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Background: Oxidative stress is increased in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients and leads to the development of graft versus host disease (GVHD). Mesenchymal stromal cells (MSCs) can ameliorate GVHD by regulating the function of T cells. However, whether MSCs can modulate erythrocyte antioxidant metabolism and thus reduce GVHD is not known., Methods: Forty female BALB/c mice were randomly assigned to four groups: the control, GVHD high , hPMSC, and PBS groups. A hypoxanthine/xanthine oxidase system was used to steadily and gradually produce superoxide in an in vitro experiment. A scanning microscope was used to examine the ultrastructure of erythrocytes. Laser diffraction analyses were used to analyze erythrocyte deformability. Western blotting was used to measure the expression of the erythrocyte membrane skeleton proteins Band 3 and β-Spectrin. Corresponding kits were used to assess the levels of oxidative damage and the activity of antioxidant enzymes., Results: Morphological and deformability defects were significantly increased in erythrocytes from GVHD patients. Band 3 and β-Spectrin expression was also reduced in GVHD patients and model mice. Furthermore, we observed significantly increased oxidative stress-induce injury and decreased antioxidant capability in erythrocytes from both GVHD patients and model mice. Subsequent research showed that human placenta-derived MSC (hPMSC) therapy decreased the GVHD-induced redox imbalance in erythrocytes. Furthermore, our findings suggested that upregulating glucose metabolism promoted both the de novo synthesis and recycling of GSH, which is the primary mechanism by which hPMSCs mediate the increase in antioxidant capacity in erythrocytes., Conclusion: Together, our findings suggest that hPMSCs can increase antioxidant capacity by increasing erythrocyte GSH production and thus ameliorate GVHD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background: The activation of T cells and imbalanced redox metabolism enhances the development of graft-versus-host disease (GVHD). Human placenta-derived mesenchymal stromal cells (hPMSCs) can improve GVHD through regulating T cell responses. However, whether hPMSCs balance the redox metabolism of CD4 + IL-10 + T cells and liver tissue and alleviate GVHD remains unclear. This study aimed to investigate the effect of hPMSC-mediated treatment of GVHD associated with CD4 + IL-10 + T cell generation via control of redox metabolism and PD-1 expression and whether the Nrf2 and NF-κB signaling pathways were both involved in the process., Methods: A GVHD mouse model was induced using 6-8-week-old C57BL/6 and Balb/c mice, which were treated with hPMSCs. In order to observe whether hPMSCs affect the generation of CD4 + IL-10 + T cells via control of redox metabolism and PD-1 expression, a CD4 + IL-10 + T cell culture system was induced using human naive CD4 + T cells. The percentage of CD4 + IL-10 + T cells and their PD-1 expression levels were determined in vivo and in vitro using flow cytometry, and Nrf2, HO-1, NQO1, GCLC, GCLM, and NF-κB levels were determined by western blotting, qRT-PCR, and immunofluorescence, respectively. Hematoxylin-eosin, Masson's trichrome, and periodic acid-Schiff staining methods were employed to analyze the changes in hepatic tissue., Results: A decreased activity of superoxide dismutase (SOD) and a proportion of CD4 + IL-10 + T cells with increased PD-1 expression were observed in GVHD patients and the mouse model. Treatment with hPMSCs increased SOD activity and GCL and GSH levels in the GVHD mouse model. The percentage of CD4 + IL-10 + T cells with decreased PD-1 expression, as well as Nrf2, HO-1, NQO1, GCLC, and GCLM levels, both in the GVHD mouse model and in the process of CD4 + IL-10 + T cell generation, were also increased, but NF-κB phosphorylation and nuclear translocation were inhibited after treatment with hPMSCs, which was accompanied by improvement of hepatic histopathological changes., Conclusions: The findings suggested that hPMSC-mediated redox metabolism balance and decreased PD-1 expression in CD4 + IL-10 + T cells were achieved by controlling the crosstalk between Nrf2 and NF-κB, which further provided evidence for the application of hPMSC-mediated treatment of GVHD.

Human mesenchymal stromal cells (MSCs) harbor immunomodulatory properties to induce the generation of suppressive T cells. MSCs have been successfully used in treating graft-versus-host disease (GVHD) accompanied by abundant inflammatory cytokines such as IL-27. This study investigated the effects of IL-27 on the human placenta-derived MSCs (hPMSCs) to induce generation of CD4 + IL-10 + IFN-γ + T cells in vitro and in the humanized xenogenic GVHD NOD/SCID model. The results showed that the percentages of CD4 + IL-10 + IFN-γ + T cells were significantly increased in activated human PBMC from both healthy donors and GVHD patients with hPMSCs and in the liver and spleen of hPMSC-treated GVHD mice, and the level of CD4 + IL-10 + IFN-γ + T cells in the liver was greater than that in the spleen in hPMSC-treated GVHD mice. The serum level of IL-27 decreased and the symptoms abated in hPMSC-treated GVHD. Further, in vitro results showed that IL-27 promoted the regulatory effects of hPMSCs by enhancing the generation of CD4 + IL-10 + IFN-γ + T cells from activated PBMC. Activation occurred through increases in the expression of programmed death ligand 2 (PDL2) in hPMSCs via the JAK/STAT signaling pathway. These findings indicated that hPMSCs could alleviate GVHD mice symptoms by upregulating the production of CD4 + IL-10 + IFN-γ + T cells in the spleen and liver and downregulating serum levels of IL-27. In turn, the ability of hPMSCs to induce the generation of CD4 + IL-10 + IFN-γ + T cells could be promoted by IL-27 through increases in PDL2 expression in hPMSCs. The results of this study will be of benefit for the application of hPMSCs in clinical trials., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Aims: To examine whether human placenta mesenchymal stem/stromal cells (hpMSCs) mitigate graft-versus-host-disease (GVHD) via regulation of Th17 and Tr1., Materials and Methods: hpMSCs or phosphate buffered saline (PBS, as a control) were injected into humanized xeno-GVHD NOD/SCID mouse model. Effects on body weights and survival times were determined. In addition, various assays, including flow cytometry (FCM) and HE stain, were performed on tissues (liver, spleen, lung and intestine) from these hpMSCs versus PBS treated GVHD mice. Th17 cell number in vitro was analyzed by FCM., Key Findings: hpMSCs reduced weight loss, along with IL-6 and IL-17 production to prolong the survival of GVHD mice. Th17 cell number was down-regulated obviously in hpMSCs treated GVHD mice. Conversely, Tr1 cell number and TGF-β production were enhanced by hpMSCs. Moreover, knockdown of programmed death ligand 2 (PD-L2) increased Th17 cell number from PMA activated T cells co-cultured with hpMSCs., Significance: hpMSCs can modulate the balance between Th17 and Tr1 cells to alleviate GVHD. In addition, PD-L2 as expressed on hpMSCs inhibits the generation of Th17 subset from activated T cells. These data suggest that hpMSCs attenuate GVHD through inhibition of severe inflammatory responses resulting from T cell differentiation., (Copyright © 2018. Published by Elsevier Inc.)