Increased production of humoral factor and PD-L1 expression induced by cytokine stimulation play a key role in the immunosuppressive effects of stem cells derived from human exfoliated deciduous teeth

IF 2.2 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Shin Tsunekawa , Makoto Kato , Kenta Iwasaki , Yuko Miwa , Yusuke Hayashi , Takako Izumoto , Akihito Yamamoto , Tatsuhito Himeno , Masaki Kondo , Takaaki Kobayashi , Hideki Kamiya , Kohei Ishiyama
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引用次数: 0

Abstract

Background

Recently, the efficacy of mesenchymal stem cells (MSC) targeting transplant immunosuppression has been reported, and their application to islet transplantation is also expected. However, since the stability of functional manifestation of MSC remains unclear, we have investigated the stability and efficacy of cytokine-stimulated stem cells from human exfoliated deciduous teeth (SHED) in the human immune system in order to establish a safety clinical application.

Methods

SHED were stimulated with TNF-α, IL-1β, and IFN-γ, which were elevated post-transplant in the liver. Flow cytometry was used to analyze surface antigen expression. Human peripheral blood mononuclear cells (PBMC) were co-cultured with stimulated SHED directly or indirectly to assess PBMC proliferation. Cytotoxicity assay evaluated PBMC-induced damage to induced pluripotent stem (iPS) cell-derived human pancreatic beta-like cells. ELISA measured immunomodulatory factor secretion.

Results

Programmed death-ligand 1 (PD-L1) expression was assessed, and PBMC were co-cultured with stimulated SHED in the presence of anti-PD-L1 antibody. SHED were also reaggregated with dissociated human pancreatic islets to generate islet-like organoids, and insulin secretion was measured. Stimulated SHED showed minimal change in cell surface markers but significantly inhibited PBMC proliferation and cytotoxicity, Stimulated SHED produced elevated levels of immunosuppressive factors and expressed PD-L1. The immunosuppressive effect was partially inhibited by inhibiting cell contact between SHED and PBMC or blocking the PD-1/PD-L1 pathway. Furthermore, insulin secretion was enhanced in reaggregated human pancreatic islets with SHED.

Conclusions

We demonstrated that the use of SHED in its activated state effectively suppresses immune response and maintains graft function at the time of islet transplantation.
细胞因子刺激诱导的体液因子和PD-L1表达的增加在人脱落乳牙干细胞的免疫抑制作用中起关键作用
近年来,间充质干细胞(mesenchymal stem cells, MSC)靶向移植免疫抑制的疗效已被报道,其在胰岛移植中的应用也备受期待。然而,由于MSC功能表现的稳定性尚不清楚,我们研究了细胞因子刺激的人脱落乳牙干细胞(SHED)在人免疫系统中的稳定性和有效性,以建立安全的临床应用。方法用肝移植后升高的TNF-α、IL-1β和IFN-γ刺激sshed。流式细胞术检测表面抗原表达。将人外周血单个核细胞(PBMC)与受刺激的SHED直接或间接共培养,以评估PBMC的增殖情况。细胞毒性试验评估了pbmc对诱导多能干细胞(iPS)衍生的人胰腺β样细胞的损伤。ELISA法检测免疫调节因子的分泌。结果检测程序性死亡配体1 (programmed death-ligand 1, PD-L1)的表达,并在抗PD-L1抗体存在下,将PBMC与受刺激的SHED共培养。SHED也与游离的人胰岛重新聚集,生成胰岛样器官,并测量胰岛素分泌。受刺激的SHED细胞表面标志物变化不大,但明显抑制PBMC增殖和细胞毒性,受刺激的SHED产生免疫抑制因子水平升高并表达PD-L1。通过抑制SHED与PBMC之间的细胞接触或阻断PD-1/PD-L1通路,部分抑制免疫抑制作用。此外,患有SHED的重组人胰岛的胰岛素分泌增强。结论在胰岛移植过程中,激活状态的SHED可有效抑制免疫反应,维持移植物功能。
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来源期刊
Biochemistry and Biophysics Reports
Biochemistry and Biophysics Reports Biochemistry, Genetics and Molecular Biology-Biophysics
CiteScore
4.60
自引率
0.00%
发文量
191
审稿时长
59 days
期刊介绍: Open access, online only, peer-reviewed international journal in the Life Sciences, established in 2014 Biochemistry and Biophysics Reports (BB Reports) publishes original research in all aspects of Biochemistry, Biophysics and related areas like Molecular and Cell Biology. BB Reports welcomes solid though more preliminary, descriptive and small scale results if they have the potential to stimulate and/or contribute to future research, leading to new insights or hypothesis. Primary criteria for acceptance is that the work is original, scientifically and technically sound and provides valuable knowledge to life sciences research. We strongly believe all results deserve to be published and documented for the advancement of science. BB Reports specifically appreciates receiving reports on: Negative results, Replication studies, Reanalysis of previous datasets.
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