Human Chorionic Villous Mesenchymal Stem Cells Modify the Functions of Human Dendritic Cells, and Induce an Anti-Inflammatory Phenotype in CD1+Dendritic Cells
Human Chorionic Villous Mesenchymal Stem Cells Modify the Functions of Human Dendritic Cells, and Induce an Anti-Inflammatory Phenotype in CD1+Dendritic Cells
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DOI：
10.1007/s12015-014-9562-8
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发表时间：
2015-06-01
影响因子：
4.8
通讯作者：
Abumaree, M. H.
中科院分区：
文献类型：
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作者：
Abomaray, F. M.;Al Jumah, M. A.;Abumaree, M. H.
背景来源于人足月胎盘绒毛膜绒毛的间充质干细胞（Mesenchymal stem cells，pMSCs）因其多向分化潜能和免疫调节能力而引起人们的广泛兴趣。这些特性是其在干细胞移植和再生医学领域临床应用的基础。先前，我们表明pMSC在人巨噬细胞中诱导抗炎表型。在这项研究中，我们确定是否pMSCs修饰人单核细胞分化和成熟为树突状细胞（DC）。方法用白细胞介素4（IL-4）和粒细胞-巨噬细胞集落刺激因子（GM-CSF）刺激单核细胞向未成熟树突状细胞（iDC）分化，并与pMSCs共培养。使用脂多糖（LPS）诱导iDC成熟为成熟树突状细胞（mDC）。使用流式细胞术和酶联免疫吸附测定（ELISA）来量化pMSC共培养对DC分化的影响，所述DC分化使用DC的独特标记物CD 1a以及在DC的免疫功能中重要的其他分子。结果与pMSCs共培养后，单核细胞分化为iDCs受到抑制，LPS处理的iDCs成熟也受到抑制，表现为CD 1a和CD 83的表达降低。pMSCs对iDC分化的抑制作用呈剂量依赖性。此外，pMSC与iDC和mDC共培养导致表型和功能变化，如共刺激分子（CD 40、CD 80、CD 83和CD 86）的表达降低和刺激CD 4（+）T细胞增殖的能力降低所示。此外，pMSC共培养增加了iDC上的主要组织相容性复合物（MHC-II）分子的表面表达，但降低了mDC上的MHC-II表达。此外，pMSC与iDC或mDC共培养增加了免疫抑制分子[B7 H3、B7 H4、CD 273、CD 274和吲哚胺-吡咯2，3-双加氧酶（IDO）]的表达。此外，与pMSC共培养的iDC和mDC的IL-12和IL-23的分泌减少。此外，在T细胞增殖实验中，pMSC与mDC共培养降低了IL-12和INF-γ的分泌，同时增加了IL-10的分泌。结论pMSC对DC的分化、成熟和功能以及T细胞的增殖具有抑制作用，提示pMSC可以在多个水平上调控免疫应答。
Background Mesenchymal stem cells derived from the chorionic villi of human term placenta (pMSCs) have drawn considerable interest because of their multipotent differentiation potential and their immunomodulatory capacity. These properties are the foundation for their clinical application in the fields of stem cell transplantation and regenerative medicine. Previously, we showed that pMSCs induce an anti-inflammatory phenotype in human macrophages. In this study, we determined whether pMSCs modify the differentiation and maturation of human monocytes into dendritic cells (DCs). The consequences on dendritic function and on T cell proliferation were also investigated.Methods Interleukin-4 (IL-4) and granulocyte-macrophage colony stimulating factor (GM-CSF) were used to stimulate the differentiation of monocytes into immature dendritic cells (iDCs), which were subsequently co-cultured with pMSCs. Lipopolysaccharide (LPS) was used to induce maturation of iDCs into mature dendritic cells (mDCs). Flow cytometry and enzyme-linked immunosorbent assays (ELISA) were used to quantify the effect pMSC co-culturing on DC differentiation using CD1a, a distinctive marker of DCs, as well as other molecules important in the immune functions of DCs. The phagocytic activity of iDCs co-cultured with pMSCs, and the effects of iDCs and mDC stimulation on T cell proliferation, were also investigated.Results Monocyte differentiation into iDCs was inhibited when co-cultured with pMSCs and maturation of iDCs by LPS treatment was also prevented in the presence of pMSCs as demonstrated by reduced expression of CD1a and CD83, respectively. The inhibitory effect of pMSCs on iDC differentiation was dose dependent. In addition, pMSC co-culture with iDCs and mDCs resulted in both phenotypic and functional changes as shown by reduced expression of costimulatory molecules (CD40, CD80, CD83 and CD86) and reduced capacity to stimulate CD4(+) T cell proliferation. In addition, pMSC co-culture increased the surface expression of major histocompatibility complex (MHC-II) molecules on iDCs but decreased MHC-II expression on mDCs. Moreover, pMSC co-culture with iDCs or mDCs increased the expression of immunosuppressive molecules [B7H3, B7H4, CD273, CD274 and indoleamine-pyrrole 2,3-dioxygenase (IDO). Additionally, the secretion of IL-12 and IL-23 by iDCs and mDCs co-cultured with pMSCs was decreased. Furthermore, pMSC co-culture with mDCs decreased the secretion of IL-12 and INF-gamma whilst increasing the secretion of IL-10 in a T cell proliferation experiment. Finally, pMSC co-culture with iDCs induced the phagocytic activity of iDCs.Conclusions We have shown that pMSCs have an inhibitory effect on the differentiation, maturation and function of DCs, as well as on the proliferation of T cells, suggesting that pMSCs can control the immune responses at multiple levels.