scholarly journals Mesenchymal Stem Cells Improve the Structure and Function of the Graft-Versus-Host Disease Receptor Thymus: CCR9 Plays an Important Role in Its Homing Thymus

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5599-5599
Author(s):  
Xin Zhang ◽  
Ke Zhao ◽  
Jiabao He ◽  
Andy Peng Xiang ◽  
Qifa Liu
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Untreated Group ◽  
Thymic Epithelial Cells ◽  
Frozen Sections ◽  
Host Disease ◽  
Graft Versus Host

Background: Insufficient thymic function of allogeneic hematopoietic stem cell transplantation (allo-HSCT) receptors results in continuous production of alloreactive T cells, which leads to the development of graft-versus-host disease (GVHD), especially chronic GVHD (cGVHD). We have previously found that patients with acute GVHD (aGVHD) treated with mesenchymal stem cells (MSCs) have increased thymic output and decreased incidence of cGVHD, thus hypothesized that MSCs may reduce the incidence of cGVHD by remodeling the thymus. Chemokine receptor 9 (CCR9), the receptor that specifically guides migration of T-lineage precursors into thymus, is also expressed on MSCs, and thus may be a key factor mediating MSCs homing to the thymus. This in turn allows MSCs to reduce GVHD by repairing thymus tissue structure and saving thymus function. Methods: We carried out studies in a murine GVHD model of fully MHC-mismatched myeloablative bone marrow transplantation (C57BL/6 to BALB/c), a model that can observe the prolongation of aGVHD to cGVHD. We randomly divided GVHD mice into four groups, including three MSCs treated groups and one untreated group. CCR9 over-expressed (MSC/CCR9+), knocked-down (MSC/CCR9-) and empty-load MSCs (MSC/Control) were generated and administrated intravenously at dose of 5 × 105 cells/infusion at 7th and 21th day post HCT to the treated groups respectively to compare their thymic homing ability, and therapeutic effects of GVHD with the untreated group. Clinical scores were recorded once every five days to evaluate GVHD symptoms. Mice of MSCs treated groups and the untreated group were sacrificed at 30d, 45d and 60d after HCT. Thymuses of each group were collected and assessed for size and weight before being manufactured into frozen sections or thymic single-cell suspension. We then analyzed the number and distribution of MSCs in the thymus of the treated groups to assess the role of CCR9 in thymic homing, and analyzed the expression of thymic T cells subsets (CD4+CD8-, CD4-CD8+, CD4+CD8+ T, CD4+CD25+Foxp3+Tregs), thymic epithelial cells (TECs) substes (CD45-CD326+Ly51+ cortical TECs and CD45-CD326+UEA-1+ medullary TECs) and the level of T cell receptor rearrangement excision circles (TRECs) in thymus among the four groups to evaluate the repair effect of MSCs for thymus. Radiation-pretreated murine TECs were cultured alone or co-cultured with murine MSCs in vitro to assess the effect of MSCs on damaged TECs. Results: The infusion of MSC/CCR9+ potently alleviated the clinical signs of GVHD and prolonged the survival of GVHD mice (P<0.05 versus MSC/CCR9- and untreated group). Significant increases in thymus size and weight were observed in the MSC/CCR9+ group, as well as the number of total thymocytes and the more organized cortical medullary structure compared to the other groups. MSCs enter the thymus from the microvascular region at the cortex-medium junction. MSC/CCR9+ were found to appear in the cortex-medium junction of thymus in a greater amount 24 hours after the first infusion, then distribute throughout the whole thymus and relocate in proximity with TECs 48 hours thereafter. MSC/Control could be observed in the cortical and cortex-medium junction, whereas MSC/CCR9- was observed only in the cortex-medium junction with a small amount of distribution. Immunofluorescence of thymus frozen sections showed that, compared with other groups, TECs had decreased apoptosis and significantly increased proliferation and maturation levels in MSC/CCR9+ group, indicating MSCs potently repaired injured TECs and promoted their proliferation and maturation. The number of TECs and its proportion of thymus stroma were significantly improved, including cortical TEC and medullary TECs. As for thymocyte, MSC/CCR9+ infusion significantly increased the number and proportion of CD4+CD8+T cells and Tregs, which were reported deficiency in GVHD thymus. Furthermore, MSC/CCR9+ administration resulted in a remarkable increase in the levels of TRECs in the thymocyte at 45d and 60d after HCT (P<0.05 versus MSC/CCR9- and untreated group). In vitro study showed co-cultured TECs had a decreased apoptosis and increased proliferation compared to TECs cultured alone. Conclusion: This study demonstrates that CCR9 plays an important role in guiding migration of MSCs to thymus and thus highly intensify their issue repair and immunomodulatory effect to rescue thymus function in GVHD model. Disclosures No relevant conflicts of interest to declare.

Mesenchymal Stem Cells for Treatment of Severe Acute Graft-Versus-Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5304-5304 ◽  
Author(s):  
Katarina Le Blanc ◽  
Francesco Frassoni ◽  
Lynne Ball ◽  
Edoardo Lanino ◽  
Berit Sundberg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Mesenchymal stem cells (MSC) from adult bone marrow have the capacity to differentiate into several mesenchymal tissues and inhibit T-cell alloreactivity in vitro. Within the EBMT MSC expansion consortium we have used MSC to treat grades III–IV acute graft-versus-host disease (GvHD) in 40 patients. The MSC dose was median 1.0 (range 0.4–9) 10^6 cells/kg body weight of the recipient. No side-effects were seen after MSC infusions. Nineteen patients received one dose, 19 patients received two doses, two patients received three and five doses respectively. MSC donors were in five cases HLA-identical sibling donors, 19 haploidentical donors and 41 third-party HLA-mismatched donors. Among the 40 patients treated for severe acute GvHD, 19 had complete responses, nine showed improvement, seven patients did not respond, four had stable disease and one patient was not evaluated due to short follow-up. Twenty-one patients are alive between six weeks up to 3.5 years after transplantation. Nine of these patients have extensive chronic GvHD. One patient with ALL has recurrent leukaemia and one patient has denovo AML of recipient origin. We conclude that MSC have immunomodulatory and tissue repairing effects and should be further explored as treatment of severe acute GvHD in prospective randomized trials.

Mesenchymal Stem Cells for Treatment of Severe Acute Graft-Versus-Host Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2918-2918 ◽  
Author(s):  
Katarina Le Blanc ◽  
Francesco Frassoni ◽  
Lynne Ball ◽  
Edoardo Lanino ◽  
Berit Sundberg ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host ◽  
Acute Graft

Abstract Mesenchymal stem cells (MSC) from adult bone marrow have the capacity to differentiate into several mesenchymal tissues and inhibit T-cell alloreactivity in vitro. Within the EBMT MSC expansion consortium we have used MSC to treat grades III-IV acute graft-versus-host disease (GvHD) in 40 patients. The MSC dose was median 1.0 (range 0.4–9) 10^6 cells/kg body weight of the recipient. No side-effects were seen after MSC infusions. Nineteen patients received one dose, 19 patients received two doses, two patients received three and five doses respectively. MSC donors were in five cases HLA-identical sibling donors, 19 haploidentical donors and 41 third-party HLA-mismatched donors. Among the 40 patients treated for severe acute GvHD, 21 had complete responses, eight showed improvement, eight patients did not respond, two had stable disease and one patient was not evaluated due to short follow-up. Twenty patients are alive between six weeks up to 3.5 years after transplantation. Nine of these patients have extensive chronic GvHD. One patient with ALL has recurrent leukaemia and one patient has denovo AML of recipient origin. We conclude that MSC have immunomodulatory and tissue repairing effects and should be further explored as treatment of severe acute GvHD in prospective randomized trials.

scholarly journals MiR-223 Derived from Mesenchymal Stem Cell Exosomes Alleviates Acute Graft-Versus-Host Disease

2020 ◽  
Author(s):  
Weijiang Liu ◽  
Na Zhou ◽  
Peng Wang ◽  
Yuanlin Liu ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
High Throughput Sequencing ◽  
Human Umbilical Cord ◽  
Host Disease ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Acute Graft

Abstract Background Mesenchymal stem cells (MSCs) have been utilized in treating acute graft-versus-host disease (aGvHD) as they show strong immunosuppressive capacity, but the mechanisms are not well defined.Methods In this study, we demonstrated that microRNA-223 (miR-223) derived from exosomes secreted by human umbilical cord mesenchymal stem cells (huc-MSCs) and murine compact bone mesenchymal stem cells (mb-MSCs) could inhibit aGvHD progression by reducing the migration and homing of donor T cells in aGvHD mice.Results MiR-223 was one of the conserved microRNAs highly expressed in huc-MSCs exosomes and mMSCs exosomes, which was identified by high-throughput sequencing. MiR-223 derived from MSC exosomes showed enhanced immunosuppressive capacity, as it could inhibit expression of the target gene ICAM-1 and restrain adhesion and migration of T cells in vitro. Moreover, miR-223Agomir was effective in reducing the inflammatory reaction, and declining the donor T cells infiltration into the spleen, liver and intestine in aGvHD mice. Subsequently, it could alleviate aGvHD symptoms. Taken together, the MSC exosome derived miR-223 could attenuate aGvHD in mice through regulating ICAM-1 expression.Conclusions Our results unveil a new role for MSC exosomes derived miR-223 in the treatment of aGvHD.

scholarly journals The Therapeutic Effect of ICAM-1-Overexpressing Mesenchymal Stem Cells on Acute Graft-Versus-Host Disease

2018 ◽  
Vol 46 (6) ◽  
pp. 2624-2635 ◽  
Author(s):  
Bo Tang ◽  
Xue Li ◽  
Yuanlin Liu ◽  
Xiuhui Chen ◽  
Ximei Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Mouse Model ◽  
Graft Versus Host Disease ◽  
Culture Methods ◽  
Graft Versus Host

Background/Aims: Mesenchymal stem cells (MSCs) do not readily migrate to appropriate sites, and this creates a major obstacle for their use in the treatment of graft-versus-host disease (GVHD). Intercellular adhesion molecule-1 (ICAM-1) can guide the homing of various immune cells to the proper anatomical location within secondary lymphoid organs (SLOs), which are the major niches for generating immune responses or tolerance. MSCs rarely migrate to SLOs after intravenous infusion, and are constitutively low expression of ICAM-1. So in our previous work, ICAM-1 was engineered into a murine MSC line C3H10T1/2 by retrovirus transfection system (ICAM-1MSCs). Here, we hypothesized that ICAM-1highMSCs may significantly improve their immunomodulatory effect. Methods: We used different co-culture methods combined with real-time PCR and flow cytometry to evaluate ICAM-1highMSCs immunomodulatory effect on dendritic cells (DCs) and T cells in vitro and in vivo. MSCs were labeled with carboxyfluorescein diacetate succinimidylester (CFSE) to detect its distribution in mouse model. Results: Our in vitro analyses revealed ICAM-1 MSCs could suppress DCs maturation according to co-culture methods and suppress the T cell immune response according to the mixed lymphocyte response (MLR) and lymphoblast transformation test (LTT) tests. We found that infusion of ICAM-1highMSCs potently prolonged the survival of GVHD mouse model. The infused ICAM-1highMSCs migrate to SLOs in vivo, and suppressed DCs maturation, suppressed CD4+ T cell differentiation to Th1 cells, and increased the ratios of Treg cells. Conclusions: Taken together, these data demonstrate that ICAM-1highMSCs had an enhanced immunosuppressive effect on DCs and T cells, which may help explain the protective effect in a GVHD model. This exciting therapeutic strategy may improve the clinical efficacy of MSC-based therapy for GVHD.

scholarly journals Clinical Application of Mesenchymal Stem Cells in the Treatment and Prevention of Graft-versus-Host Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-17 ◽  
Author(s):  
Yi Lin ◽  
William J. Hogan
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Animal Studies ◽  
Cell Transplant ◽  
Differentiation Potential ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Mesenchymal stem cells (MSCs) represent a heterogeneous population of stromal cells with pluripotent mesenchymal differentiation potential. They have been found to have immunosuppressive properties and the ability to modulate angiogenesis and endogenous tissue repair byin vitroand animal studies. Clinical trials have examined the utility of these cells in autoimmune and inflammatory conditions. In particular, in allogeneic hematopoietic stem cell transplant (HSCT), multiple studies have been conducted to explore the use of MSC to treat acute and chronic graft-versus-host disease (GVHD) and for cotransplantation with HSCT to promote HSC engraftment and prevent GVHD. We review here the results of these studies and discuss some challenges of this treatment modality in this disease setting.

Mesenchymal Stem Cells for Treatment of Severe Acute and Extensive Chronic Graft-Versus-Host Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 143-143 ◽  
Author(s):  
Katarina Le Blanc ◽  
Francesco Frassoni ◽  
Lynne Ball ◽  
Mehmet Uzunel ◽  
Edoardo Lanini ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Early Death ◽  
Third Party ◽  
Host Disease ◽  
Graft Versus Host

Abstract Mesenchymal stem cells (MSC) from adult bone marrow have the capacity to differentiate to several mesenchymal tissues and inhibit T-cell alloreactivity in vitro. We have used MSC to treat grades III-IV acute graft-versus-host disease (GVHD) in 14 patients and extensive chronic GVHD in two patients. The MSC dose was median 1.0 (range 0.4–9) x 10E6 cells/kg body weight of the recipient. No side-effects were seen after MSC infusions. Nine patients received one dose, six patients received two doses and one patient received three doses. MSC donors were in two cases HLA-identical sibling donors, twelve haploidentical donors and ten third-party HLA-mismatched donors. Among the 14 patients treated for severe acute GVHD, six had complete responses, four showed improvement and one had stable disease. Three were not evaluable: two due to early death and one due to short follow-up. MSC donor DNA was detected in lymph node and colon in one of the patients who died. Among the 14 patients treated for severe acute GVHD, nine are alive between two months up to three years after transplantation. Four of these patients have extensive chronic GVHD. One patient transplanted for AML in relapse has recurrent leukaemia. The two patients treated for extensive chronic GVHD had transient responses. One of them died of Epstein-Barr virus lymphoma. We conclude that MSC have immune-modulatory and tissue repairing effects and therefore may be used for treatment of severe GVHD.

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