Impaired Function of Bone Marrow Mesenchymal Stem Cells from Immune Thrombocytopenia Patients in Inducing Regulatory Dendritic Cell Differentiation Through the Notch-1/Jagged-1 Signaling Pathway
Impaired Function of Bone Marrow Mesenchymal Stem Cells from Immune Thrombocytopenia Patients in Inducing Regulatory Dendritic Cell Differentiation Through the Notch-1/Jagged-1 Signaling Pathway
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免疫性血小板减少症患者的骨髓间充质干细胞通过 Notch-1/Jagged-1 信号通路诱导调节性树突状细胞分化的功能受损
DOI：
10.1089/scd.2017.0078
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发表时间：
2017
影响因子：
4
通讯作者：
Zhang Jia-min
中科院分区：
文献类型：
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作者：
Xu Lin-lin;Fu Hai-xia;Zhang Jia-min;Feng Fei-er;Wang Qian-ming;Zhu Xiao-lu;Xue Jing;Wang Chen-cong;Chen Qi;Liu Xiao;Wang Ya-zhe;Qin Ya-zhen;Kong Yuan;Chang Ying-Jun;Xu Lan-ping;Liu Kai-yan;Huang Xiao-jun;Zhang Xiao-hui;Xu Lin-lin;Fu Hai-xia;Zhang Jia-min
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（dc）在自身耐受性的破坏中起着至关重要的作用。研究已经确定了间充质干细胞（MSCs）在促进调节性dc （regdc）发育中的功能。我们之前的研究表明，ITP中的MSCs会导致T细胞和B细胞衰老、凋亡和免疫抑制作用受损。然而，目前尚不清楚在ITP中MSCs对regDC诱导的影响是否会改变。我们的数据表明，ITP中的MSCs抑制CD1a+DC和CD14+DC从CD34+造血祖细胞（CD34+HPCs）分化的能力受损。ITP中与MSCs分化的DCs表现出共刺激分子CD80/CD86的表达增加和促炎白介素-12 （IL-12）的分泌增加。因此，在ITP中，MSCs诱导的dc缺乏耐受性。在ITP中，与MSCs分化的dc表现出抑制CD3+T细胞增殖、抑制辅助性T细胞（Th）1分化以及诱导无能和调节性T细胞（Tregs）的能力受损。在ITP的MSCs中检测Notch信号组分的表达。在ITP的MSCs中发现了配体Jagged-1、受体Notch-1胞内结构域（NICD-1）和靶基因Hes-1的表达降低。在CD34+HPCs中添加具有生物活性的Jagged-1可以促进regDC分化。在Jagged-1包被板上培养时，ITP中的MSCs表现出Notch-1通路激活、Jagged-1表达和诱导regdc功能的增强。研究发现，全反式维甲酸（ATRA）预处理可以部分恢复ITP患者和健康对照中MSCs诱导CD34+来源的regdc的能力。我们的数据阐明了ITP中的MSCs诱导CD34+- regdc的能力受损，这与Notch-1/Jagged-1信号通路有关。ATRA可以部分纠正间充质干细胞的损伤，表明ATRA可以作为ITP的潜在治疗选择。
Immune thrombocytopenia (ITP) is an autoimmune disease in which dendritic cells (DCs) play a crucial role in the breakdown of self-tolerance. Studies have identified the function of mesenchymal 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 effects of MSCs on regDC induction are altered in ITP. Our data demonstrated that MSCs 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 proinflammatory interleukin-12 (IL-12). Accordingly, the tolerogenic characteristics were deficient in DCs induced by MSCs in ITP. DCs differentiated with MSCs in ITP exhibited an impaired ability to inhibit CD3+T cell proliferation, to suppress T helper (Th)1 cell differentiation, and to induce anergic and regulatory T cells (Tregs). The expression of Notch signaling components was measured in MSCs in ITP. Reduced expression of the ligand Jagged-1, the receptor Notch-1 intracellular domain (NICD-1), and the target gene Hes-1 was identified in MSCs in ITP. The addition of biologically active Jagged-1 to CD34+HPCs was observed to promote regDC differentiation. When cultured on Jagged-1-coated plates, MSCs in ITP showed an enhancement of the Notch-1 pathway activation, Jagged-1 expression, and the function in 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, 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 alternative for ITP.