Abstract
BackgroundMesenchymal stromal cells (MSCs) are proven to have immunosuppressive functions via various mechanisms. These mechanisms were demonstrated by administering bone marrow derived human MSCs (hMSCs) to graft versus host disease (GVHD) murine models.MethodsBALB/c host mice were irradiated prior to receiving C57BL/6 donor T cell depleted bone marrow (TCDBM) cells (negative control) and donor CD4+ T lymphocyte with (treatment group) or without hMSCs (positive control). The presence of hMSCs in target tissues and lymphoid organs was documented by using in vivo imaging and measuring the expression of EphB2 and ephrin-B2 by RTqPCR. Survival rate and GVHD score were also monitored. Tissue sections were obtained for histopathologic analysis. Flow cytometry was used to document donor T cell alloreactivity and expression of CCR5, CXCR3 and CCR7. ELISA was utilized to determine levels of proinflammatory cytokines, RANTES (CCL5) and phosphorylated STAT 5A/B. RTqPCR was performed to quantify expression of CCL3 and CXCL9. Western blotting was performed to qualitatively measure iNOS expression.ResultsSurvival rate and GVHD score improved with hMSC treatment. Pathologic changes of GVHD were abrogated. Documentation of suppression of RANTES, CCL3, CXCL9, CCR5 and CXCR3 with simultaneous decrease of donor T cell alloreactivity was demonstrated 6 days after transplantation, along with reduction of levels of inflammatory cytokines, suppression of STAT 5A/B phosphorylation, increased expression of CCR7 and increased production of nitrous oxide by hMSCs. Documentation of homing of hMSCs to lymphoid organs and target tissues was also performed.ConclusionsThese mechanisms contribute to the current understanding of MSC mechanisms of immunosuppression and forms a comprehensive picture of how they exert immunosuppression in an in vivo model of immune dysregulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s40164-015-0007-0) contains supplementary material, which is available to authorized users.
Highlights
Mesenchymal stromal cells (MSCs) are proven to have immunosuppressive functions via various mechanisms
Results Human mesenchymal stromal cells (hMSC) migrate towards graft versus host disease (GVHD) target organs In order to identify the earliest time we would be able to detect the presence of hMSCs in the GVHD target organs and to answer whether hMSCs home to these organs, hMSCs were stained with CM-Dil and injected into host mice at the time of transplantation
Migration patterns were observed towards the liver, colon, lungs and spleen. 6 days after transplantation, hMSCs can be localized in the liver, colon lung and spleen of GHVD host mice (Figure 1A-B)
Summary
Mesenchymal stromal cells (MSCs) are proven to have immunosuppressive functions via various mechanisms. Bone marrow derived stromal cells were reported to be able to suppress T cell proliferation leading to various studies that attempted to explain the mechanisms of immunonodulation induced by MSCs and paving the way for its probable clinical utility in graft versus host disease (GVHD) [10] Most of these mechanisms were explained either by obtaining MSCs of murine sources and infusing them to mice with the alloreactive reaction dependent on the mouse immune system (i.e. non-humanized GVHD models) [11,12] or by acquiring hMSCs administering them to immunodeficient mice whose immune system is reconstituted with human immune cells (i.e. humanized GVHD models) [13,14,15]. In this study we explained the immunosuppressive mechanisms of MSCs using bone marrow derived hMSCs infused to non-humanized GVHD mice
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