University of Iowa Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242, USA.
University of Iowa Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, IA 52242, USA; Department of Health and Human Physiology, University of Iowa, Iowa City, IA 52242, USA.
Mol Ther. 2018 Mar 7;26(3):860-873. doi: 10.1016/j.ymthe.2017.12.013. Epub 2017 Dec 19.
The use of mesenchymal stromal cell (MSC) therapy for the treatment of type 2 diabetes (T2D) and T2D complications is promising; however, the investigation of MSC function in the setting of T2D has not been thoroughly explored. In our current study, we investigated the phenotype and function of MSCs in a simulated in vitro T2D environment. We show that palmitate, but not glucose, exposure impairs MSC metabolic activity with moderate increases in apoptosis, while drastically affecting proliferation and morphology. In co-culture with peripheral blood mononuclear cells (PBMCs), we found that MSCs not only lose their normal suppressive ability in high levels of palmitate, but actively support and enhance inflammation, resulting in elevated PBMC proliferation and pro-inflammatory cytokine release. The pro-inflammatory effect of MSCs in palmitate was partially reversed via palmitate removal and fully reversed through pre-licensing MSCs with interferon-gamma and tumor necrosis factor alpha. Thus, palmitate, a specific metabolic factor enriched within the T2D environment, is a potent modulator of MSC immunosuppressive function, which may in part explain the depressed potency observed in MSCs isolated from T2D patients. Importantly, we have also identified a robust and durable pre-licensing regimen that protects MSC immunosuppressive function in the setting of T2D.
间充质基质细胞 (MSC) 疗法在治疗 2 型糖尿病 (T2D) 和 T2D 并发症方面具有广阔的应用前景；然而，在 T2D 背景下对 MSC 功能的研究尚未得到充分探索。在我们目前的研究中，我们在模拟的体外 T2D 环境中研究了 MSC 的表型和功能。我们发现，棕榈酸而非葡萄糖暴露会损害 MSC 的代谢活性，导致中度细胞凋亡，同时严重影响增殖和形态。在与外周血单核细胞 (PBMC) 的共培养中，我们发现 MSC 不仅在高浓度棕榈酸下丧失正常的抑制能力，而且还积极支持和增强炎症，导致 PBMC 增殖和促炎细胞因子释放增加。MSC 在棕榈酸中的促炎作用部分通过去除棕榈酸逆转，通过干扰素-γ和肿瘤坏死因子-α预先许可 MSC 完全逆转。因此，棕榈酸作为 T2D 环境中富集的特定代谢因子，是 MSC 免疫抑制功能的有效调节剂，这部分解释了从 T2D 患者中分离出的 MSC 观察到的功能抑制。重要的是，我们还确定了一种强大且持久的预先许可方案，可保护 MSC 在 T2D 环境下的免疫抑制功能。
