Ex vivo pretreatment of human vessels with siRNA nanoparticles provides protein silencing in endothelial cells.
Ex vivo pretreatment of human vessels with siRNA nanoparticles provides protein silencing in endothelial cells.
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DOI：
10.1038/s41467-017-00297-x
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发表时间：
2017-08-04
影响因子：
16.6
通讯作者：
Mark Saltzman W
中科院分区：
文献类型：
--
作者：
Cui J;Qin L;Zhang J;Abrahimi P;Li H;Li G;Tietjen GT;Tellides G;Pober JS;Mark Saltzman W
人内皮细胞是排斥反应的起始者和靶点。通过小干扰RNA基因转染术前修饰内皮细胞可以改变移植后宿主反应的性质。通过小干扰RNA靶向II类反式激活因子来消融内皮细胞II类主要组织相容性复合体分子，可以降低人内皮细胞招募和激活同种异体反应性T细胞的能力。在这里，我们报告了小干扰RNA释放聚(胺-共-酯)纳米颗粒的发展，其特点是其高含量的疏水内酯。我们发现，一次针对第二类反式激活因子的小干扰RNA在移植到免疫缺陷小鼠宿主后，至少在4到6周内减弱了内皮细胞上主要组织相容性复合体第二类的表达。此外，在体外和体内，沉默主要组织相容性复合体II类可以减少同种异体T细胞反应。这些数据表明，在人体器官体外常温机器灌流过程中，潜在的聚胺-共酯纳米颗粒可以用于修饰内皮细胞，并在移植后产生持续的效果。基因沉默技术在治疗移植后宿主排斥反应中的应用并不持久，而且可能会产生全身性影响。在这里，作者利用siRNA的纳米载体在植入前对动脉进行体外治疗，随后减弱体内的免疫反应。
Human endothelial cells are initiators and targets of the rejection response. Pre-operative modification of endothelial cells by small interfering RNA transfection could shape the nature of the host response post-transplantation. Ablation of endothelial cell class II major histocompatibility complex molecules by small interfering RNA targeting of class II transactivator can reduce the capacity of human endothelial cells to recruit and activate alloreactive T cells. Here, we report the development of small interfering RNA-releasing poly(amine-co-ester) nanoparticles, distinguished by their high content of a hydrophobic lactone. We show that a single transfection of small interfering RNA targeting class II transactivator attenuates major histocompatibility complex class II expression on endothelial cells for at least 4 to 6 weeks after transplantation into immunodeficient mouse hosts. Furthermore, silencing of major histocompatibility complex class II reduces allogeneic T-cell responses in vitro and in vivo. These data suggest that poly(amine-co-ester) nanoparticles, potentially administered during ex vivo normothermic machine perfusion of human organs, could be used to modify endothelial cells with a sustained effect after transplantation. The use of gene silencing techniques in the treatment of post-transplantation host rejection is not long lasting and can have systemic effects. Here, the authors utilize a nanocarrier for siRNA for treatment of arteries ex vivo prior to implantation subsequently attenuating immune reaction in vivo.
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影响因子：
16.8
作者：
Pober JS;Tellides G
通讯作者：
Tellides G
影响因子：
8
作者：
Fröhlich E
通讯作者：
Fröhlich E
影响因子：
8.8
作者：
Nicholson, M. L.;Hosgood, S. A.
通讯作者：
Hosgood, S. A.
影响因子：
10.8
作者：
Gary, Dana J.;Puri, Nitin;Won, You-Yeon
通讯作者：
Won, You-Yeon
影响因子：
6.2
作者：
Jamil, B;Nicholls, K;Walker, RG
通讯作者：
Walker, RG