Mesenchymal stem cells engineered to express selectin ligands and IL-10 exert enhanced therapeutic efficacy in murine experimental autoimmune encephalomyelitis.
Mesenchymal stem cells engineered to express selectin ligands and IL-10 exert enhanced therapeutic efficacy in murine experimental autoimmune encephalomyelitis.
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DOI：
10.1016/j.biomaterials.2015.11.005
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发表时间：
2016-01
期刊：
影响因子：
14
通讯作者：
Zhao W
中科院分区：
文献类型：
--
作者：
Liao W;Pham V;Liu L;Riazifar M;Pone EJ;Zhang SX;Ma F;Lu M;Walsh CM;Zhao W
在临床前和临床研究中，间充质干细胞（MSC）的全身给药有可能改善多发性硬化症（MS）的症状。然而，基于间充质干细胞的多发性硬化症治疗的疗效可能取决于发炎组织的细胞数量以及旁分泌和免疫调节因子的受控产生。此前，我们报道了通过 mRNA 转染表达 P-选择素糖蛋白配体-1 (PSGL-1) 和 Sialyl-Lewisx (SLeX) 的工程化 MSC，有助于将抗炎细胞因子白细胞介素-10 (IL-10) 靶向递送至发炎的耳朵。在这里，我们评估了通过三重 PSGL1/SLeX/IL-10 工程靶向输送 MSC 是否可以改善小鼠实验性自身免疫性脑脊髓炎 (EAE)（人类多发性硬化症的小鼠模型）的治疗结果。我们发现 PSGL-1/SLeX mRNA 转染显着增强 MSC 归巢到发炎的脊髓。这与体外流动室测定的结果一致，其中 PSGL-1/SleX mRNA 转染显着增加了激活的脑微血管内皮细胞上滚动和贴壁细胞的百分比，模拟了 EAE 中血脑/脊髓屏障的发炎内皮。此外，IL-10转染的MSC对EAE小鼠的CD4+T淋巴细胞的增殖显示出显着的抑制活性。在 EAE 小鼠中，用 PSGL-1/SLeX/IL-10 工程化的 MSC 进行体内治疗，表现出优于天然（未修饰）MSC 的治疗功能，这通过显着改善髓鞘形成和减少淋巴细胞浸润脊髓白质来证明。我们的定向输送性能增强 MSC 的策略有可能用于提高基于 MSC 的治疗多发性硬化症和其他中枢神经系统 (CNS) 疾病的有效性。
Systemic administration of mesenchymal stem cells (MSCs) affords the potential to ameliorate the symptoms of Multiple Sclerosis (MS) in both preclinical and clinical studies. However, the efficacy of MSC-based therapy for MS likely depends on the number of cells that home to inflamed tissues and on the controlled production of paracrine and immunomodulatory factors. Previously, we reported that engineered MSCs expressing P-selectin glycoprotein ligand-1 (PSGL-1) and Sialyl-Lewisx (SLeX) via mRNA transfection facilitated the targeted delivery of anti-inflammatory cytokine interleukin-10 (IL-10) to inflamed ear. Here, we evaluated whether targeted delivery of MSCs with triple PSGL1/SLeX/IL-10 engineering improves therapeutic outcomes in mouse experimental autoimmune encephalomyelitis (EAE), a murine model for human MS. We found PSGL-1/SLeX mRNA transfection significantly enhanced MSC homing to the inflamed spinal cord. This is consistent with results from in vitro flow chamber assays in which PSGL-1/SleX mRNA transfection significantly increased the percentage of rolling and adherent cells on activated brain microvascular endothelial cells, which mimic the inflamed endothelium of blood brain/spinal cord barrier in EAE. In addition, IL-10-transfected MSCs show significant inhibitory activity on the proliferation of CD4+ T lymphocytes from EAE mice. In vivo treatment with MSCs engineered with PSGL-1/SLeX/IL-10 in EAE mice exhibited a superior therapeutic function over native (unmodified) MSCs, evidenced by significantly improved myelination and decreased lymphocytes infiltration into the white matter of the spinal cord. Our strategy of targeted delivery of performance-enhanced MSCs could potentially be utilized to increase the effectiveness of MSC-based therapy for MS and other central nervous system (CNS) disorders.