Genetic Modification of Mesenchymal Stem Cells to Overexpress CXCR4 and CXCR7 Does Not Improve the Homing and Therapeutic Potentials of These Cells in Experimental Acute Kidney Injury
Genetic Modification of Mesenchymal Stem Cells to Overexpress CXCR4 and CXCR7 Does Not Improve the Homing and Therapeutic Potentials of These Cells in Experimental Acute Kidney Injury
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DOI：
10.1089/scd.2011.0588
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发表时间：
2012-11-01
影响因子：
4
通讯作者：
Zeinali, Sirous
中科院分区：
文献类型：
--
作者：
Gheisari, Yousof;Azadmanesh, Kayhan;Zeinali, Sirous
一些研究检测了骨髓间充质干细胞(MSCs)在肾衰竭中的治疗潜力。然而，最近的发现表明，移植后，这些细胞在肾脏中的水平非常低。基质衍生因子-1(SDF-1)与其受体CXCR4的相互作用在迁移和归巢过程中起着至关重要的作用。最近，CXCR7也被认为是另一种与CXCR4相互作用并调节其功能的SDF-1受体。本研究利用慢病毒载体系统在BALB/c骨髓间充质干细胞中分别和同时过表达CXCR4和CXCR7，并在顺铂诱导的小鼠急性肾损伤模型中评价了这两种细胞的归巢和肾保护作用。利用流式细胞术、免疫组织化学和实时定量聚合酶链式反应方法检测GFP标记的MSCs，我们发现，尽管大量被困在肺中，但天然的MSCs很少回到肾脏和骨髓，而且CXCR4和/或CXCR7的上调不能显著影响这一比率。移植天然或基因工程的骨髓间充质干细胞都不能改善肾衰竭。我们的结论是，CXCR4和CXCR7受体在小鼠骨髓间充质干细胞中的过表达并不能改善这些细胞的归巢和治疗潜力，这可能是由于这些细胞在体外扩增过程中承受着严重的染色体异常。
The therapeutic potential of bone marrow mesenchymal stem cells (MSCs) in kidney failure has been examined in some studies. However, recent findings indicate that after transplantation, these cells home to kidneys at very low levels. Interaction of stromal derived factor-1 (SDF-1) with its receptor, CXCR4, is of pivotal importance in migration and homing. Recently, CXCR7 has also been recognized as another SDF-1 receptor that interacts with CXCR4 and modulates its functions. In this study, CXCR4 and CXCR7 were separately and simultaneously overexpressed in BALB/c bone marrow MSCs by using a lentiviral vector system and the homing and renoprotective potentials of these cells were evaluated in a mouse model of cisplatin-induced acute kidney injury. Using flow cytometry, immunohistochemistry, and real-time PCR methods for detection of GFP-labeled MSCs, we found that although considerably entrapped in lungs, native MSCs home very rarely to kidneys and bone marrow and this rate cannot be significantly affected by CXCR4 and/or CXCR7 upregulation. Transplantation of neither native nor genetically engineered MSCs ameliorated kidney failure. We concluded that overexpression of CXCR4 and CXCR7 receptors in murine MSCs cannot improve the homing and therapeutic potentials of these cells and it can be due to severe chromosomal abnormalities that these cells bear during ex vivo expansion.