Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Anatomy, Medical Sciences Faculty, Tarbiat Modares University, Tehran, Iran.
J Cell Biochem. 2018 Mar;119(3):2939-2950. doi: 10.1002/jcb.26500. Epub 2017 Dec 12.
Stromal cell-derived factor-1α (SDF-1α) has been known to implicate in homing of MSCs, and resveratrol has been reported to have a positive influence on SDF-1 level in the site of injury. In this study, a combined strategy was applied to evaluate bone marrow-derived MSCs (BMSCs) homing to the rat model of liver cirrhosis induced by common bile duct ligation (CBDL): (1) pretreatment delivery of resveratrol into the cirrhotic liver, and (2) transplantation of ex vivo BMSC preconditioning with SDF-1α. BMSCs were preconditioned with 10 ng/µL SDF-1α for 1 h and then labeled with the CM-Dil. Cirrhosis was induced by CBDL. Animals received intraperitoneal injection of resveratrol for 7 days, started on day 28 of CBDL post-operative. On day 36 post-operative, 1 × 10 of SDF-1α-preconditioned BMSCs was injected via caudal vein. Animals were sacrificed at 72 h post-cell transplantation. Immunofluorescence and flow cytometry assessments showed that the BMSC+SDF+RV group had an increased rate of homing into the liver, but it had a decreased rate of homing into the lung and spleen, as compared with the other groups (P < 0.05). The BMSC+SDF+RV group showed high protein expression of SIRT1, but low protein expression of p53 in the liver (P < 0.05 vs other groups). CXCR4 and matrix metalloproteinase (MMP)-9 highly expressed in SDF-1α-preconditioned BMSCs in vitro, and that AKTs and CXCL12 expressed in injured liver undergoing resveratrol injection. Our findings suggest that reseveratrol pretreatment prior to SDF-1α preconditioning could be a promising strategy for designing cell-based therapies for liver cirrhosis.
基质细胞衍生因子-1α（SDF-1α）已被证实与间充质干细胞的归巢有关，而白藜芦醇已被报道对损伤部位的 SDF-1 水平有积极影响。在这项研究中，应用了一种联合策略来评估骨髓来源的间充质干细胞（BMSCs）向胆总管结扎（CBDL）诱导的大鼠肝硬化模型中的归巢：（1）将白藜芦醇预处理输送到肝硬化肝脏中，和（2）用 SDF-1α 预处理体外 BMSC 移植。BMSCs 用 10ng/μL SDF-1α 预处理 1 小时，然后用 CM-Dil 标记。通过 CBDL 诱导肝硬化。动物在 CBDL 术后第 28 天开始接受腹腔注射白藜芦醇 7 天。术后第 36 天，通过尾静脉注射 1×10 的 SDF-1α 预处理的 BMSCs。细胞移植后 72 小时处死动物。免疫荧光和流式细胞术评估显示，与其他组相比，BMSC+SDF+RV 组有更高的归巢到肝脏的比率，但归巢到肺和脾的比率降低（P<0.05）。BMSC+SDF+RV 组肝脏中 SIRT1 的蛋白表达较高，但 p53 的蛋白表达较低（与其他组相比，P<0.05）。体外 SDF-1α 预处理的 BMSCs 中 CXCR4 和基质金属蛋白酶（MMP）-9 高表达，而受损肝脏中注射白藜芦醇后 AKTs 和 CXCL12 表达。我们的研究结果表明，SDF-1α 预处理前进行白藜芦醇预处理可能是设计针对肝硬化的细胞治疗的一种有前途的策略。
