Human adipose-derived mesenchymal stem cells alleviate obliterative bronchiolitis in a murine model via IDO.
Human adipose-derived mesenchymal stem cells alleviate obliterative bronchiolitis in a murine model via IDO.
复制标题
人脂肪间充质干细胞通过 IDO 缓解小鼠模型中的闭塞性细支气管炎
DOI：
10.1186/s12931-017-0599-5
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发表时间：
2017-06-15
影响因子：
5.8
通讯作者：
Xu J
中科院分区：
文献类型：
--
作者：
Zheng G;Qiu G;Ge M;He J;Huang L;Chen P;Wang W;Xu Q;Hu Y;Shu Q;Xu J
背景肺移植的长期存活受到闭塞性细支气管炎（obliterative bronchiolitis，OB）的影响。脂肪源性干细胞（ASC）被证明比来自骨髓和胎盘的间充质干细胞（MSC）具有更强的免疫抑制能力。我们研究的目的是评估反复给药的ASCs对OB的影响和吲哚胺2，3-双加氧酶（IDO）介导的ASCs在异位气管移植（HTT）model.MethodsFor体外研究中的保护作用，ASCs用干扰素-γ（IFN-γ）治疗。在体内研究中，将来自BALB/c或C57 BL/6供体的气管移植到C57 BL/6受体中以建立HTT模型。在移植后第0、1、3、5、8、12、15、20和25天，向同种异体受体小鼠静脉内施用磷酸盐缓冲盐水、1 × 106人ASC或1 × 106人ASC加1-甲基色氨酸（1-MT）（IDO抑制剂）。在第3，7，14和28天，血清，气管和脾脏样品收获analysis.ResultsASCs归巢异位气管移植后输注。多剂量ASC显著增加同种异体移植物中的气管IDO水平。与同系移植物相比，同种异体移植物和血清IFN-γ水平显著升高。IFN-γ在体外提高ASC中IDO的表达和活性。ASCs减轻了同种异体移植物中的OB，表现为减少上皮丢失、上皮细胞凋亡和管腔内梗阻。ASCs对OB的作用可被1-MT阻断。1-MT还阻断了ASCs诱导的促炎和抗炎细胞因子以及CD 3 + T细胞浸润的改变。ASC不仅诱导脾水平的CD 4 + CD 25 + Foxp 3+调节性T细胞（Treg），而且诱导产生IL-10和TGF-β的Treg。此外，IDO抑制消除了ASCs诱导的脾Treg的变化。此外，Treg减少环磷酰胺治疗并没有改变ASCs对气管IDO表达的影响，在同种异体移植物确认Treg诱导是下游IDO. ConclusionsRepeatedDose的ASCs能够改善OB。ASC至少部分地通过升高IDO表达起作用。ASC通过IDO依赖性机制促进Treg的产生并抑制T细胞浸润。
BackgroundLong-term survival of lung transplantation is hindered by the development of obliterative bronchiolitis (OB). Adipose-derived stem cells (ASCs) were documented to have more potent immunosuppressive ability than mesenchymal stem cells (MSCs) from bone marrow and placenta. The goal of our study is to evaluate the effect of repeated administration of ASCs on OB and the involvement of indoleamine 2,3-dioxygenase (IDO) mediating the protective effect of ASCs in a heterotopic tracheal transplantation (HTT) model.MethodsFor studies in vitro, ASCs were treated with interferon-γ (IFN-γ). For in vivo study, tracheas from BALB/c or C57BL/6 donors were transplanted into C57BL/6 recipients to create a HTT model. On days 0, 1, 3, 5, 8, 12, 15, 20 and 25 post-transplant, the allogeneic recipient mice were administered intravenously with phosphate buffered saline, 1 × 106human ASCs, or 1 × 106human ASCs plus 1-methyltryptophan (1-MT), an IDO inhibitor. On days 3, 7, 14 and 28, serum, trachea and spleen samples were harvested for analysis.ResultsASCs homed to heterotopic tracheal grafts after infusion. Multiple doses of ASCs significantly increased tracheal IDO levels in allografts. There were significant increases in graft and serum IFN-γ levels in allografts compared with isografts. IFN-γ elevated IDO expression and activity in ASCs in vitro. ASCs alleviated OB in allografts as evidenced by reduced epithelial loss, epithelial apoptosis, and intraluminal obstruction. The effects of ASCs on OB were blocked by 1-MT. 1-MT also blocked the alterations in pro and anti-inflammatory cytokines as well as CD3+ T cell infiltration induced by ASCs. ASCs induced not only splenic levels of CD4+CD25+Foxp3+ regulatory T cells (Treg) but also IL-10 and TGF-β-producing Treg. Furthermore, IDO inhibition abolished the changes of splenic Treg induced by ASCs. In addition, Treg reduction by cyclophosphamide treatment did not alter the effects of ASCs on tracheal IDO expression in allografts confirming Treg induction is downstream of IDO.ConclusionsRepeated doses of ASCs are capable of ameliorating OB. ASCs act at least in part via elevating IDO expression. ASCs promote the generation of Treg and suppress T cell infiltration via an IDO-dependent mechanism.