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• W2014098786 abstract "Mesenchymal stem/progenitor cells (MSCs) were reported to enhance the survival of cellular and organ transplants. However, their mode of action was not established. We here used a mouse model of corneal allotransplantation and demonstrated that peri-transplant intravenous (i.v.) infusion of human MSCs (hMSCs) decreased the early surgically induced inflammation and reduced the activation of antigen-presenting cells (APCs) in the cornea and draining lymph nodes (DLNs). Subsequently, immune rejection was decreased, and allograft survival was prolonged. Quantitative assays for human GAPDH revealed that <10 hMSCs out of 1 × 106 injected cells were recovered in the cornea 10 hours to 28 days after i.v. infusion. Most of hMSCs were trapped in lungs where they were activated to increase expression of the gene for a multifunctional anti-inflammatory protein tumor necrosis factor-α stimulated gene/protein 6 (TSG-6). i.v. hMSCs with a knockdown of TSG-6 did not suppress the early inflammation and failed to prolong the allograft survival. Also, i.v. infusion of recombinant TSG-6 reproduced the effects of hMSCs. Results suggest that hMSCs improve the survival of corneal allografts without engraftment and primarily by secreting TSG-6 that acts by aborting early inflammatory responses. The same mechanism may explain previous reports that MSCs decrease rejection of other organ transplants. Mesenchymal stem/progenitor cells (MSCs) were reported to enhance the survival of cellular and organ transplants. However, their mode of action was not established. We here used a mouse model of corneal allotransplantation and demonstrated that peri-transplant intravenous (i.v.) infusion of human MSCs (hMSCs) decreased the early surgically induced inflammation and reduced the activation of antigen-presenting cells (APCs) in the cornea and draining lymph nodes (DLNs). Subsequently, immune rejection was decreased, and allograft survival was prolonged. Quantitative assays for human GAPDH revealed that <10 hMSCs out of 1 × 106 injected cells were recovered in the cornea 10 hours to 28 days after i.v. infusion. Most of hMSCs were trapped in lungs where they were activated to increase expression of the gene for a multifunctional anti-inflammatory protein tumor necrosis factor-α stimulated gene/protein 6 (TSG-6). i.v. hMSCs with a knockdown of TSG-6 did not suppress the early inflammation and failed to prolong the allograft survival. Also, i.v. infusion of recombinant TSG-6 reproduced the effects of hMSCs. Results suggest that hMSCs improve the survival of corneal allografts without engraftment and primarily by secreting TSG-6 that acts by aborting early inflammatory responses. The same mechanism may explain previous reports that MSCs decrease rejection of other organ transplants. Organ transplantation is the final therapeutic option in a variety of devastating diseases. However, postoperative survival is most often limited by rejection of the transplants by the immune system. Moreover, prolonged administration of immunosuppressive agents to prevent rejection can produce renal or hepatic toxicity and increase the susceptibility to malignancies or infections. One recent strategy for improving the engraftment of transplants of cells and organs is the pre- or concurrent administration of mesenchymal stem/progenitor cells (MSCs). Systemic infusion of MSCs was reported to decrease graft rejection in animal models, and thus the results have prompted a number of clinical trials.1Hoogduijn MJ Popp FC Grohnert A Crop MJ van Rhijn M Rowshani AT MISOT Study Group et al.Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT).Transplantation. 2010; 90: 124-126Crossref PubMed Scopus (66) Google Scholar,2Le Blanc K Frassoni F Ball L Locatelli F Roelofs H Lewis I Developmental Committee of the European Group for Blood and Marrow Transplantation et al.Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study.Lancet. 2008; 371: 1579-1586Abstract Full Text Full Text PDF PubMed Scopus (2175) Google Scholar,3English K French A Wood KJ Mesenchymal stromal cells: facilitators of successful transplantation.Cell Stem Cell. 2010; 7: 431-442Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar,4Popp FC Eggenhofer E Renner P Geissler EK Piso P Schlitt HJ et al.Mesenchymal stem cells can affect solid organ allograft survival.Transplantation. 2009; 87 (9 Suppl): S57-S62Crossref PubMed Google Scholar Previous studies largely attributed the improved survival of transplants to the immunomodulatory effects of MSCs.3English K French A Wood KJ Mesenchymal stromal cells: facilitators of successful transplantation.Cell Stem Cell. 2010; 7: 431-442Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar,4Popp FC Eggenhofer E Renner P Geissler EK Piso P Schlitt HJ et al.Mesenchymal stem cells can affect solid organ allograft survival.Transplantation. 2009; 87 (9 Suppl): S57-S62Crossref PubMed Google Scholar,5Singer NG Caplan AI Mesenchymal stem cells: mechanisms of inflammation.Annu Rev Pathol. 2011; 6: 457-478Crossref PubMed Scopus (641) Google Scholar,6Uccelli A Moretta L Pistoia V Mesenchymal stem cells in health and disease.Nat Rev Immunol. 2008; 8: 726-736Crossref PubMed Scopus (2599) Google Scholar Most of the data, however, were based on in vitro experiments that may or may not reflect actions of MSCs in vivo. In order to define how MSCs improve the engraftment of organ transplants, we here adopted a mouse model of allogeneic corneal transplantation, a model in which the temporal sequence of events from the introduction of the alloantigen to immune rejection is distinct and well-established.7Forrester JV Xu H Kuffová L Dick AD McMenamin PG Dendritic cell physiology and function in the eye.Immunol Rev. 2010; 234: 282-304Crossref PubMed Scopus (148) Google Scholar,8Catron DM Rusch LK Hataye J Itano AA Jenkins MK CD4+ T cells that enter thedraining lymph nodes after antigen injection participate in the primary response andbecome central-memory cells.J Exp Med. 2006; 203: 1045-1054Crossref PubMed Scopus (129) Google Scholar,9Kuffová L Lumsden L Veselá V Taylor JA Filipec M Holán V et al.Kinetics of leukocyte and myeloid cell traffic in the murine corneal allograft response.Transplantation. 2001; 72: 1292-1298Crossref PubMed Scopus (29) Google Scholar We demonstrated that intravenous (i.v.) administration of human MSCs (hMSCs) at the time of grafting decreased the immune response and prolonged the survival of corneal allografts primarily by suppressing the surgery-induced inflammation in the early postoperative period. Suppression of inflammation subsequently inhibited the afferent loop of the alloimmune response by decreasing the activation of dendritic cells (DCs) in the cornea and draining lymph nodes (DLNs). Of special interest was the finding that the beneficial effects of hMSCs were observed without engraftment of the cells in the cornea, but rather were dependent on hMSCs being trapped in the lungs after i.v. infusion with subsequent activation to express the gene for tumor necrosis factor-α stimulated gene/protein 6 (TSG-6), a multifunctional protein10Milner CM Higman VA Day AJ TSG-6: a pluripotent inflammatory mediator.Biochem Soc Trans. 2006; 34 (Pt 3): 446-450Crossref PubMed Scopus (69) Google Scholar,11Wisniewski HG Vilcek J Cytokine-induced gene expression at the crossroads of innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14.Cytokine Growth Factor Rev. 2004; 15: 129-146Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar that acts in part by aborting the early phase of inflammation partially through the modulation of nuclear factor (NF)-κB signaling in resident macrophages.12Choi H Lee RH Bazhanov N Oh JY Prockop DJ Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-?B signaling in resident macrophages.Blood. 2011; 118: 330-338Crossref PubMed Scopus (488) Google Scholar,13Oh JY Choi H Lee RH Roddy GW Ylöstalo JH Wawrousek E et al.Identification of the HSPB4/TLR2/NF-?B axis in macrophage as a therapeutic target for sterile inflammation of the cornea.EMBO Mol Med. 2012; 4: 435-448Crossref PubMed Scopus (39) Google Scholar To determine whether i.v. hMSCs prolong the survival of corneal allografts, we performed orthotropic corneal allotransplantation using C57BL/6 mice (H-2b) as donors and BALB/c(H-2d) as recipients. Recipient mice received 1 × 106 hMSCs i.v. either once immediately after surgery (day 0) or twice at 1 day before surgery (day –1) and again immediately after surgery (day 0). Hank's balanced salt solution (HBSS) was injected i.v. as a vehicle control. Syngeneic corneal autografts (BALB/c-to-BALB/c) were performed to serve as negative controls. For the follow-up period of 42 days, 7 of 12 B6 corneal grafts in BALB/c mice (allografts) were rejected within 28 days with a mean survival time of 21.3 days, whereas all of the BALB/c corneal grafts in BALB/c mice (autografts, n = 12) survived (Figure 1a). i.v. hMSCs significantly prolonged the survival of corneal allografts. Eleven out of 12 allografts remained free of rejection in mice that received two injections of i.v. hMSCs (P = 0.006 versus allografts in the HBSS group), and 9 of 12 allografts survived in mice that received a single injection of hMSCs (P = 0.047 versus allografts in the HBSS group). We performed histological studies on the grafts at day 28. In the rejected allografts of HBSS-injected animals, hematoxylin–eosin staining of sections showed extensive infiltration of inflammatory cells (Figure 1b). In contrast, inflammatory infiltrates were markedly decreased in the allografts from mice treated with hMSCs. Similar results were observed by immunostaining of the sections for CD3+ T cells (Figure 1c). There was extensive infiltration of CD3+ T cells in the rejected grafts from vehicle control animals and minimal infiltration of CD3+ T cells in the allografts from mice that received hMSCs. Therefore, the data demonstrated that peri-transplant injection of i.v. hMSCs prolonged the survival of corneal allografts and prevented rejection. Two injections (day –1 and day 0) were more effective than a single injection (day 0). In order to examine the effects of hMSCs, we analyzed corneal grafts for the time course of expression of inflammation- and immune-related molecules. Since the rejection of corneal allografts occurred by day 28 and the surviving grafts remained free of rejection after day 28 (Figure 1a), we analyzed corneal grafts at day 28 for the immune rejection and the grafts at days 3 and 7 for the early surgery-induced inflammation. We found that both autografts and allografts demonstrated the same early increases at days 3 and 7 of the inflammatory cytokines interleukin (IL)-6, IL-1β, and IL-12 as well as myeloperoxidase as a semiquantitative measure of neutrophil infiltration(Figures 2a,b and 3).14Oh JY Roddy GW Choi H Lee RH Ylöstalo JH Rosa Jr RH et al.Anti-inflammatory protein TSG-6 reduces inflammatory damage to the cornea following chemical and mechanical injury.Proc Natl Acad Sci USA. 2010; 107: 16875-16880Crossref PubMed Scopus (179) Google Scholar This finding indicates that the inflammation was induced by surgery and the similar amount of damage was applied to tissues by surgery between auto- and allografts. In contrast, there were marked differences between autografts and allografts in the late immune response. In allografts but not in autografts, there was a gradual increase up to day 28 in the transcript levels of T cell-derived cytokines (IL-2 and interferon (IFN)-γ) and effector molecules implicated in the allograft rejection (granzyme A, granzyme B, and perforin) (Figures 2a,b and 4).15Choy JC Granzymes and perforin in solid organ transplant rejection.Cell Death Differ. 2010; 17: 567-576Crossref PubMed Scopus (62) Google Scholar i.v. infusion of hMSCs decreased both early inflammatory phase and late immune response (Figure 2c). At days 3 and 7, the levels of inflammatory cytokines were markedly reduced in allografts from mice that received hMSCs. The levels of the transcripts for IL-6 and IL-1β were reduced by about half, and the transcript for IL-12a was reduced to baseline levels. Similar decreases were seen at day 7 in levels of myeloperoxidase and ELISA for IL-1β and IL-12 (Figure 3). The decrease in the inflammatory phase produced by hMSCs was accompanied by a decrease in the immune response. At 28 days, there was a marked decrease in the levels of transcripts for IL-2, IFN-γ, granzyme A, granzyme B, and perforin in the allografts from mice that received hMSCs as well as the protein level of IFN-γ (Figures 2c and 4). Also, flow cytometry demonstrated that the number of CD44+ CD69+ cells as markers for activated CD4 T cells was decreased in DLNs in mice treated with hMSCs (Supplementary Figure S1).Figure 3Intravenous (i.v.) human mesenchymal stem cells (hMSCs) decreased the early inflammatory response in corneal allografts. (a) The amount of myeloperoxidase as a measure of neutrophil infiltration was significantly decreased by hMSCs at day 7 after transplantation. (b–f) Also, the levels of proinflammatory cytokines, IL-6, IL-1β, and IL-12 were significantly decreased by i.v. hMSCs at day 7. Results indicate that inflammatory responses in the early postoperative period after transplantation surgery were suppressed by i.v. hMSCs. Auto: autografts, Allo: allografts, Allo MSCx1: allografts that received hMSCs once immediately after transplantation, Allo MSCx2:allografts that received hMSCs on the day before transplantation and immediately after transplantation. n = 5 in each group. *P < 0.05; **P < 0.01.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 4Intravenous (i.v.) human mesenchymal stem cells (hMSCs) suppressed the late T cell-mediated immune response in corneal allografts. (a,b) The transcript levels of activated CD4 T-cell cytokines (IL-2 and IFN-γ) and protein level of (c) IFN-γ were significantly decreased in the allografts that received i.v. hMSCs at day 28 after surgery, compared to the grafts without i.v. hMSCs. (d–f) Also, the transcript levels of CD8 T-cell effector molecules (granzyme A, granzyme B, and perforin) were significantly decreased by i.v. hMSCs. Auto: autografts, Allo: allografts, Allo MSCx1: allografts that received hMSCs once immediately after transplantation, Allo MSCx2:allografts that received hMSCs on the day before transplantation and immediately after transplantation. n = 5 in each group. *P < 0.05; **P < 0.01.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Therefore, the results indicated that hMSCs suppressed the surgery-induced inflammation in the early postoperative period and, apparently as a result, decreased the subsequent immune rejection of corneal allografts. Previous studies demonstrated that the principal antigen-presenting cells (APCs) of the cornea, Langerhans cells, reside in basal epithelium in the limbal area of the cornea.7Forrester JV Xu H Kuffová L Dick AD McMenamin PG Dendritic cell physiology and function in the eye.Immunol Rev. 2010; 234: 282-304Crossref PubMed Scopus (148) Google Scholar Also, CD11b+CD11c+ cells having dendritic morphology are present in the anterior stroma, and a population of CD11b+CD11c– cells having macrophage morphology is present in the posterior stroma.16Hamrah P Huq SO Zhang Q Dana MR Corneal immunity is mediated by heterogenous population of antigen-presenting cells.J Leukocyte Biol. 2003; 74: 172-178Crossref PubMed Scopus (248) Google Scholar In response to inflammatory insults including transplantation surgery, APCs undergo maturation by overexpressing major histocompatibility complex (MHC) class II.17Dana MR Corneal antigen-presenting cells: diversity, plasticity, and disguise: the Cogan lecture.Invest Ophthalmol Vis Sci. 2004; 45: 722-7; 721Crossref PubMed Scopus (61) Google Scholar,18Dana R Comparison of topical interleukin-1 vs tumor necrosis factor-alpha blockade with corticosteroid therapy on murine corneal inflammation, neovascularization, and transplant survival (an American Ophthalmological Society thesis).Trans Am Ophthalmol Soc. 2007; 105: 330-343PubMed Google ScholarActivated APCs, most of which are of host origin, take up graft-derived antigens in the cornea and migrate to DLNs, where they present antigens to host T cells causing the T cell-mediated immune rejection.7Forrester JV Xu H Kuffová L Dick AD McMenamin PG Dendritic cell physiology and function in the eye.Immunol Rev. 2010; 234: 282-304Crossref PubMed Scopus (148) Google Scholar,19Kuffová L Netuková M Duncan L Porter A Stockinger B Forrester JV Cross presentation of antigen on MHC class II via the draining lymph node after corneal transplantation in mice.J Immunol. 2008; 180: 1353-1361Crossref PubMed Scopus (42) Google Scholar Thus, we next examined whether the decrease in inflammation by i.v. hMSCs might lead to a reduction in the activation of APCs in the cornea and DLNs. First, we examined the whole-mounted epithelial sheets of the cornea for host-derived MHC class II (murine Iad) at one week after transplantation. We selected the 1-week time-point, because it is the time at which allosensitization takes place and allorejection is not yet initiated.7Forrester JV Xu H Kuffová L Dick AD McMenamin PG Dendritic cell physiology and function in the eye.Immunol Rev. 2010; 234: 282-304Crossref PubMed Scopus (148) Google Scholar Therefore, it allowed us to examine the afferent sensitization arm of alloimmunity. Immunostaining showed that the number of MHC class II+ cells in the cornea was markedly lower in the allografts from mice treated with hMSCs compared to the autografts or allografts without hMSCs (Figure 5). Next, we analyzed subsets of MHC class II+ cell population in DLNs (cervical LNs ipsilateral to the transplanted eye). Flow cytometry showed that the proportions of DCs, both MHC II+CD11b+CD11c+ cells and MHC II+CD11b–CD11c+ cells, were significantly decreased in mice treated with hMSCs (Figure 6). Two injections of hMSCs (day –1 and day 0) were more effective than a single injection (day 0). In addition to DCs, the proportion of MHC II+CD11b–CD11c+ cells representing macrophages was significantly decreased in the group treated with i.v. hMSCs. The findings of similar increases in APCs in the cornea and DLNs between auto- and allografts suggested that a transplant procedure and surgically induced inflammation contributed to activation of APCs, which is consistent with the data reported previously.18Dana R Comparison of topical interleukin-1 vs tumor necrosis factor-alpha blockade with corticosteroid therapy on murine corneal inflammation, neovascularization, and transplant survival (an American Ophthalmological Society thesis).Trans Am Ophthalmol Soc. 2007; 105: 330-343PubMed Google Scholar Treatment with i.v. hMSCs was accompanied by reduced activation of APCs in the cornea and DLNs as well as reduced inflammation in the grafts. The data, therefore, indicated that the afferent limb of the alloimmune response was inhibited by hMSCs.Figure 6Intravenous (i.v.) human mesenchymal stem cells (hMSCs) decreased the number of activated antigen-presenting cells in ipsilateral cervical lymph nodes 1 week following transplantation. (a) Flow cytometry showed that the proportions of dendritic cells (DCs), both MHC II+CD11b+CD11c+ cells (b) and MHC II+CD11b−CD11c+ cells (c),were significantly decreased in mice treated with hMSCs. In addition, the proportion of MHC II+CD11b+CD11c−cells representing macrophages was significantly decreased by i.v. (d) hMSCs. n = 4 in each group. Auto: autografts, Allo: allografts, Allo MSCx1: allografts that received hMSCs once immediately after transplantation, Allo MSCx2:allografts that received hMSCs on the day before transplantation and immediately after transplantation.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Previous reports showed that the vast majority of hMSCs infused i.v. in mice were trapped in lungs and disappeared with a half-life of ~24 hours without long-term engraftment into injured tissues such as the cornea or heart.20Roddy GW Oh JY Lee RH Bartosh TJ Ylostalo J Coble K et al.Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-a stimulated gene/protein 6.Stem Cells. 2011; 29: 1572-1579Crossref PubMed Scopus (202) Google Scholar,21Lee RH Pulin AA Seo MJ Kota DJ Ylostalo J Larson BL et al.Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6.Cell Stem Cell. 2009; 5: 54-63Abstract Full Text Full Text PDF PubMed Scopus (1387) Google Scholar To determine whether hMSCs engrafted in the transplanted cornea after i.v. injection, we carried out quantitative reverse transcription (RT)-PCR assays for human-specific GAPDH in the corneas from mice that received two i.v. infusions of 1 × 106 hMSCs at day –1 and day 0 of corneal transplantation (Supplementary Figure S2 and Table S1). Results demonstrated that <10 hMSCs were present in corneas 10 hours to 28 days after the transplants. Therefore, the beneficial effects of the hMSCs were not explained by the i.v. administered cells engrafting in the cornea. Since the majority of i.v. hMSCs were trapped in lungs21Lee RH Pulin AA Seo MJ Kota DJ Ylostalo J Larson BL et al.Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6.Cell Stem Cell. 2009; 5: 54-63Abstract Full Text Full Text PDF PubMed Scopus (1387) Google Scholar and did not engraft in the cornea (Supplementary Figure S2 and Table S1), we next examined the hypothesis that the effects of hMSCs on corneal grafts were mediated by trophic factors produced from the cells trapped in lungs. We used human-specific quantitative RT-PCR assays to screen the lungs 10 hours after corneal allotransplantation in mice that received i.v. hMSCs twice at day –1 and day 0. Data revealed that ~10% of injected cells were present in lungs (Supplementary Figure S3). We assayed for the expression of immunomodulatory and anti-inflammatory molecules that have been previously shown to be secreted by MSCs: COX2, NOS2, IDO, CCL2, TGF-β, TSG-6, STC-1, and PTX3.3English K French A Wood KJ Mesenchymal stromal cells: facilitators of successful transplantation.Cell Stem Cell. 2010; 7: 431-442Abstract Full Text Full Text PDF PubMed Scopus (252) Google Scholar,22Lee RH Oh JY Choi H Bazhanov N Therapeutic factors secreted by mesenchymal stromal cells and tissue repair.J Cell Biochem. 2011; 112: 3073-3078Crossref PubMed Scopus (66) Google Scholar We found that the most highly upregulated human transcript was for the anti-inflammatory protein TSG-6 (113.8-fold) (Supplementary Figure S4). To explore the role of TSG-6 in preventing graft rejection, we knocked down the expression of TSG-6 in hMSCs by transient transfection with siRNA and injected the cells into mice with corneal allografts twice at day –1 and day 0 of surgery. Three out of six allografts were rejected in mice that received a two-time injection of hMSCs with TSG-6 knockdown, whereas all (6/6) of the allografts remained free of rejection at 28 days in mice that received a two-time injection of hMSCs with scrambled siRNA control (P = 0.047; generalized Wilcoxon test) (Figure 7a). Additionally, hMSCs with TSG-6 knockdown were not effective in suppressing corneal inflammation at day 7 (Figure 7b). Also, levels of transcripts for activated T cell-derived cytokines and effector enzymes in corneal grafts were not suppressed by hMSCs with TSG-6 knockdown, whereas hMSCs with scrambled siRNA significantly decreased the levels of transcripts for T-cell cytokines and enzymes (Figure 7c-h). Next, we tested the hypothesis that systemically administered rhTSG-6 could reproduce the effects of i.v. hMSCs by reducing the surgery-induced inflammation in corneal allografts. We administered 35 µg of rhTSG-6 in 100 µl phosphate-buffered saline (PBS) by tail vein injection immediately after corneal allotransplantation. The survival of corneal allografts was significantly prolonged in mice treated with rhTSG-6, compared to PBS-injected controls (the mean survival time: 25.6 ± 1.5 days in the TSG-6 treated grafts and 18.6 ± 3.1 days in the PBS-treated grafts; P = 0.042; generalized Wilcoxon test) (Figure 8a). The expression of MPO and proinflammatory cytokines (IL-6, IL-1β, IL-12a, and IL-12b) in the cornea at day 7 was significantly decreased following rhTSG-6 injection (Figure 8b–f). Also, levels of transcripts for T cell-related cytokines, IL-2, IFN-γ, granzyme B, and perforin, were significantly decreased in the allografts from mice treated with TSG-6 at day 28 (Figure 8g–j). As summarized in Supplementary Figure S5, the results demonstrated that i.v. hMSCs increased the survival of the allografts without long-term engraftment by aborting the early inflammatory response and by decreasing activation of APCs in corneas after transplantation surgery. Similar results were obtained with i.v. recombinant TSG-6. Our data are consistent with the current paradigm that hMSCs can produce therapeutic benefits without engraftment into injured tissues and primarily by upregulating the genes that modulate excessive inflammatory and immune reactions.23Prockop DJ Kota DJ Bazhanov N Reger RL Evolving paradigms for repair of tissues by adult stem/progenitor cells (MSCs).J Cell Mol Med. 2010; 14: 2190-2199Crossref PubMed Scopus (216) Google Scholar,24Uccelli A Prockop DJ Why should mesenchymal stem cells (MSCs) cure autoimmune diseases.Curr Opin Immunol. 2010; 22: 768-774Crossref PubMed Scopus (121) Google Scholar In the present experiment, the multifunctional anti-inflammatory protein TSG-610Milner CM Higman VA Day AJ TSG-6: a pluripotent inflammatory mediator.Biochem Soc Trans. 2006; 34 (Pt 3): 446-450Crossref PubMed Scopus (69) Google Scholar,11Wisniewski HG Vilcek J Cytokine-induced gene expression at the crossroads of innate immunity, inflammation and fertility: TSG-6 and PTX3/TSG-14.Cytokine Growth Factor Rev. 2004; 15: 129-146Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar accounted for beneficial effects of the hMSCs that were infused i.v.. Since proinflammatory cytokines, including IL-1, play a critical role in recruitment, activation, and migration of APCs such as Langerhans cells,17Dana MR Corneal antigen-presenting cells: diversity, plasticity, and disguise: the Cogan lecture.Invest Ophthalmol Vis Sci. 2004; 45: 722-7; 721Crossref PubMed Scopus (61) Google Scholar,18Dana R Comparison of topical interleukin-1 vs tumor necrosis factor-alpha blockade with corticosteroid therapy on murine corneal inflammation, neovascularization, and transplant survival (an American Ophthalmological Society thesis).Trans Am Ophthalmol Soc. 2007; 105: 330-343PubMed Google Scholar suppression of inflammation early after grafting by hMSCs might contribute to a prolonged survival of corneal allografts through inhibition of the afferent loop of the immune response. In addition to suppressing inflammation, MSCs may also have other effects on the immune system. A large number of in vitro and in vivo data demonstrate that MSCs can be immunosuppressive through their interaction with a broad range of immune cells (T and B cells, regulatory T cells, NK cells, DCs, macrophages, and neutrophils) and by secreting a number of molecules such as IDO, PGE2, nitric oxide, CCL2, TGF-β, TSG-6, IL-10, or HLA-G.24Uccelli A Prockop DJ Why should mesenchymal stem cells (MSCs) cure autoimmune diseases.Curr Opin Immunol. 2010; 22: 768-774Crossref PubMed Scopus (121) Google Scholar,25Siegel G Schäfer R Dazzi F The immunosuppressive properties of mesenchymal stem cells.Transplantation. 2009; 87 (9 Suppl): S45-S49Crossref PubMed Google Scholar,26Ren G Zhang L Zhao X Xu G Zhang Y Roberts AI et al.Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide.Cell Stem Cell. 2008; 2: 141-150Abstract Full Text Full Text PDF PubMed Scopus (1541) Google Scholar,27Rafei M Campeau PM Aguilar-Mahecha A Buchanan M Williams P Birman E et al.Mesenchymal stromal cells ameliorate experimental autoimmune encephalomyelitis by inhibiting CD4 Th17 T cells in a CC chemokine ligand 2-dependent manner.J Immunol. 2009; 182: 5994-6002Crossref PubMed Scopus (287) Google Scholar,28Crop M Baan C Weimar W Hoogduijn M Potential of mesenchymal stem cells as immune therapy in solid-organ transplantation.Transpl Int. 2009; 22: 365-376Crossref PubMed Scopus (68) Google Scholar This considerable diversity and discrepancy in experimental findings for the immune-modulatory mechanisms of MSCs probably reflects their remarkable ability to respond to the microenvironments of injured tissues. In the present experiment, we injected hMSCs i.v. 1 day before and at the time of transplantation. Although the cells rapidly disappeared from the system after injection,21Lee RH Pulin AA Seo MJ Kota DJ Ylostalo J Larson BL et al.Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammato" @default.
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• W2014098786 title "Intravenous Mesenchymal Stem Cells Prevented Rejection of Allogeneic Corneal Transplants by Aborting the Early Inflammatory Response" @default.
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