1 Peking University People's Hospital, Peking University Institute of Hematology , Beijing, China .
2 Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation , Beijing, China .
Stem Cells Dev. 2017 Nov 15;26(22):1648-1661. doi: 10.1089/scd.2017.0078. Epub 2017 Oct 24.
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.
免疫性血小板减少症（ITP）是一种自身免疫性疾病，树突状细胞（DCs）在自身耐受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）发育中的作用。我们之前的工作表明，ITP 中的 MSC 表现出衰老、凋亡，并对 T 和 B 细胞的免疫抑制作用受损。然而，ITP 中 MSC 对 regDC 诱导的影响是否改变尚不清楚。我们的数据表明，ITP 中的 MSC 抑制 CD34 造血祖细胞（CD34 HPC）分化为 CD1a DC 和 CD14 DC 的能力受损。ITP 中 MSC 分化的 DC 表现出共刺激分子 CD80/CD86 的表达增加和前炎症性白细胞介素-12（IL-12）的分泌增加。因此，ITP 中 MSC 诱导的 DC 的耐受特性缺失。ITP 中 MSC 分化的 DC 抑制 CD3 T 细胞增殖、抑制辅助性 T 细胞（Th）1 细胞分化以及诱导无能和调节性 T 细胞（Treg）的能力受损。测量了 ITP 中的 MSC 中 Notch 信号成分的表达。发现 ITP 中的 MSC 中配体 Jagged-1、受体 Notch-1 细胞内结构域（NICD-1）和靶基因 Hes-1 的表达减少。在 CD34 HPC 中添加具有生物活性的 Jagged-1 可促进 regDC 分化。当在 Jagged-1 包被的平板上培养时，ITP 中的 MSC 显示 Notch-1 通路激活、Jagged-1 表达和诱导 regDC 的功能增强。发现全反式视黄酸（ATRA）预处理可部分恢复 ITP 患者和健康对照者 MSC 诱导 CD34 衍生的 regDC 的能力。我们的数据表明，ITP 中的 MSC 在诱导 CD34-regDCs 方面存在缺陷，与 Notch-1/Jagged-1 信号通路有关。ATRA 可以部分纠正 MSC 的损伤，表明 ATRA 可以作为 ITP 的潜在治疗选择。
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