Dataset Information

Steroids Enable Mesenchymal Stromal Cells to Promote CD8⁺ T Cell Proliferation Via VEGF-C.

ABSTRACT: Mesenchymal stromal cells (MSCs) function as a formidable regulator of inflammation and tissue homeostasis and expanded MSCs are shown to be effective in treating various inflammatory diseases. Their therapeutic effects require the existence of certain inflammatory cytokines. However, in the absence of sufficient proinflammatory stimuli or in the presence of anti-inflammatory medications, MSCs are animated to promote immune responses and unable to alleviate inflammatory disorders. In this study, it is demonstrated that steroid co-administration interferes the efficacy of MSCs in treating acute graft-versus-host disease (aGvHD). Molecular analysis reveals that vascular endothelial growth factor C (VEGF-C) is highly induced in MSCs by steroids and TNFα and VEGF-C in turn promotes CD8⁺ T cell response. This immune promoting effect is abolished by blockade or specific genetic ablation of VEGFR3 in CD8⁺ T cells. Additionally, administration of VEGF-C alone exacerbates aGvHD progression through eliciting more vigorous CD8⁺ T cell activation and proliferation. Further studies demonstrate that VEGF-C augments the PI3K/AKT signaling process and the expression of downstream genes, such as Cyclin D1. Thus, the data demonstrate that steroids can reverse the immunosuppressive effect of MSCs via promoting VEGF-C-augmented CD8⁺ T cell response and provide novel information for designing efficacious MSC-based therapies.

SUBMITTER: Gan Y

PROVIDER: S-EPMC8224440 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Steroids Enable Mesenchymal Stromal Cells to Promote CD8<sup>+</sup> T Cell Proliferation Via VEGF-C.

Gan Yurun Y Zhang Tao T Chen Xiaodong X Cao Wei W Lin Liangyu L Du Liming L Wang Yu Y Zhou Fei F He Xuefeng X He Yulong Y Gan Jianhe J Sheng Huiming H Sorokin Lydia L Shi Yufang Y Wang Ying Y

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210502 12

Mesenchymal stromal cells (MSCs) function as a formidable regulator of inflammation and tissue homeostasis and expanded MSCs are shown to be effective in treating various inflammatory diseases. Their therapeutic effects require the existence of certain inflammatory cytokines. However, in the absence of sufficient proinflammatory stimuli or in the presence of anti-inflammatory medications, MSCs are animated to promote immune responses and unable to alleviate inflammatory disorders. In this study, ...[more]

PMID: 34194927

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Project description:BackgroundThe tumour microenvironment contributes to chemotherapy resistance in gliomas, and glioma-associated mesenchymal stromal/stem cells (gaMSCs) are important stromal cell components that play multiple roles in tumour progression. However, whether gaMSCs affect chemotherapy resistance to the first-line agent temozolomide (TMZ) remains unclear. Herein, we explored the effect and mechanism of gaMSCs on resistance to TMZ in glioma cells.MethodsHuman glioma cells (cell line U87MG and primary glioblastoma cell line GBM-1) were cultured in conditioned media of gaMSCs and further treated with TMZ. The proliferation, apoptosis and migration of glioma cells were detected by Cell Counting Kit-8 (CCK-8), flow cytometry and wound-healing assays. The expression of FOXS1 in glioma cells was analysed by gene microarray, PCR and Western blotting. Then, FOXS1 expression in glioma cells was up- and downregulated by lentivirus transfection, and markers of the epithelial-mesenchymal transformation (EMT) process were detected. Tumour-bearing nude mice were established with different glioma cells and treated with TMZ to measure tumour size, survival time and Ki-67 expression. Finally, the expression of IL-6 in gaMSC subpopulations and its effects on FOXS1 expression in glioma cells were also investigated.ResultsConditioned media of gaMSCs promoted the proliferation, migration and chemotherapy resistance of glioma cells. The increased expression of FOXS1 and activation of the EMT process in glioma cells under gaMSC-conditioned media were detected. The relationship of FOXS1, EMT and chemotherapy resistance in glioma cells was demonstrated through the regulation of FOXS1 expression in vitro and in vivo. Moreover, FOXS1 expression in glioma cells was increased by secretion of IL-6 mainly from the CD90low gaMSC subpopulation.ConclusionsCD90low gaMSCs could increase FOXS1 expression in glioma cells by IL-6 secretion, thereby activating epithelial-mesenchymal transition and resistance to TMZ in glioma cells. These results indicate a new role of gaMSCs in chemotherapy resistance and provide novel therapeutic targets.

Dataset Information

Steroids Enable Mesenchymal Stromal Cells to Promote CD8⁺ T Cell Proliferation Via VEGF-C.

Publications

Steroids Enable Mesenchymal Stromal Cells to Promote CD8<sup>+</sup> T Cell Proliferation Via VEGF-C.

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Dataset Information

Steroids Enable Mesenchymal Stromal Cells to Promote CD8+ T Cell Proliferation Via VEGF-C.

Publications

Steroids Enable Mesenchymal Stromal Cells to Promote CD8<sup>+</sup> T Cell Proliferation Via VEGF-C.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Steroids Enable Mesenchymal Stromal Cells to Promote CD8⁺ T Cell Proliferation Via VEGF-C.