Human Amniotic Mesenchymal Stem Cells Inhibit aGVHD by Regulating Balance of Treg and T Effector Cells.
Human Amniotic Mesenchymal Stem Cells Inhibit aGVHD by Regulating Balance of Treg and T Effector Cells.
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DOI：
10.2147/jir.s323054
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发表时间：
2021
影响因子：
4.5
通讯作者：
Ping B
中科院分区：
文献类型：
--
作者：
Gao Y;Li W;Bu X;Xu Y;Cai S;Zhong J;Du M;Sun H;Huang L;He Y;Hu X;Liu Q;Jin H;Wang Q;Ping B
急性移植物抗宿主病（aGVHD）仍然是异基因造血细胞移植（allo-HCT）后移植相关死亡的主要原因。人羊膜间充质干细胞（human amniotic mesenchymal stem cells，hAMSCs）是一种新型的间充质干细胞（mesenchymal stem cells，MSCs），与骨髓间充质干细胞（bone marrow mesenchymal stem cells，BM-MSCs）相比，具有更强的增殖和免疫调节能力。此外，由于羊膜通常在分娩后被作为医疗废物处理，因此可以方便且无创地获得hAMSC。本研究的目的是探讨hAMSCs移植对人源化aGVHD小鼠模型的治疗效果及其机制。将人外周血单个核细胞（PBMC）移植到NOD-PrkdcscidIL 2 r γnull（NPG）小鼠体内，收集健康孕妇分娩后废弃胎盘的人羊膜，从羊膜中提取hAMSC并体外扩增，建立人源化aGVHD小鼠模型。将小鼠分为未处理组（Control）、aGVHD组（aGVHD）和hAMSC处理组（aGVHD+ hAMSC），将GFP标记的hAMSC接种于aGVHD小鼠，观察hAMSC的归巢能力。采用流式细胞术和流式细胞仪微球阵列（CBA）分别检测各组靶器官中效应性T细胞和调节性T细胞（T细胞亚群）水平及细胞因子水平。我们使用NPG小鼠成功地建立了人源化aGVHD小鼠模型。hAMSC具有通过减少肠的绒毛钝化和淋巴细胞浸润同时减少炎性水肿、组织破坏和淋巴细胞浸润到肝和肺的实质中来抑制该小鼠模型中的aGVHD的能力。hAMSC可抑制aGVHD靶器官中CD 3 + CD 4 + T细胞和CD 3 + CD 8 + T细胞的表达，增加T淋巴细胞比例，降低IL-17 A、INF-γ和TNF水平。NPG鼠环境能够活化人T细胞以产生aGVHD病理学，从而模拟如在人中的aGVHD。在人源化小鼠中，hAMSC通过调节T细胞和T效应细胞的平衡来减少靶器官内的炎性细胞因子分泌，从而控制aGVHD。
Acute graft versus host disease (aGVHD) remains a leading cause of transplant-related mortality following allogeneic haematopoietic cell transplantation (allo-HCT). Human amniotic mesenchymal stem cells (hAMSCs) are a novel mesenchymal stem cells (MSCs), which have stronger proliferation and immunomodulatory ability compared with bone marrow mesenchymal stem cells (BM-MSCs). Besides, as the amniotic membrane is often treated as medical waste after delivery, hAMSCs can be obtained conveniently and noninvasively. The aim of this study was to explore the therapeutic efficacy and underlying mechanisms of hAMSCs transplantation for the humanized aGVHD mouse model. We established a humanized aGVHD mouse model by transplanting human peripheral blood mononuclear cells (PBMCs) into NOD-PrkdcscidIL2rγnull (NPG) mice, human amniotic membrane collected from discarded placenta of healthy pregnant women after delivery and hAMSCs were extracted from amniotic membrane and expanded in vitro. Mice were divided into untreated group (Control), aGVHD group (aGVHD), and hAMSCs treatment group (aGVHD+hAMSCs), the hAMSCs labeled with GFP were administered to aGVHD mice to explore the homing ability of hAMSCs. T effector and regulatory T cells (Tregs) levels and cytokines of each group in target organs were detected by flow cytometry and cytometric bead array (CBA), respectively. We successfully established a humanized aGVHD mouse model using NPG mice. The hAMSCs have the ability to inhibit aGVHD in this mouse model through reduced villous blunting and lymphocyte infiltration of the gut while reducing inflammatory edema, tissue destruction and lymphocyte infiltration into the parenchyma of the liver and lung. hAMSCs suppressed CD3+CD4+ T and CD3+CD8+ T cell expression and increased the proportion of Tregs, and besides, hAMSCs can reduce the levels of IL-17A, INF-γ, and TNF in aGVHD target organs. The NPG murine environment was capable of activating human T cells to produce aGVHD pathology to mimic aGVHD as in humans. The hAMSCs controlled aGVHD by decreasing inflammatory cytokine secretion within target organs by modulating the balance of Tregs and T effector cells in humanized mice.