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1.
Ren G  Zhang L  Zhao X  Xu G  Zhang Y  Roberts AI  Zhao RC  Shi Y 《Cell Stem Cell》2008,2(2):141-150
Mesenchymal stem cells (MSCs) can become potently immunosuppressive through unknown mechanisms. We found that the immunosuppressive function of MSCs is elicited by IFNgamma and the concomitant presence of any of three other proinflammatory cytokines, TNFalpha, IL-1alpha, or IL-1beta. These cytokine combinations provoke the expression of high levels of several chemokines and inducible nitric oxide synthase (iNOS) by MSCs. Chemokines drive T cell migration into proximity with MSCs, where T cell responsiveness is suppressed by nitric oxide (NO). This cytokine-induced immunosuppression was absent in MSCs derived from iNOS(-/-) or IFNgammaR1(-/-) mice. Blockade of chemokine receptors also abolished the immunosuppression. Administration of wild-type MSCs, but not IFNgammaR1(-/-) or iNOS(-/-) MSCs, prevented graft-versus-host disease in mice, an effect reversed by anti-IFNgamma or iNOS inhibitors. Wild-type MSCs also inhibited delayed-type hypersensitivity, while iNOS(-/-) MSCs aggravated it. Therefore, proinflammatory cytokines are required to induce immunosuppression by MSCs through the concerted action of chemokines and NO.  相似文献   

2.
Mesenchymal stem cells (MSCs) have been employed successfully to treat various immune disorders in animal models and clinical settings. Our previous studies have shown that MSCs can become highly immunosuppressive upon stimulation by inflammatory cytokines, an effect exerted through the concerted action of chemokines and nitric oxide (NO). Here, we show that MSCs can also enhance immune responses. This immune-promoting effect occurred when proinflammatory cytokines were inadequate to elicit sufficient NO production. When inducible nitric oxide synthase (iNOS) production was inhibited or genetically ablated, MSCs strongly enhance T-cell proliferation in vitro and the delayed-type hypersensitivity response in vivo. Furthermore, iNOS(-/-) MSCs significantly inhibited melanoma growth. It is likely that in the absence of NO, chemokines act to promote immune responses. Indeed, in CCR5(-/-)CXCR3(-/-) mice, the immune-promoting effect of iNOS(-/-) MSCs is greatly diminished. Thus, NO acts as a switch in MSC-mediated immunomodulation. More importantly, the dual effect on immune reactions was also observed in human MSCs, in which indoleamine 2,3-dioxygenase (IDO) acts as a switch. This study provides novel information about the pathophysiological roles of MSCs.  相似文献   

3.
Mesenchymal stem cells (MSCs) are not only able to evade the immune system, but they have also been demonstrated to exert profound immunosuppressive properties on T cell proliferation. However, their effect on the initiators of the immune response, the dendritic cells (DCs), are relatively unknown. In the present study, the effects of human MSCs on the differentiation and function of both CD34+ -derived DCs and monocyte-derived DCs were investigated. The presence of MSCs during differentiation blocked the differentiation of CD14+CD1a- precursors into dermal/interstitial DCs, without affecting the generation of CD1a+ Langerhans cells. In line with these observations, MSCs also completely prevented the generation of immature DCs from monocytes. The inhibitory effect of MSCs on DC differentiation was dose dependent and resulted in both phenotypical and functional modifications, as demonstrated by a reduced expression of costimulatory molecules and hampered capacity to stimulate naive T cell proliferation. The inhibitory effect of MSCs was mediated via soluble factors. Taken together, these data demonstrate that MSCs, next to the antiproliferative effect on T cells, have a profound inhibitory effect on the generation and function of both CD34+ -derived and monocyte-derived DCs, indicating that MSCs are able to modulate immune responses at multiple levels.  相似文献   

4.
Mesenchymal stem cells (MSCs) inhibit proliferation of allogeneic T cells and express low levels of major histocompatibility complex class I (MHCI), MHCII and vascular adhesion molecule-1 (VCAM-1). We investigated whether their immunosuppressive properties and low immunophenotype protect allogeneic rat MSCs against cytotoxic lysis in vitro and result in a reduced immune response in vivo. Rat MSCs were partially protected against alloantigen-specific cytotoxic T cells in vitro. However, after treatment with IFN-γ and IL-1β, MSCs upregulated MHCI, MHCII and VCAM-1, and cytotoxic lysis was significantly increased. In vivo, allogeneic T cells but not allogeneic MSCs induced upregulation of the activation markers CD25 and CD71 as well as downregulation of CD62L on CD4(+) T cells from recipient rats. However, intravenous injection of allo-MSCs in rats led to the formation of alloantibodies with the capacity to facilitate complement-mediated lysis, although IgM levels were markedly decreased compared with animals that received T cells. The allo-MSC induced immune response was sufficient to lead to significantly reduced survival of subsequently injected allo-MSCs. Interestingly, no increased immunogenicity of IFN-γ stimulated allo-MSCs was observed in vivo. Both the loss of protection against cytotoxic lysis under inflammatory conditions and the induction of complement-activating antibodies will likely impact the utility of allogeneic MSCs for therapeutic applications.  相似文献   

5.
Mesenchymal stromal cells (MSCs) have been shown to have an immunosuppressive effect. Previously, we demonstrated that nitric oxide (NO) is one of the immunomodulatory mediators of MSCs. We herein show that primary mouse bone marrow MSCs and three cell lines that mimic MSCs suppress both differentiation and proliferation in Th1 condition, whereas the suppression in Th2 condition is mild. NO production is inversely correlated with T cell proliferation in Th1 and Th2 conditions. NO is highly induced in Th1 and minimally induced in Th2. Moreover, an inhibitor of NO synthase restores both proliferation and interferon-gamma (IFN-gamma) production in Th1 condition. Furthermore, an anti-IFN-gamma antibody strongly inhibits NO production and an inhibitor of NF-kappaB reduces the level of induction of inducible NO synthase (iNOS) in MSCs. Taken together, our results suggest that NO plays a significant role in the modification of Th1 and Th2 differentiation by MSCs, and that both IFN-gamma and NF-kappaB are critical for NO production by MSCs.  相似文献   

6.
7.
Adipose‐derived stem cells (ASCs) are highly attractive for cell‐based therapies in tissue repair and regeneration because they have multilineage differentiation capacity and are immunosuppressive. However, the detailed epigenetic mechanisms of their immunoregulatory capacity are not fully defined. In this study, we found that Mysm1 was induced in ASCs treated with inflammatory cytokines. Adipose‐derived stem cells with Mysm1 knockdown exhibited attenuated immunosuppressive capacity, evidenced by less inhibition of T cell proliferation, more pro‐inflammatory factor secretion and less nitric oxide (NO) production in vitro. Mysm1‐deficient ASCs exacerbated inflammatory bowel diseases but inhibited tumour growth in vivo. Mysm1‐deficient ASCs also showed depressed miR‐150 expression. When transduced with Mysm1 overexpression lentivirus, ASCs exhibited enhanced miR‐150 expression. Furthermore, Mysm1‐deficient cells transduced with lentivirus containing miR‐150 mimics produced less pro‐inflammatory factors and more NO. Our study reveals a new role of Mysm1 in regulating the immunomodulatory activities of ASCs by targeting miR‐150. These novel insights into the mechanisms through which ASCs regulate immune reactions may lead to better clinical utility of these cells.  相似文献   

8.
Sheng H  Wang Y  Jin Y  Zhang Q  Zhang Y  Wang L  Shen B  Yin S  Liu W  Cui L  Li N 《Cell research》2008,18(8):846-857
Bone-marrow-derived mesenchymal stem cells (MSCs) have been shown to possess immunosuppressive properties, e.g., by inhibiting T cell proliferation. Activated T cells can also enhance the immunosuppression ability of MSCs. The precise mechanisms underlying MSC-mediated immunosuppression remain largely undefined, although both cell-cell contact and soluble factors have been implicated; nor is it clear how the immunosuppressive property of MSCs is modulated by T cells. Using MSCs isolated from mouse bone marrow, we show here that interferon gamma (IFNγ), a well-known proinflammatory cytokine produced by activated T cells, plays an important role in priming the immunosuppressive property of MSCs. Mechanistically, IFNγ acts directly on MSCs and leads to up-regulation of B7-H1, an inhibitory surface molecule in these stem cells. MSCs primed by activated T cells derived from IFNγ-/- mouse exhibited dramatically reduced ability to suppress T cell proliferation, a defect that can be rescued by supplying exogenous IFNγ. Moreover, siRNA-mediated knockdown of B7-H1 in MSCs abolished immunosuppression by these cells. Taken together, our results suggest that IFNγ plays a critical role in triggering the immunosuppresion by MSCs through upregulating B7-H1 in these cells, and provide evidence supporting the cell-cell contact mechanism in MSC-mediated immunosuppression.  相似文献   

9.
10.
Mesenchymal stromal cells (MSCs) may be derived from a variety of tissues, with human umbilical cord (UC) providing an abundant and noninvasive source. Human UC-MSCs share similar in vitro immunosuppressive properties as MSCs obtained from bone marrow and cord blood. However, the mechanisms and cellular interactions used by MSCs to control immune responses remain to be fully elucidated. In this paper, we report that suppression of mitogen-induced T cell proliferation by human UC-, bone marrow-, and cord blood-MSCs required monocytes. Removal of monocytes but not B cells from human adult PBMCs (PBMNCs) reduced the immunosuppressive effects of MSCs on T cell proliferation. There was rapid modulation of a number of cell surface molecules on monocytes when PBMCs or alloantigen-activated PBMNCs were cultured with UC-MSCs. Indomethacin treatment significantly inhibited the ability of UC-MSCs to suppress T cell proliferation, indicating an important role for PGE(2). Monocytes purified from UC-MSC coculture had significantly reduced accessory cell and allostimulatory function when tested in subsequent T cell proliferation assays, an effect mediated in part by UC-MSC PGE(2) production and enhanced by PBMNC alloactivation. Therefore, we identify monocytes as an essential intermediary through which UC-MSCs mediate their suppressive effects on T cell proliferation.  相似文献   

11.
Mesenchymal stem cells (MSCs) are believed to exert their regenerative effects through differentiation and modulation of inflammatory responses. However, the relationship between the severity of inflammation and stem cell-mediated tissue repair has not been formally investigated. In this study, we applied different concentrations of dexamethasone (Dex) to anti-CD3-activated splenocyte cultured with or without MSCs. As expected, Dex exhibited a classical dose-dependent inhibition of T-cell proliferation. Surprisingly, although MSCs also blocked T-cell proliferation, the presence of Dex unexpectedly showed a dose-dependent reversion of T-cell proliferation. This effect of Dex was found to be exerted through interfering STAT1 phosphorylation-prompted expression of inducible nitric oxide synthase (iNOS). Interestingly, inflammation-induced chemokines in MSCs was unaffected. To test the role of inflammation severity in stem cell-mediated tissue repair, we employed mice with carbon tetrachloride-induced advanced liver fibrosis and found that although MSCs alone were effective, concurrent administration of Dex abrogated the therapeutic effects of MSCs on fibrin deposition, serum levels of bilirubin, albumin, and aminotransferases, as well as T-lymphocyte infiltration, especially IFN-γ+CD4+ and IL-17A+CD4+T cells. Likewise, iNOS−/− MSCs, which produce chemokines but not nitric oxide under inflammatory conditions, are ineffective in treating advanced liver fibrosis. Therefore, inflammation has a critical role in MSC-mediated tissue repair. In addition, concomitant application of MSCs with steroids should be avoided.  相似文献   

12.
Mesenchymal stem cells (MSCs) are studied for their potential clinical use in regenerative medicine, tissue engineering and tumour therapy. However, the therapeutic application of MSCs in tumour therapy still remains limited unless the immunosuppressive role of MSCs for tumour growth in vivo is better understood. In this study, we investigated the mechanism of MSCs favouring tumour escape from immunologic surveillance in inflammatory microenvironment. We first compared the promotive capacity of bone marrow-derived MSCs on B16 melanoma cells growth in vivo, pre-incubated or not with the inflammatory cytokines interferon (IFN)-γ and tumour necrosis factor (TNF)-α. We showed that the development of B16 melanoma cells is faster when co-injected with MSCs pre-incubated with IFN-γ and TNF-α compared with control groups. Moreover, tumour incidence increases obviously in allogeneic recipients when B16 melanoma cells were co-injected with MSCs pre-incubated with IFN-γ and TNF-α. We then demonstrated that the immunosuppressive function of MSCs was elicited by IFN-γ and TNF-α. These cytokine combinations provoke the expression of inducible nitric oxide synthase (iNOS) by MSCs. The impulsive effect of MSCs treated with inflammatory cytokines on B16 melanoma cells in vivo can be reversed by inhibitor or short interfering RNA of iNOS. Our results suggest that the MSCs in tumour inflammatory microenvironment may be elicited of immunosuppressive function, which will help tumour to escape from the immunity surveillance.  相似文献   

13.
Z Gu  X Cao  J Jiang  L Li  Z Da  H Liu  C Cheng 《Cellular signalling》2012,24(12):2307-2314
Previous studies have indicated that bone marrow-derived mesenchymal stem cells (MSCs) from patients with systemic lupus erythematosus (SLE) exhibited impaired proliferation, differentiation, and immune modulation capacities. Thus, MSCs may be associated with the pathogenesis of SLE. The aim of this study was to determine whether MSCs from SLE patients were senescent and to determine the mechanism underlying this phenomenon. MSCs from both untreated and treated SLE patients showed characteristics of senescence. The expression of p16(INK4A) was significantly increased, whereas levels of CDK4, CDK6 and p-Rb expression were decreased in the MSCs from both untreated and treated SLE patients. Knockdown of p16(INK4A) expression reversed the senescent features of MSCs and upregulated TGF-β expression. In vitro, when purified CD4+ T cells were incubated with p16(INK4A)-silenced SLE MSCs, the percentage of regulatory T cells was significantly increased. Further, we have found that p16(INK4A) promotes MSC senescence via the suppression of the extracellular signal regulated kinase (ERK) pathway. p16(INK4A) knockdown up-regulated ERK1/2 activation. Our results demonstrated that MSCs from SLE patients were senescent and that p16 (INK4A) plays an essential role in the process by inhibiting ERK1/2 activation.  相似文献   

14.
Mesenchymal stem cells (MSCs) are widely used in experimental treatments for various conditions that involve normal tissue regeneration via inflammatory repair. It is known that MSCs can secrete multiple soluble factors and suppress inflammation. Even though the effect of MSCs on inflammation has been extensively studied, the effect of inflammation on MSCs is poorly understood. One of the major cytokines released at the site of inflammation is tumor necrosis factor alpha (TNF-α) which is known to induce MSC invasion and proliferation. Therefore, we wanted to test the effects of TNF-α exposure on MSCs derived from human bone marrow. We found, as expected, that cell proliferation was significantly enhanced during TNF-α exposure. However, according to the cell surface marker analysis, the intensity of several antigens in the minimum criteria panel for MSCs proposed by International Society of Cellular Therapy (ISCT) was decreased dramatically, and in certain cases, the criteria for MSCs were not fulfilled. In addition, TNF-α exposure resulted in a significant but transient increase in human leukocyte antigen and CD54 expression. Additional proteomic analysis by two-dimensional difference gel electrophoresis and mass spectrometry revealed three proteins whose expression levels decreased and 8 proteins whose expression levels increased significantly during TNF-α exposure. The majority of these proteins could be linked to immunosuppressive and signalling pathways. These results strongly support reactive and immunosuppressive activation of MSCs during TNF-α exposure, which might influence MSC differentiation stage and capacity.  相似文献   

15.
In this study, we aimed to explore the role of liver kinase b1 (Lkb1) in the biological characteristics and immune regulation of amniotic mesenchymal stem cells (AMSCs). AMSCs were identified via the cell surface markers using flow cytometry. We knocked down the expression of Lkb1 in AMSCs using lentivirus-mediated Lkb1-specific shRNA. The efficiency of the knockdown was detected by flow cytometry, RT-qPCR, and western blot. The AMSC-related phenotype was determined by flow cytometric analysis via staining surface markers. Fibroblast colony-forming cells (CFU-F) assay and Ki-67 intracellular staining assay were used to determine the proliferative capacity. The differentiated and immunosuppressive capabilities were determined by conditional induction of differentiation and co-culture experiments. We observed that AMSCs along with Lkb1 knockdown (AMSCs-Lkb1) displayed similar cellular morphology and surface antigen expression patterns as those observed in AMSCs. However, AMSCs-Lkb1 exhibited an enhanced differentiation capacity towards osteogenesis and chondrogenesis while it showed defective proliferation and increased apoptosis. Furthermore, AMSCs-Lkb1 showed an enhanced immunosuppressive capacity by directly inhibiting conventional T cells and indirectly inducing production of regulatory T cells (Treg). Interestingly, Treg produced by AMSCs-Lkb1 displayed stronger proliferative capacity as compared to those produced by AMSCs. Our results indicate that Lkb1 plays a vital role in maintaining self-renewal of AMSCs and regulating immune equivalence, and may hold potential for the clinical management of diseases such as GVHD.  相似文献   

16.
Mesenchymal stromal cells (MSCs) are promising candidates for the treatment of graft‐versus‐host and autoimmune diseases. Here, by virtue of their immunosuppressive effects, they are discussed to exhibit inhibitory actions on various immune effector cells, including T lymphocytes that promote the underlying pathology. While it becomes apparent that MSCs exhibit their therapeutic effect in a transient manner, they are usually transplanted from third party donors into heavily immunocompromised patients. However, little is known about potential late complications of persisting third party MSCs in these patients. We therefore analysed the effect of gamma irradiation on the potency and proliferation of MSCs to elucidate an irradiation dose, which would allow inhibition of MSC proliferation while at the same time preserving their immunosuppressive function. Bone marrow‐derived MSCs (BM‐MSCs) were gamma‐irradiated at increasing doses of 5, 10 and 30 Gy and subsequently assessed by colony formation unit (CFU)‐assay, Annexin V‐staining and in a mixed lymphocyte reaction, to assess colony growth, apoptosis and the immunosuppressive capacity, respectively. Complete loss of proliferative capacity measured by colony formation was observed after irradiation with a dose equal to or greater than 10 Gy. No significant decrease of viable cells was detected, as compared to non‐irradiated BM‐MSCs. Notably, irradiated BM‐MSCs remained highly immunosuppressive in vitro for at least 5 days after irradiation. Gamma irradiation does not impair the immunosuppressive capacity of BM‐MSCs in vitro and thus might increase the safety of MSC‐based cell products in clinical applications.  相似文献   

17.
Dendritic cells (DCs) can initiate immune responses or confer immune tolerance depending on functional status. LPS-induced DC maturation is defined by enhanced surface expression of CD80 and CD86. MicroRNAs are critical for the regulation of DC function and immunity, and the microRNA let-7i was upregulated during LPS-induced DC maturation. Downregulation of let-7i significantly impeded DC maturation as evidenced by reduced CD80 and CD86 expression. DCs stimulated by LPS promoted T cell proliferation in coculture, whereas LPS-stimulated DCs with downregulated let-7i were not effective at stimulating T cell proliferation but promoted expansion of the regulatory T cell (Treg) population. There were two subpopulations of LPS-stimulated DCs with downregulated let-7i, CD86(-) and CD86(+), and it was the CD86(-) DCs that were more effective in inducing T cell hyporesponsiveness and enhancing Treg numbers, indicating that this DC population had tolerogenic properties. Furthermore, Tregs with upregulated IL-10 underscored the tolerogenic effect of CD86(-) DCs. Suppressor of cytokine signaling 1 (SOCS1), a crucial mediator of DC maturation, was confirmed as a let-7i target gene by luciferase construct assay. Suppression or overexpression of let-7i caused reciprocal alterations in SOCS1 protein expression, but had no significant effects on SOCS1 mRNA levels, indicating that let-7i regulated SOCS1 expression by translational suppression. The modulation of SOCS1 protein by let-7i was mainly restricted to CD86(-) DCs. Our study demonstrates that let-7i regulation of SOCS1 is critical for LPS-induced DC maturation and immune function. Dynamic regulation of let-7i may fine-tune immune responses by inducing Ag-specific immune tolerance.  相似文献   

18.
《Cytokine》2015,72(2):145-153
Since clinical application of MSCs requires long-term ex vivo culture inducing senescence in MSCs and reducing the therapeutic activity of transplanted MSCs, numerous efforts have been attempted to sustain the active state of MSCs. Substance P (SP) is a neuropeptide that functions to activate the cellular physiological responses of MSCs, including proliferation, migration, and secretion of specific cytokines. In this study, we explored the potential of SP to restore the weakened immune modulating activity of MSCs resulting from long-term culture by measuring T cell activity and interleukin-2 (IL-2) secretion of CD4+ Jurkat leukemic T cells and primary CD4+ T cells. As the number of cell passages increased, the immunosuppressive function of MSCs based on T cell activity decreased. This weakened activity of MSCs could be restored by SP treatment and nullified by co-treatment of an NK1 receptor blocker. Higher levels of transforming growth factor beta 1 (TGF-β1) secretion were noted in the medium of SP-treated late passage MSC cultures, but IL-10 levels did not change. SP-treated MSC-conditioned medium decreased T cell activity and IL-2/Interferon gamma (IFN-g) secretion in T cells even in the activation by lipopolysaccharide (LPS) or CD3/CD28 antibodies, both of which were successfully blocked by inhibiting the TGF beta signaling pathway. This stimulatory effect of SP on late passage MSCs was also confirmed in direct cell–cell contact co-culture of MSCs and CD4+ Jurkat T cells. Collectively, our study suggests that SP pretreatment to MSCs may recover the immunosuppressive function of late passage MSCs by potentiating their ability to secrete TGF-β1, which can enhance the therapeutic activity of ex vivo expanded MSCs in long-term culture.  相似文献   

19.
Mesenchymal stem cells (MSCs) are a type of immunosuppressive stromal cell found in multiple tissues and organs. However, whether MSCs possess immunosupportive characteristics remains unclear. In this study, we showed that the lymph nodes contain immunosupportive MSCs. They produce and secrete a high level of MCP-1 to promote T-cell proliferation and differentiation, in contrast to bone marrow MSCs (BMMSCs), which repress T-cell activation. Unlike BMMSCs, lymph node MSCs (LNMSCs) fail to respond to activated T-cell-induced production of PD-L1 to induce T-cell apoptosis. Mechanistically, MCP-1 activates phospho-Erk to sustain T-cell proliferation and activation while it represses NF-κB/PD-L1 pathway to avoid induction of T-cell apoptosis. Interestingly, inflammatory lymph node-derived LNMSCs abolish their immunosupportive function due to reduction of MCP-1 expression. Finally, we show that systemic infusion of LNMSCs rescues immunosuppression in cytoxan (CTX)-treated mice. This study reveals a previously unrecognized mechanism underlying MSC-based immunoregulation using the MCP-1/PD-L1 axis to energize T cells and suggests a potential to use MSCs to treat immunosuppressive disorders.Subject terms: Apoptosis, Mesenchymal stem cells, Immune cell death, T cells  相似文献   

20.
Suppression of immune response by mesenchymal stem/stromal cells (MSCs) is well documented. However, their regulatory effects on immune cells, especially regulatory dendritic cells, are not fully understood. We have identified a novel Sca-1(+)Lin(-)CD117(-) MSC population isolated from mouse embryonic fibroblasts (MEF) that suppressed lymphocyte proliferation in vitro. Moreover, the Sca-1(+)Lin(-)CD117(-) MEF-MSCs induced hematopoietic stem/progenitor cells to differentiate into novel regulatory dendritic cells (DCs) (Sca-1(+)Lin(-)CD117(-) MEF-MSC-induced DCs) when cocultured in the absence of exogenous cytokines. Small interfering RNA silencing showed that Sca-1(+)Lin(-)CD117(-) MEF-MSCs induced the generation of Sca-1(+)Lin(-)CD117(-) MEF-MSC-induced DCs via IL-10-activated SOCS3, whose expression was regulated by the JAK-STAT pathway. We observed a high degree of H3K4me3 modification mediated by MLL1 and a relatively low degree of H3K27me3 modification regulated by SUZ12 on the promoter of SOCS3 during SOCS3 activation. Importantly, infusion of Sca-1(+)CD117(-)Lin(-) MEF-MSCs suppressed the inflammatory response by increasing DCs with a regulatory phenotype. Thus, our results shed new light on the role of MSCs in modulating regulatory DC production and support the clinical application of MSCs to reduce the inflammatory response in numerous disease states.  相似文献   

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