He Ji-Gang, Xie Qiao-Li, Li Bei-Bei, Zhou Liang, Yan Dan
Department of Cardiovascular Surgery, First People's Hospital of Yunnan Province, Kunming, Yunnan Province, China.
Department of Cardiology, First People's Hospital of Yunnan Province, Kunming, Yunnan Province, China.
Cell Transplant. 2018 Nov;27(11):1657-1683. doi: 10.1177/0963689718805375. Epub 2018 Oct 12.
The immunosuppressive activity of mesenchymal stem cells (MSCs) has been exploited to induce tolerance after organ transplantation. The indoleamine 2,3-dioxygenase (IDO) may have beneficial effects in the immunoregulatory properties of MSCs. It was recently revealed that exosomes derived from MSCs play important roles in mediating the biological functions of MSCs. This study aimed to explore the roles of exosomes derived from MSCs in the induction of immune tolerance.
Dendritic cells (DCs) and T-cells were cultured with exosomes derived from rat bone marrow MSCs (BMSCs) overexpressing IDO1 or controls. For the in-vivo study, rats received heart transplants and were treated with exosomes from IDO-BMSCs and heart function was evaluated. Flow cytometry was used to detect expression of cell surface markers. Cytokine levels were detected in culture supernatants or serum samples. Protein and microRNA expressions in exosomes were investigated by chips.
Exosomes from IDO-BMSCs cultured with DCs and T-cells (1) downregulated CD40, CD86, CD80, MHC-II, CD45RA, CD45RA+CD45RB, OX62, and upregulated CD274 expression, (2) increased the number of regulatory T-cells (Tregs) and decreased the number of CD8+ T-cells, and (3) decreased the levels of pro-inflammatory cytokines, but increased the levels of anti-inflammatory cytokines compared with the other groups. Transplanted rats, which were injected with exosomes from IDO-BMSCs, had reduced allograft-targeting immune responses and improved cardiac allograft function. Exosomes secreted by IDO-BMSCs exhibited significant upregulations of the immunoregulatory protein FHL-1, miR-540-3p, and a downregulation of miR-338-5p.
Exosomes derived from IDO-BMSCs can be used to promote immunotolerance and prolong the survival of cardiac allografts.
间充质干细胞（MSCs）的免疫抑制活性已被用于诱导器官移植后的免疫耐受。吲哚胺2,3-双加氧酶（IDO）可能对MSCs的免疫调节特性具有有益作用。最近发现，源自MSCs的外泌体在介导MSCs的生物学功能中起重要作用。本研究旨在探讨源自MSCs的外泌体在诱导免疫耐受中的作用。
用来自过表达IDO1的大鼠骨髓间充质干细胞（BMSCs）或对照的外泌体培养树突状细胞（DCs）和T细胞。对于体内研究，大鼠接受心脏移植并用来自IDO-BMSCs的外泌体进行治疗，并评估心脏功能。流式细胞术用于检测细胞表面标志物的表达。在培养上清液或血清样品中检测细胞因子水平。通过芯片研究外泌体中的蛋白质和微小RNA表达。
与DCs和T细胞一起培养的IDO-BMSCs来源的外泌体（1）下调CD40、CD86、CD80、MHC-II、CD45RA、CD45RA+CD45RB、OX62，并上调CD274表达，（2）增加调节性T细胞（Tregs）的数量并减少CD8+T细胞的数量，并且（与其他组相比，（3）降低促炎细胞因子水平，但增加抗炎细胞因子水平。注射了来自IDO-BMSCs的外泌体的移植大鼠具有降低的同种异体移植靶向免疫反应并改善了心脏同种异体移植功能。IDO-BMSCs分泌的外泌体表现出免疫调节蛋白FHL-1、miR-540-3p的显著上调和miR-338-5p的下调。
源自IDO-BMSCs的外泌体可用于促进免疫耐受并延长心脏同种异体移植的存活时间。
