D. J. Prockop, 1997 Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 2767174
15 - D. C. Colter, I. Sekiya, D. J. Prockop, 2001 Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc Natl Acad Sci U S A 9878417845
16 - M. F. Pittenger, A. M. Mackay, S. C. Beck, R. K. Jaiswal, R. Douglas, J. D. Mosca, M. A. Moorman, D. W. Simonetti, S. Craig, D. R. Marshak, 1999 Multilineage potential of adult human mesenchymal stem cells. Science 284143147
17 - M. Reyes, T. Lund, T. Lenvik, D. Aguiar, L. Koodie, C. M. Verfaillie, 2001 Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 9826152625
18 - E. D. Thomas, K. G. Blume, 1999 Historical markers in the development of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 5341346
19 - J. F. Welter, L. A. Solchaga, K. J. Penick, 2007 Simplification of aggregate culture of human mesenchymal stem cells as a chondrogenic screening assay. Biotechniques 42:732, 734-737.
20 - Silva. da, L. Meirelles, A. I. Caplan, N. B. Nardi, 2008 In search of the in vivo identity of mesenchymal stem cells. Stem Cells 2622872299
21 - P. A. Zuk, M. Zhu, H. Mizuno, J. Huang, J. W. Futrell, A. J. Katz, P. Benhaim, H. P. Lorenz, M. H. Hedrick, 2001 Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7211228
22 - U. Noth, A. M. Osyczka, R. Tuli, N. J. Hickok, K. G. Danielson, R. S. Tuan, 2002 Multilineage mesenchymal differentiation potential of human trabecular bone-derived cells. J Orthop Res 2010601069
23 - R. H. Lee, B. Kim, I. Choi, H. Kim, H. S. Choi, K. Suh, Y. C. Bae, J. S. Jung, 2004 Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem 14311324
24 - J. G. Toma, M. Akhavan, K. J. Fernandes, F. Barnabe-Heider, A. Sadikot, D. R. Kaplan, F. D. Miller, 2001 Isolation of multipotent adult stem cells from the dermis of mammalian skin. Nat Cell Biol 3778784
25 - K. A. Keyser, K. E. Beagles, H. P. Kiem, 2007 Comparison of mesenchymal stem cells from different tissues to suppress T-cell activation. Cell Transplant 16555562
26 - A. Muraglia, R. Cancedda, R. Quarto, 2000 Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J Cell Sci 113 ( Pt 7):11611166
27 - P. A. Zuk, M. Zhu, P. Ashjian, D. A. De Ugarte, J. I. Huang, H. Mizuno, Z. C. Alfonso, J. K. Fraser, P. Benhaim, M. H. Hedrick, 2002 Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 1342794295
28 - M. Di Nicola, C. Carlo-Stella, M. Magni, M. Milanesi, P. D. Longoni, P. Matteucci, S. Grisanti, A. M. Gianni, 2002 Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 9938383843
29 - A. Bartholomew, C. Sturgeon, M. Siatskas, K. Ferrer, K. Mc Intosh, S. Patil, W. Hardy, S. Devine, D. Ucker, R. Deans, A. Moseley, R. Hoffman, 2002 Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol 304248
30 - K. Le Blanc, L. Tammik, B. Sundberg, S. E. Haynesworth, O. Ringden, 2003 Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 571120
31 - A. Augello, R. Tasso, S. M. Negrini, A. Amateis, F. Indiveri, R. Cancedda, G. Pennesi, 2005 Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur J Immunol 3514821490
32 - K. Le Blanc, I. Rasmusson, B. Sundberg, C. Gotherstrom, M. Hassan, M. Uzunel, O. Ringden, 2004 Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 36314391441
33 - B. Maitra, E. Szekely, K. Gjini, M. J. Laughlin, J. Dennis, S. E. Haynesworth, O. N. Koc, 2004 Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant 33597604
34 - S. Aggarwal, M. F. Pittenger, 2005 Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 10518151822
35 - S. Beyth, Z. Borovsky, D. Mevorach, M. Liebergall, Z. Gazit, H. Aslan, E. Galun, J. Rachmilewitz, 2005 Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 10522142219
36 - A. Augello, R. Tasso, S. M. Negrini, R. Cancedda, G. Pennesi, 2007 Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum 5611751186
37 - L. Chen, W. Zhang, H. Yue, Q. Han, B. Chen, M. Shi, J. Li, B. Li, S. You, Y. Shi, R. C. Zhao, 2007 Effects of human mesenchymal stem cells on the differentiation of dendritic cells from CD34+ cells. Stem Cells Dev 16719731
38 - W. Zhang, W. Ge, C. Li, S. You, L. Liao, Q. Han, W. Deng, R. C. Zhao, 2004 Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev 13263271
39 - R. Ramasamy, H. Fazekasova, E. W. Lam, I. Soeiro, G. Lombardi, F. Dazzi, 2007 Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 837176
40 - R. Maccario, M. Podesta, A. Moretta, A. Cometa, P. Comoli, D. Montagna, L. Daudt, A. Ibatici, G. Piaggio, S. Pozzi, F. Frassoni, F. Locatelli, 2005 Interaction of human mesenchymal stem cells with cells involved in alloantigen-specific immune response favors the differentiation of CD4+ T-cell subsets expressing a regulatory/suppressive phenotype. Haematologica 90516525
41 - A. Moretta, 2002 Natural killer cells and dendritic cells: rendezvous in abused tissues. Nat Rev Immunol 2957964
42 - A. Moretta, C. Bottino, M. Vitale, D. Pende, R. Biassoni, M. C. Mingari, L. Moretta, 1996 Receptors for HLA class-I molecules in human natural killer cells. Annu Rev Immunol 14619648
43 - G. M. Spaggiari, A. Capobianco, S. Becchetti, M. C. Mingari, L. Moretta, 2006 Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood 10714841490
44 - G. M. Spaggiari, A. Capobianco, H. Abdelrazik, F. Becchetti, M. C. Mingari, L. Moretta, 2008 Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 11113271333
45 - A. Poggi, C. Prevosto, A. M. Massaro, S. Negrini, S. Urbani, I. Pierri, R. Saccardi, M. Gobbi, M. R. Zocchi, 2005 Interaction between human NK cells and bone marrow stromal cells induces NK cell triggering: role of NKp30 and NKG2D receptors. J Immunol 17563526360
46 - Jan. de Kuiper, N. M. I. N. M. v. B. C. C. B. W. W. M. J. H. M. J. Human mesenchymal stem cells are susceptible to lysis by CD8 + T-cells and NK cells. Cell Transplant.
47 - L. Raffaghello, G. Bianchi, M. Bertolotto, F. Montecucco, A. Busca, F. Dallegri, L. Ottonello, V. Pistoia, 2008 Human mesenchymal stem cells inhibit neutrophil apoptosis: a model for neutrophil preservation in the bone marrow niche. Stem Cells 26151162
48 - S. Brandau, M. Jakob, H. Hemeda, K. Bruderek, S. Janeschik, F. Bootz, S. Lang, Tissue-resident mesenchymal stem cells attract peripheral blood neutrophils and enhance their inflammatory activity in response to microbial challenge. J Leukoc Biol 8810051015
49 - C. G. Craddock , JrS. Perry, L. E. Ventzke, J. S. Lawrence, 1960 Evaluation of marrow granulocytic reserves in normal and disease states. Blood 15840855
50 - W. T. Tse, J. D. Pendleton, W. M. Beyer, M. C. Egalka, E. C. Guinan, 2003 Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75389397
51 - R. Meisel, A. Zibert, M. Laryea, U. Gobel, W. Daubener, D. Dilloo, 2004 Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood 10346194621
52 - E. Zappia, S. Casazza, E. Pedemonte, F. Benvenuto, I. Bonanni, E. Gerdoni, D. Giunti, A. Ceravolo, F. Cazzanti, F. Frassoni, G. Mancardi, A. Uccelli, 2005 Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 10617551761
53 - I. Rasmusson, O. Ringden, B. Sundberg, K. Le Blanc, 2005 Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 3053341
54 - M. Krampera, S. Glennie, J. Dyson, D. Scott, R. Laylor, E. Simpson, F. Dazzi, 2003 Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 10137223729
55 - S. Glennie, I. Soeiro, P. J. Dyson, E. W. Lam, F. Dazzi, 2005 Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 10528212827
56 - G. Ren, L. Zhang, X. Zhao, G. Xu, Y. Zhang, A. I. Roberts, R. C. Zhao, Y. Shi, 2008 Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2141150
57 - F. Benvenuto, S. Ferrari, E. Gerdoni, F. Gualandi, F. Frassoni, V. Pistoia, G. Mancardi, A. Uccelli, 2007 Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells 2517531760
58 - M. E. Groh, B. Maitra, E. Szekely, O. N. Koc, 2005 Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. Exp Hematol 33928934
59 - B. Fadeel, A. Ahlin, J. I. Henter, S. Orrenius, M. B. Hampton, 1998 Involvement of caspases in neutrophil apoptosis: regulation by reactive oxygen species. Blood 9248084818
60 - I. Rasmusson, O. Ringden, B. Sundberg, K. Le Blanc, 2003 Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells. Transplantation 7612081213
61 - D. Figueroa-Tentori, S. Querol, I. A. Dodi, A. Madrigal, R. Duggleby, 2008 High purity and yield of natural Tregs from cord blood using a single step selection method. J Immunol Methods 339228235
62 - J. Y. Oh, M. K. Kim, M. S. Shin, H. J. Lee, J. H. Ko, W. R. Wee, J. H. Lee, 2008 The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells 2610471055
63 - Z. Selmani, A. Naji, I. Zidi, B. Favier, E. Gaiffe, L. Obert, C. Borg, P. Saas, P. Tiberghien, N. Rouas-Freiss, E. D. Carosella, F. Deschaseaux, 2008 Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+CD25highFOXP3+ regulatory T cells. Stem Cells 26212222
64 - A. Corcione, F. Benvenuto, E. Ferretti, D. Giunti, V. Cappiello, F. Cazzanti, M. Risso, F. Gualandi, G. L. Mancardi, V. Pistoia, A. Uccelli, 2006 Human mesenchymal stem cells modulate B-cell functions. Blood 107367372
65 - P. Comoli, F. Ginevri, R. Maccario, M. A. Avanzini, M. Marconi, A. Groff, A. Cometa, M. Cioni, L. Porretti, W. Barberi, F. Frassoni, F. Locatelli, 2008 Human mesenchymal stem cells inhibit antibody production induced in vitro by allostimulation. Nephrol Dial Transplant 2311961202
66 - E. Traggiai, S. Volpi, F. Schena, M. Gattorno, F. Ferlito, L. Moretta, A. Martini, 2008 Bone marrow-derived mesenchymal stem cells induce both polyclonal expansion and differentiation of B cells isolated from healthy donors and systemic lupus erythematosus patients. Stem Cells 26562569
67 - I. Rasmusson, K. Le Blanc, B. Sundberg, O. Ringden, 2007 Mesenchymal stem cells stimulate antibody secretion in human B cells. Scand J Immunol 65336343
68 - J. Stagg, S. Pommey, N. Eliopoulos, J. Galipeau, 2006 Interferon-gamma-stimulated marrow stromal cells: a new type of nonhematopoietic antigen-presenting cell. Blood 10725702577
69 - J. L. Chan, K. C. Tang, A. P. Patel, L. M. Bonilla, N. Pierobon, N. M. Ponzio, P. Rameshwar, 2006 Antigen-presenting property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood 10748174824
70 - M. Feuerer, P. Beckhove, N. Garbi, Y. Mahnke, A. Limmer, M. Hommel, G. J. Hammerling, B. Kyewski, A. Hamann, V. Umansky, V. Schirrmacher, 2003 Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat Med 911511157
71 - Q. Xue, X. Y. Luan, Y. Z. Gu, H. Y. Wu, G. B. Zhang, G. H. Yu, H. T. Zhu, M. Wang, W. Dong, Y. J. Geng, X. G. Zhang, The negative co-signaling molecule b7-h4 is expressed by human bone marrow-derived mesenchymal stem cells and mediates its T-cell modulatory activity. Stem Cells Dev 192738
72 - M. K. Majumdar, M. Keane-Moore, D. Buyaner, W. B. Hardy, M. A. Moorman, K. R. Mc Intosh, J. D. Mosca, 2003 Characterization and functionality of cell surface molecules on human mesenchymal stem cells. J Biomed Sci 10228241
73 - B. T. Fife, K. E. Pauken, T. N. Eagar, T. Obu, J. Wu, Q. Tang, M. Azuma, M. F. Krummel, J. A. Bluestone, 2009 Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. Nat Immunol 1011851192
74 - D. Franceschini, M. Paroli, V. Francavilla, M. Videtta, S. Morrone, G. Labbadia, A. Cerino, M. U. Mondelli, V. Barnaba, 2009 PD-L1 negatively regulates CD4+CD25+Foxp3+ Tregs by limiting STAT-5 phosphorylation in patients chronically infected with HCV. J Clin Invest 119551564
75 - B. T. Fife, J. A. Bluestone, 2008 Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 224166182
76 - A. D. Salama, T. Chitnis, J. Imitola, M. J. Ansari, H. Akiba, F. Tushima, M. Azuma, H. Yagita, M. H. Sayegh, S. J. Khoury, 2003 Critical role of the programmed death-1 (PD-1) pathway in regulation of experimental autoimmune encephalomyelitis. J Exp Med 1987178
77 - W. A. Teft, M. G. Kirchhof, J. Madrenas, 2006 A molecular perspective of CTLA-4 function. Annu Rev Immunol 246597
78 - X. Ni, Y. Q. Jia, W. T. Meng, L. Zhong, Y. Zeng, 2009 Expression of B7-H1 molecule on human bone marrow mesenchymal stem cells and its effects on T lymphocyte proliferation). Zhongguo Shi Yan Xue Ye Xue Za Zhi 17990993
79 - R. J. Greenwald, G. J. Freeman, A. H. Sharpe, 2005 The B7 family revisited. Annu Rev Immunol 23515548
80 - N. Martin-Orozco, Y. H. Wang, H. Yagita, C. Dong, 2006 Cutting Edge: Programmed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens. J Immunol 17782918295
81 - S. Hatachi, Y. Iwai, S. Kawano, S. Morinobu, M. Kobayashi, M. Koshiba, R. Saura, M. Kurosaka, T. Honjo, S. Kumagai, 2003 CD4+ PD-1+ T cells accumulate as unique anergic cells in rheumatoid arthritis synovial fluid. J Rheumatol 3014101419
82 - R. J. Deans, A. B. Moseley, 2000 Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28875884
83 - K. Le Blanc, C. Tammik, K. Rosendahl, E. Zetterberg, O. Ringden, 2003 HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31890896
84 - C. Gotherstrom, O. Ringden, C. Tammik, E. Zetterberg, M. Westgren, K. Le Blanc, 2004 Immunologic properties of human fetal mesenchymal stem cells. Am J Obstet Gynecol 190239245
85 - O. Ringden, M. Uzunel, I. Rasmusson, M. Remberger, B. Sundberg, H. Lonnies, H. U. Marschall, A. Dlugosz, A. Szakos, Z. Hassan, B. Omazic, J. Aschan, L. Barkholt, K. Le Blanc, 2006 Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 8113901397
86 - N. El Haddad, D. Heathcote, R. Moore, S. Yang, J. Azzi, B. Mfarrej, M. Atkinson, M. H. Sayegh, J. S. Lee, P. G. Ashton-Rickardt, R. Abdi, Mesenchymal stem cells express serine protease inhibitor to evade the host immune response. Blood 11711761183
87 - S. M. Devine, A. M. Bartholomew, N. Mahmud, M. Nelson, S. Patil, W. Hardy, C. Sturgeon, T. Hewett, T. Chung, W. Stock, D. Sher, S. Weissman, K. Ferrer, J. Mosca, R. Deans, A. Moseley, R. Hoffman, 2001 Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion. Exp Hematol 29244255
88 - A. Bartholomew, S. Patil, A. Mackay, M. Nelson, D. Buyaner, W. Hardy, J. Mosca, C. Sturgeon, M. Siatskas, N. Mahmud, K. Ferrer, R. Deans, A. Moseley, R. Hoffman, S. M. Devine, 2001 Baboon mesenchymal stem cells can be genetically modified to secrete human erythropoietin in vivo. Hum Gene Ther 1215271541
89 - S. M. Devine, C. Cobbs, M. Jennings, A. Bartholomew, R. Hoffman, 2003 Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into nonhuman primates. Blood 10129993001
90 - K. W. Liechty, Kenzie. T. C. Mac, A. F. Shaaban, A. Radu, A. M. Moseley, R. Deans, D. R. Marshak, A. W. Flake, 2000 Human mesenchymal stem cells engraft and demonstrate site-specific differentiation after in utero transplantation in sheep. Nat Med 612821286
91 - K. H. Grinnemo, A. Mansson, G. Dellgren, D. Klingberg, E. Wardell, V. Drvota, C. Tammik, J. Holgersson, O. Ringden, C. Sylven, K. Le Blanc, 2004 Xenoreactivity and engraftment of human mesenchymal stem cells transplanted into infarcted rat myocardium. J Thorac Cardiovasc Surg 12712931300
92 - M. Krampera, L. Cosmi, R. Angeli, A. Pasini, F. Liotta, A. Andreini, V. Santarlasci, B. Mazzinghi, G. Pizzolo, F. Vinante, P. Romagnani, E. Maggi, S. Romagnani, F. Annunziato, 2006 Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24386398
93 - J. M. Ryan, F. Barry, J. M. Murphy, B. P. Mahon, 2007 Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 149353363
94 - D. Chabannes, M. Hill, E. Merieau, J. Rossignol, R. Brion, J. P. Soulillou, I. Anegon, M. C. Cuturi, 2007 A role for heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells. Blood 11036913694
95 - F. Djouad, L. M. Charbonnier, C. Bouffi, P. Louis-Plence, C. Bony, F. Apparailly, C. Cantos, C. Jorgensen, D. Noel, 2007 Mesenchymal stem cells inhibit the differentiation of dendritic cells through an interleukin-6-dependent mechanism. Stem Cells 2520252032
96 - M. Sioud, New insights into mesenchymal stromal cell-mediated T-cell suppression through galectins. Scand J Immunol 737984
97 - J. M. Ilarregui, D. O. Croci, G. A. Bianco, M. A. Toscano, M. Salatino, M. E. Vermeulen, J. R. Geffner, G. A. Rabinovich, 2009 Tolerogenic signals delivered by dendritic cells to T cells through a galectin-1-driven immunoregulatory circuit involving interleukin 27 and interleukin 10. Nat Immunol 10981991
98 - F. Morandi, L. Raffaghello, G. Bianchi, F. Meloni, A. Salis, E. Millo, S. Ferrone, V. Barnaba, V. Pistoia, 2008 Immunogenicity of human mesenchymal stem cells in HLA-class I-restricted T-cell responses against viral or tumor-associated antigens. Stem Cells 2612751287
99 - A. Nasef, N. Mathieu, A. Chapel, J. Frick, S. Francois, C. Mazurier, A. Boutarfa, S. Bouchet, N. C. Gorin, D. Thierry, L. Fouillard, 2007 Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G. Transplantation 84231237
100 - T. V. Lanz, C. A. Opitz, P. P. Ho, A. Agrawal, C. Lutz, M. Weller, A. L. Mellor, L. Steinman, W. Wick, M. Platten, Mouse mesenchymal stem cells suppress antigen-specific TH cell immunity independent of indoleamine 2,3-dioxygenase 1 (IDO1). Stem Cells Dev 19657668
101 - M. Rafei, E. Birman, K. Forner, J. Galipeau, 2009 Allogeneic mesenchymal stem cells for treatment of experimental autoimmune encephalomyelitis. Mol Ther 1717991803
102 - L. Bai, D. P. Lennon, V. Eaton, K. Maier, A. I. Caplan, S. D. Miller, R. H. Miller, 2009 Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 5711921203
103 - Y. Ding, D. Xu, G. Feng, A. Bushell, R. J. Muschel, K. J. Wood, 2009 Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and-9. Diabetes 5817971806
104 - E. Gonzalez-Rey, P. Anderson, M. A. Gonzalez, L. Rico, D. Buscher, M. Delgado, 2009 Human adult stem cells derived from adipose tissue protect against experimental colitis and sepsis. Gut 58929939
105 - M. A. Gonzalez, E. Gonzalez-Rey, L. Rico, D. Buscher, M. Delgado, 2009 Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses. Gastroenterology 136978989
106 - F. Tanaka, K. Tominaga, M. Ochi, T. Tanigawa, T. Watanabe, Y. Fujiwara, K. Ohta, N. Oshitani, K. Higuchi, T. Arakawa, 2008 Exogenous administration of mesenchymal stem cells ameliorates dextran sulfate sodium-induced colitis via anti-inflammatory action in damaged tissue in rats. Life Sci 83771779
107 - S. K. Kang, E. S. Jun, Y. C. Bae, J. S. Jung, 2003 Interactions between human adipose stromal cells and mouse neural stem cells in vitro. Brain Res Dev Brain Res 145141149
108 - C. P. Zhao, C. Zhang, S. N. Zhou, Y. M. Xie, Y. H. Wang, H. Huang, Y. C. Shang, W. Y. Li, C. Zhou, M. J. Yu, S. W. Feng, 2007 Human mesenchymal stromal cells ameliorate the phenotype of SOD1-G93A ALS mice. Cytotherapy 9414426
109 - R. H. Lee, M. J. Seo, R. L. Reger, J. L. Spees, A. A. Pulin, S. D. Olson, D. J. Prockop, 2006 Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci U S A 1031743817443
110 - K. Sato, K. Ozaki, I. Oh, A. Meguro, K. Hatanaka, T. Nagai, K. Muroi, K. Ozawa, 2007 Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109228234
111 - G. Almeida-Porada, C. D. Porada, N. Tran, E. D. Zanjani, 2000 Cotransplantation of human stromal cell progenitors into preimmune fetal sheep results in early appearance of human donor cells in circulation and boosts cell levels in bone marrow at later time points after transplantation. Blood 9536203627
112 - D. Orlic, J. Kajstura, S. Chimenti, I. Jakoniuk, S. M. Anderson, B. Li, J. Pickel, R. Mc Kay, B. Nadal-Ginard, D. M. Bodine, A. Leri, P. Anversa, 2001 Bone marrow cells regenerate infarcted myocardium. Nature 410701705
113 - N. Eliopoulos, J. Stagg, L. Lejeune, S. Pommey, J. Galipeau, 2005 Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood 10640574065
114 - A. J. Nauta, G. Westerhuis, A. B. Kruisselbrink, E. G. Lurvink, R. Willemze, W. E. Fibbe, 2006 Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 10821142120
115 - H. A. Papadaki, M. Tsagournisakis, V. Mastorodemos, C. Pontikoglou, A. Damianaki, K. Pyrovolaki, K. Stamatopoulos, A. Fassas, A. Plaitakis, G. D. Eliopoulos, 2005 Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis. Bone Marrow Transplant 3610531063
116 - C. Bocelli-Tyndall, A. Barbero, C. Candrian, R. Ceredig, A. Tyndall, I. Martin, 2006 Human articular chondrocytes suppress in vitro proliferation of anti-CD3 activated peripheral blood mononuclear cells. J Cell Physiol 209732734
117 - M. C. Kastrinaki, P. Sidiropoulos, S. Roche, J. Ringe, S. Lehmann, H. Kritikos, V. M. Vlahava, B. Delorme, G. D. Eliopoulos, C. Jorgensen, P. Charbord, T. Haupl, D. T. Boumpas, H. A. Papadaki, 2008 Functional, molecular and proteomic characterisation of bone marrow mesenchymal stem cells in rheumatoid arthritis. Ann Rheum Dis 67741749
118 - J. M. Murphy, K. Dixon, S. Beck, D. Fabian, A. Feldman, F. Barry, 2002 Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum 46704713
119 - J. C. Fernandes, J. Martel-Pelletier, J. P. Pelletier, 2002The role of cytokines in osteoarthritis pathophysiology. Biorheology 39237246
120 - M. B. Goldring, 2001 Anticytokine therapy for osteoarthritis. Expert Opin Biol Ther 1817829
121 - A. Bacigalupo, M. Valle, M. Podesta, A. Pitto, E. Zocchi, A. De Flora, S. Pozzi, S. Luchetti, F. Frassoni, M. T. Van Lint, G. Piaggio, 2005 T-cell suppression mediated by mesenchymal stem cells is deficient in patients with severe aplastic anemia. Exp Hematol 33819827
122 - B. Arnulf, S. Lecourt, J. Soulier, B. Ternaux, M. N. Lacassagne, A. Crinquette, J. Dessoly, A. K. Sciaini, M. Benbunan, C. Chomienne, J. P. Fermand, J. P. Marolleau, J. Larghero, 2007 Phenotypic and functional characterization of bone marrow mesenchymal stem cells derived from patients with multiple myeloma. Leukemia 21158163
123 - E. M. Horwitz, D. J. Prockop, L. A. Fitzpatrick, W. W. Koo, P. L. Gordon, M. Neel, M. Sussman, P. Orchard, J. C. Marx, R. E. Pyeritz, M. K. Brenner, 1999 Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5309313
124 - M. Uzunel, J. Mattsson, M. Jaksch, M. Remberger, O. Ringden, 2001 The significance of graft-versus-host disease and pretransplantation minimal residual disease status to outcome after allogeneic stem cell transplantation in patients with acute lymphoblastic leukemia. Blood 9819821984
125 - L. M. Ball, M. E. Bernardo, H. Roelofs, A. Lankester, A. Cometa, R. M. Egeler, F. Locatelli, W. E. Fibbe, 2007 Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 11027642767
126 - R. Okamoto, T. Yajima, M. Yamazaki, T. Kanai, M. Mukai, S. Okamoto, Y. Ikeda, T. Hibi, J. Inazawa, M. Watanabe, 2002 Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med 810111017
127 - T. Saito, J. Q. Kuang, B. Bittira, A. Al-Khaldi, R. C. Chiu, 2002Xenotransplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg 741924discussion 24.
128 - P. Fiorina, M. Jurewicz, A. Augello, A. Vergani, S. Dada, S. La Rosa, M. Selig, J. Godwin, K. Law, C. Placidi, R. N. Smith, C. Capella, S. Rodig, C. N. Adra, M. Atkinson, M. H. Sayegh, R. Abdi, 2009 Immunomodulatory function of bone marrow-derived mesenchymal stem cells in experimental autoimmune type 1 diabetes. J Immunol 1839931004
129 - N. G. Singer, A. I. Caplan, stem. Mesenchymal, mechanisms. cells, inflammation. of, Annu Rev Pathol 6457478
130 - M. A. Gonzalez, E. Gonzalez-Rey, L. Rico, D. Buscher, M. Delgado, 2009 Treatment of experimental arthritis by inducing immune tolerance with human adipose-derived mesenchymal stem cells. Arthritis Rheum 6010061019
131 - Rosa. O. Dela, E. Lombardo, A. Beraza, P. Mancheno-Corvo, C. Ramirez, R. Menta, L. Rico, E. Camarillo, L. Garcia, J. L. Abad, C. Trigueros, M. Delgado, D. Buscher, 2009 Requirement of IFN-gamma-mediated indoleamine 2,3-dioxygenase expression in the modulation of lymphocyte proliferation by human adipose-derived stem cells. Tissue Eng Part A 1527952806
132 - F. Djouad, V. Fritz, F. Apparailly, P. Louis-Plence, C. Bony, J. Sany, C. Jorgensen, D. Noel, 2005 Reversal of the immunosuppressive properties of mesenchymal stem cells by tumor necrosis factor alpha in collagen-induced arthritis. Arthritis Rheum 5215951603
133 - E. Schurgers, H. Kelchtermans, T. Mitera, L. Geboes, P. Matthys, Discrepancy between the in vitro and in vivo effects of murine mesenchymal stem cells on T-cell proliferation and collagen-induced arthritis. Arthritis Res Ther 12:R31.
134 - M. S. Anderson, J. A. Bluestone, 2005 The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23447485
135 - V. S. Urban, J. Kiss, J. Kovacs, E. Gocza, V. Vas, E. Monostori, F. Uher, 2008Mesenchymal stem cells cooperate with bone marrow cells in therapy of diabetes. Stem Cells 26244253
136 - A. Uccelli, V. Pistoia, L. Moretta, 2007 Mesenchymal stem cells: a new strategy for immunosuppression? Trends Immunol 28219226
137 - Y. Li, J. Chen, X. G. Chen, L. Wang, S. C. Gautam, Y. X. Xu, M. Katakowski, L. J. Zhang, M. Lu, N. Janakiraman, M. Chopp, 2002 Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59514523
138 - J. R. Munoz, B. R. Stoutenger, A. P. Robinson, J. L. Spees, D. J. Prockop, 2005 Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc Natl Acad Sci U S A 1021817118176
139 - F. J. Rivera, S. Couillard-Despres, X. Pedre, S. Ploetz, M. Caioni, C. Lois, U. Bogdahn, L. Aigner, 2006 Mesenchymal stem cells instruct oligodendrogenic fate decision on adult neural stem cells. Stem Cells 2422092219
140 - F. Togel, Z. Hu, K. Weiss, J. Isaac, C. Lange, C. Westenfelder, 2005 Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 289:F3142
141 - L. A. Ortiz, M. Dutreil, C. Fattman, A. C. Pandey, G. Torres, K. Go, D. G. Phinney, 2007 Interleukin 1 receptor antagonist mediates the antiinflammatory and antifibrotic effect of mesenchymal stem cells during lung injury. Proc Natl Acad Sci U S A 1041100211007
142 - M. Mirotsou, Z. Zhang, A. Deb, L. Zhang, M. Gnecchi, N. Noiseux, H. Mu, A. Pachori, V. Dzau, 2007 Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc Natl Acad Sci U S A 10416431648
143 - R. Ramasamy, E. W. Lam, I. Soeiro, V. Tisato, D. Bonnet, F. Dazzi, 2007 Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. Leukemia 21304310
144 - F. Djouad, P. Plence, C. Bony, P. Tropel, F. Apparailly, J. Sany, D. Noel, C. Jorgensen, 2003 Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 10238373844
145 - P. Ame-Thomas, H. Maby El, C. Hajjami, R. Monvoisin, D. Jean, S. Monnier, T. Caulet-Maugendre, T. Guillaudeux, T. Lamy, Fest, K. Tarte, 2007 Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis. Blood 109693702
146 - L. A. Liotta, E. C. Kohn, 2001 The microenvironment of the tumour-host interface. Nature 411375379
147 - A. E. Karnoub, A. B. Dash, A. P. Vo, A. Sullivan, M. W. Brooks, G. W. Bell, A. L. Richardson, K. Polyak, R. Tubo, R. A. Weinberg, 2007 Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449557563