丁酸盐调节从多基因肥胖和糖尿病小鼠中分离的脂肪来源干细胞，以增强免疫抑制作用。

Butyrate modulates adipose-derived stem cells isolated from polygenic obese and diabetic mice to drive enhanced immunosuppression.

机构信息

School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan.

Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan.

出版信息

Cytotherapy. 2021 Jul;23(7):567-581. doi: 10.1016/j.jcyt.2021.01.007. Epub 2021 Apr 16.

DOI:10.1016/j.jcyt.2021.01.007

PMID:33875384

Abstract

BACKGROUND AIMS

Adipose-derived stem cells (ASCs) offer promising therapeutic possibilities for immunomodulation. Butyrate (BA) exerts potent anti-inflammatory effects and exhibits multiple regulatory functionalities in adipose tissue (AT). The authors aimed to explore whether BA modulates ASCs to augment their immunosuppressive capabilities.

METHODS

The authors examined the potency of BA and ASCs for controlling anti-CD3 plus CD28-stimulated splenocyte proliferation in vitro, both in combination and with pre-treatment. Further, the authors investigated genes specifically upregulated by BA-treated ASCs, which were harvested from ASC-splenocyte co-culture after the removal of floating splenocytes. In addition, the authors investigated the influence of oral BA supplementation on the ex vivo immunosuppressive potency of ASCs from BALB/c and Tsumura, Suzuki, obese, diabetes (TSOD) mice.

RESULTS

BA enhanced the immunosuppressive potency of ASCs when directly added to ASC-splenocyte co-cultures or via pre-conditioning treatment. The percentages of ASC-induced Foxp3 regulatory T cells increased, whereas the numbers of ASC-suppressed T helper 17 cells further decreased after BA exposure. The messenger RNA expression levels of inducible nitric oxide (NO) synthase (iNOS), chemokines, IL-10 and amphiregulin in ASCs co-cultured with activated splenocytes were upregulated after incubation with BA. This was accompanied by an amplification of iNOS-inducing cytokines, interferon gamma and tumor necrosis factor alpha in the ASC-splenocyte co-culture, triggering ASCs to produce high NO levels under the influence of BA. Mechanistically, the authors detected BA-mediated acetylated histone H3 in ASCs. BA treatment consistently improved the immunosuppressive potency of ASCs derived from both BALB/c and TSOD mice.

CONCLUSIONS

The use of BA to counteract metaflammation by restoring the defective immunomodulation of ASCs from dysregulated AT in obese donors is recommended.

摘要

背景目的

脂肪干细胞 (ASCs) 在免疫调节方面具有有前景的治疗潜力。丁酸盐 (BA) 在脂肪组织 (AT) 中具有强大的抗炎作用，并表现出多种调节功能。作者旨在探讨 BA 是否调节 ASCs 以增强其免疫抑制能力。

方法

作者检查了 BA 和 ASCs 控制体外抗 CD3 加 CD28 刺激的脾细胞增殖的能力，包括两者的组合和预处理。此外，作者研究了 BA 处理的 ASCs 特异性上调的基因，这些基因是从 ASC-脾细胞共培养物中收获的，在去除漂浮的脾细胞后。此外，作者还研究了口服 BA 补充对 BALB/c 和 Tsumura、Suzuki、肥胖、糖尿病 (TSOD) 小鼠 ASC 的体外免疫抑制能力的影响。

结果

BA 直接添加到 ASC-脾细胞共培养物中或通过预处理处理时，增强了 ASCs 的免疫抑制能力。Foxp3 调节性 T 细胞的 ASC 诱导百分比增加，而 BA 暴露后，ASC 抑制的 Th17 细胞数量进一步减少。与激活的脾细胞共培养的 ASCs 中的诱导型一氧化氮 (NO) 合酶 (iNOS)、趋化因子、IL-10 和 Amphiregulin 的信使 RNA 表达水平在与 BA 孵育后上调。这伴随着 ASC-脾细胞共培养物中 iNOS 诱导细胞因子干扰素 γ和肿瘤坏死因子 α 的扩增，在 BA 的影响下触发 ASCs 产生高 NO 水平。从机制上讲，作者检测到 BA 介导的 ASCs 中的乙酰化组蛋白 H3。BA 治疗一致改善了来自肥胖供体失调 AT 的 ASCs 的免疫抑制能力。