Targeted Migration of Human Adipose-Derived Stem Cells to Secondary Lymphoid Organs Enhances Their Immunomodulatory Effect and Prolongs the Survival of Allografted Vascularized Composites
Targeted Migration of Human Adipose-Derived Stem Cells to Secondary Lymphoid Organs Enhances Their Immunomodulatory Effect and Prolongs the Survival of Allografted Vascularized Composites
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人类脂肪干细胞向次级淋巴器官的靶向迁移可增强其免疫调节作用并延长同种异体移植血管复合物的存活时间。
DOI：
10.1002/stem.3078
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发表时间：
2019-08-15
期刊：
影响因子：
5.2
通讯作者：
Li, Hong
中科院分区：
文献类型：
--
作者：
Ma, Tian;Luan, ShaoLiang;Li, Hong
将治疗剂靶向递送至次级淋巴器官（SLO）（其为免疫起始的小生境）为免疫不耐受诱导提供了前所未有的机会。血管化复合同种异体移植（VCA）后的同种免疫排斥反应是由T淋巴细胞介导的。人脂肪源性干细胞（Human adipose derived stem cells，hASCs）具有来源方便、免疫调节作用强等优点，但其治疗VCA的效果尚不明确。趋化因子受体7（CCR 7）可以特异性地引导免疫细胞迁移到SLO中。在那里，通过慢病毒将CCR 7-GFP或单独的GFP基因导入hASC中。hASCs/CCR 7在体外保持了多向分化和免疫调节能力，但获得了由次级淋巴器官趋化因子（SCL）（CCR 7配体）诱导的迁移能力。值得注意的是，静脉输注的hASC/CCR 7靶向地重新定位在SLO中的T细胞攻击区域。在大鼠VCA模型中，hASCs/GFP输注对同种异体移植的血管化复合物具有罕见的影响。然而，hASCs/CCR 7输注有效地延长了移植物的存活时间。同时观察其病理改变及外周血炎性细胞因子水平的变化。SLO中Th 1/Th 2和Th 17/Th 17轴的改变可能是下调排斥反应的基础。此外，脾T淋巴细胞的蛋白质组学检测也证实hASCs/CCR 7减少了与细胞质分裂、淋巴细胞增殖、分化和凋亡过程相关的蛋白质。总之，我们目前的研究表明，靶向迁移的hASCs/CCR 7的SLO高度增强其在VCA模型中的体内免疫调节作用的第一次。我们相信这种SLOs靶向策略可以提高hASC对同种异体和自身免疫疾病的临床治疗效果。干细胞2019
The targeted delivery of therapeutic agents to secondary lymphoid organs (SLOs), which are the niches for immune initiation, provides an unprecedented opportunity for immune intolerance induction. The alloimmune rejection postvascularized composite allotransplantation (VCA) is mediated by T lymphocytes. Human adipose-derived stem cells (hASCs) possess the superiority of convenient availability and potent immunoregulatory property, but their therapeutic results in the VCA is unambiguous thus far. Chemokine receptor 7 (CCR7) can specifically guide immune cells migrating into SLOs. There, genes of CCR7-GFP or GFP alone were introduced into hASCs by lentivirus. hASCs/CCR7 maintained the multidifferentiation and immunoregulatory abilities but gained the migration capacity elicited by secondary lymphoid organ chemokine (SCL) (CCR7 ligand) in vitro. Noteworthily, intravenously infused hASCs/CCR7 targetedly relocated in the T-cell aggression area in SLOs. In a rat VCA model, hASCs/GFP transfusion had rare effect on the allografted vascularized composite. However, hASCs/CCR7 infusion potently prolonged the grafts' survival time. The ameliorated pathologic exhibition and the regulated inflammatory cytokines in the peripheral blood were also observed. The altered axis of Th1/Th2 and Tregs/Th17 in SLOs may underlie the downregulated rejection response. Moreover, the proteomics examination of splenic T lymphocytes also confirmed that hASCs/CCR7 decreased the proteins related to cytokinesis, lymphocyte proliferation, differentiation, and apoptotic process. In conclusion, our present study demonstrated that targeted migration of hASCs/CCR7 to SLOs highly intensify their in vivo immunomodulatory effect in VCA model for the first time. We believe this SLOs targeting strategy may improve the clinical therapeutic efficacy of hASC for allogeneic and autogenic immune disease. Stem Cells 2019