Department of Cell Biology, Institute of Basic Medical Sciences, Taiping Road 27, Beijing 100850, PR China.
BNLMS, State Key Laboratory of Polymer Physics & Chemistry, Institute of Chemistry, Chinese Academy of Sciences, Zhongguancun No. 1 Street, Haidian District, Beijing 100190, PR China.
Biomaterials. 2015;53:688-98. doi: 10.1016/j.biomaterials.2015.03.005. Epub 2015 Mar 24.
The poly lactic-co-glycolic acid (PLGA) bio-scaffold is a biodegradable scaffold commonly used for tissue repair. However, implanted PLGA scaffolds usually cause serious inflammatory responses around grafts. To improve PLGA scaffold-based tissue repair, it is important to control the PLGA-mediated inflammatory responses. Recent evidence indicated that PLGA induce dendritic cell (DC) maturation in vitro, which may initiate host immune responses. In the present study, we explored the modulatory effects of mesenchymal stem cells (MSC) on PLGA-induced DCs (PLGA-DC). We found that mouse MSCs inhibited PLGA-DC dendrite formation, as well as co-stimulatory molecule and pro-inflammatory factor expression. Functionally, MSC-educated PLGA-DCs promoted Th2 and regulatory T cell differentiation but suppressed Th1 and Th17 cell differentiation. Mechanistically, we determined that PLGA elicited DC maturation via inducing phosphorylation of p38/MAPK and ERK/MAPK pathway proteins in DCs. Moreover, MSCs suppressed PLGA-DCs by partially inactivating those pathways. Most importantly, we found that the MSCs were capable of suppressing DC maturation and immune function in vivo. Also, the proportion of mature DCs in the mice that received MSC-PLGA constructs greatly decreased compared with that of their PLGA-film implantation counterparts. Additionally, MSCs co-delivery increased regulatory T and Th2 cells but decreased the Th1 and Th17 cell numbers in the host spleens. Histological analysis showed that MSCs alleviated the inflammatory responses around the grafted PLGA scaffolds. In summary, our findings reveal a novel function for MSCs in suppressing PLGA-induced host inflammatory response and suggest that DCs are a new cellular target in improving PLGA scaffold-based tissue repair.
聚乳酸-共-羟基乙酸（PLGA）生物支架是一种常用于组织修复的可生物降解支架。然而，植入的 PLGA 支架通常会在移植物周围引起严重的炎症反应。为了改善基于 PLGA 支架的组织修复，控制 PLGA 介导的炎症反应非常重要。最近的证据表明，PLGA 在体外诱导树突状细胞（DC）成熟，这可能引发宿主免疫反应。在本研究中，我们探讨了间充质干细胞（MSC）对 PLGA 诱导的 DC（PLGA-DC）的调节作用。我们发现，小鼠 MSC 抑制 PLGA-DC 树突形成以及共刺激分子和促炎因子的表达。功能上，MSC 教育的 PLGA-DC 促进 Th2 和调节性 T 细胞分化，但抑制 Th1 和 Th17 细胞分化。在机制上，我们确定 PLGA 通过诱导 DC 中 p38/MAPK 和 ERK/MAPK 通路蛋白的磷酸化来诱导 DC 成熟。此外，MSC 通过部分失活这些途径来抑制 PLGA-DC。最重要的是，我们发现 MSC 能够在体内抑制 DC 成熟和免疫功能。此外，与接受 PLGA 薄膜植入的小鼠相比，接受 MSC-PLGA 构建体的小鼠中成熟 DC 的比例大大降低。此外，MSC 共递送增加了调节性 T 和 Th2 细胞，但减少了宿主脾脏中 Th1 和 Th17 细胞的数量。组织学分析表明，MSC 减轻了移植物周围的炎症反应。总之，我们的研究结果揭示了 MSC 抑制 PLGA 诱导的宿主炎症反应的新功能，并表明 DC 是改善基于 PLGA 支架的组织修复的新细胞靶标。
