Abstract
Mesenchymal stromal cells (MSCs) have been applied in prevention from allograft rejection based on their immunomodulatory effects. However, conflicting results have been presented among recent studies, for which one possibility being acknowledged is that the exact effect is determined by the microenvironment when MSCs are applied in vivo. Using a hind limb composite tissue allograft model, we investigate the influence of IFN-γ-preconditioning on the immunomodulatory effects of MSCs and the subsequent allograft survival. Firstly, different doses of IFN-γ were respectively used to incubate with bone marrow–derived MSCs (BMSCs). We found that IFN-γ altered the expression of PD-L1, a major suppressor gene in the immune system during allograft rejection, in a strictly dose-dependent manner in BMSCs. Ten nanograms per milliliter IFN-γ-incubated BMSCs significantly stimulated PD-L1 expression and suppressed T cell proliferation and differentiation, while 50 ng/mL IFN-γ-incubated BMSCs sharply reduced PD-L1 expression. Moreover, we observed that, in contrast to the naive BMSC transplantation group, BMSCs pre-conditioned with 10 ng/mL IFN-γ (BMSCs-IFN-γ) significantly delayed the allograft rejection in vivo. In vitro mixed lymphocyte reaction (MLR) indicated that BMSCs-IFN-γ inhibited T lymphocyte proliferation and activation via PD-L1. Moreover, BMSCs-IFN-γ did not influence the proliferation and activation of T lymphocytes when PD-L1 protein was neutralized by the PD-L1 antibody. These data collectively reveal a role of recipient ongoing immune microenviroment in BMSC-based immunesuppressive therapy.
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This study was supported by National Natural Science Foundation Youth Program of China (No.81401593).
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Fig S1
Cells were analyzed by flow cytometry for expression of CD73 and CD34. PE-CD73 and FITC-CD34 were used to demonstrate that individual cells express CD73 but not express CD34. (PNG 59.8 kb)
Fig S2
Effect of 10 ng/ml IFN-γ on the expression of CD 45, CD105, HLA-ABC and HLA-DR in BMSCs. *P <0.05. (PNG 72.0 KB kb)
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Wang, Y., Xi, Y., Han, F. et al. Vascularized composite allograft rejection is delayed by infusion of IFN-γ-conditioned BMSCs through upregulating PD-L1. Cell Tissue Res 376, 211–220 (2019). https://doi.org/10.1007/s00441-018-2967-y
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DOI: https://doi.org/10.1007/s00441-018-2967-y