Impaired function of MSCs from ITP patients in inducing regulatory DC differentiation via the Notch-1/Jagged-1signaling pathway
首发时间:2017-05-10
Abstract:IImmune thrombocytopenia (ITP) is an autoimmune disease in which dendritic cells (DCs) play a crucial role in the break-down of self-tolerance. Studies have identified the function ofmesenchymal stem cells (MSCs)in promoting the development of regulatory DCs(regDCs). Our previous work revealed that MSCs in ITP exerted senescence, apoptosis and impaired immunosuppressive effects on T and B cells. However, it is unclear whether the effectsof MSCs onregDCinduction are altered in ITP. Our datademonstrated thatMSCs in ITP were impaired in inhibiting CD1a+DC and CD14+DC differentiation from CD34+hematopoietic progenitor cells (CD34+HPCs). DCs differentiated with MSCs in ITP exhibited an increased expression of costimulatory molecules CD80/CD86 and secretion of pro-inflammatory IL-12.Accordingly,the tolerogenic characteristics were deficient in DCs induced by MSCs in ITP.DCs differentiated with MSCs in ITP exhibitedan impaired ability to inhibit CD3+T cell proliferation, to suppressT helper (Th)1cellsdifferentiation and to induce anergic and regulatory T cells(Tregs).Theexpression of Notch signaling components was measuredinMSCs in ITP. Reduced expression of the ligand Jagged-1, the receptor Notch-1 intracellular domain(NICD-1) and the target gene Hes-1wasidentifiedin MSCs in ITP.The addition of biologically active Jagged-1 to CD34+HPCswas observed to promoteregDC differentiation.When cultured on Jagged-1-coated plates, MSCs in ITP showed an enhancement of theNotch-1 pathway activation, Jagged-1 expression and thefunctionin inducing regDCs.Pretreatment with all-trans retinoic acid(ATRA) was found to partially restore the capacity of MSCs in both ITP patients and healthy controls in inducing CD34+-derived regDCs. Our data elucidated that MSCs in ITP were impaired in inducing CD34+-regDCs, which was associated with the Notch-1/Jagged-1 signaling pathway. ATRA could partially correct the impairment of MSCs, suggesting that ATRA could serve as a potential therapeutic alternativefor ITP.
keywords: immunethrombocytopenia mesenchymal stem cells notch signaling pathway
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Notch-1/Jagged-1通路介导ITP中MSCs损伤的调节性DCs诱导功能
摘要:免疫性血小板减少症 (ITP)是一种自身免疫性疾病,其中树突状细胞 (DCs)在自身耐受发挥重要的作用。研究已证实,间充质干细胞(MSCs)有促进调节性DCs(regDCs)发育的功能。我们之前研究表明,证实ITP-MSCs衰老、凋亡增加,并且影响T细胞和B细胞的免疫抑制作用。然而,ITP-MSCs诱导regDCs的功能,尚不明确。ITP-MSCs抑制CD34+HPCs,分化CD1a+DC和CD14+DC功能损伤。ITP-MSCs作用分化的DCs表面共刺激分子CD80/CD86 表达增加,促炎性IL-12分泌增加。研究发现,ITP-MSCs诱导DCs的功能缺陷,进一步分析其抑制CD3+T细胞增殖,抑制Th1和Tc1分化,以及诱导失能和调节性T细胞的功能改变。检测ITP-MSCs的Notch通路组分表达。结果表明ITP-MSCs配体Jagged-1,受体Notch-1细胞内结构域,和靶因Hes-1的表达降低。活性Jagged-1分子加入到CD34+HPCs共培养体系,促进regDCs分化。在Jagged-1包裹的培养板培养,ITP-MSCs中Notch-1通路活化增强,Jagged-1表达增加,诱导regDCs功能增强。结果发现,ATRA的预处理能部分恢复ITP患者MSCs诱导CD34+HPCs起源的regDC的能力。ITP中MSCs诱导CD34+-regDCs的功能异常,可能与Notch-1/Jagged-1 信号通路相关。ATRA能部分纠正MSCs的功能损伤,提示ATRA可作为ITP患者的一种潜在的治疗选择
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