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首页> 外文期刊>Expert opinion on biological therapy >Deferoxamine preconditioning potentiates mesenchymal stem cell homing in vitro and in streptozotocin-diabetic rats
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Deferoxamine preconditioning potentiates mesenchymal stem cell homing in vitro and in streptozotocin-diabetic rats

机译：去铁胺预处理可增强体外和链脲佐菌素-糖尿病大鼠的间充质干细胞归巢

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Objective: Today, cell therapy is considered a promising alternative in treatment of several diseases such as type 1 diabetes. Loss of transplanted stem cell and more importantly scarcity in the number of cells reaching to target tissue is a major obstacle in cell therapy. There is evidences showing that deferoxamine (DFO), an iron chelator, increases the mobilization and homing of progenitor cells through increasing the stability of hypoxia-inducible factor 1α (HIF-1α) protein. In this study, the effect of DFO on some factors involved in homing of bone marrow-derived mesenchymal stem cell was investigated, and the other objectives of this research were to determine whether DFO is able to increase migration and subsequent homing of mesenchymal stem cell (MSCs) both in vitro and in vivo in streptozotocin-diabetic rats. Research design and methods: MSCs were treated by DFO in minimal essential medium α (αMEM) for 24 h. The expression and localization of HIF-1α were evaluated by western blotting and immunocytochemistry. The expression of C-X-C chemokine receptor type 4 (CXCR-4) and chemokine receptor 2 (CCR2) were assessed by western blotting and RT-PCR. The activity of matrix metalloproteinases (MMP) -2 and -9 were measured by gelatin zymography. Finally, in vitro migration of MSCs toward different concentrations of stromal cell-derived factor and monocyte chemotactic protein-1 were also evaluated. To demonstrate the homing of MSCs in vivo, DFO-treated chloromethyl- benzamidodialkylcarbocyanine-labeled MSCs were injected into the tail vein of rats, and the number of stained MSCs reaching to the pancreas were determined after 24 h. Results: In DFO-treated MSCs, expression of HIF-1α (p < 0.001), CXCR4 (p < 0.001), CCR2 (p < 0.001), and the activity of MMP-2 (p < 0.01) and MMP-9 (p < 0.05) were significantly increased compared to control groups. Elevation of HIF-1α, upregulation of CXCR4/CCR2 and higher activity of MMP-2/MMP-9 in DFO-treated MSCs were reversed by 2-methoxyestradiol (2-ME; 5 μmol), a HIF-1α inhibitor. The in vitro migrations as well as in vivo homing of DFO-treated MSCs were also significantly higher than control groups (p < 0.05). Conclusions: Preconditioning of MSCs by DFO prior to transplantation could increase homing of MSCs through affecting some chemokine receptors as well as proteases involved and eventually improving the efficacy of cell therapy.
机译：目的：如今，细胞疗法已被认为是治疗1型糖尿病等多种疾病的有前途的替代方法。移植干细胞的丢失，更重要的是到达目标组织的细胞数量缺乏是细胞治疗的主要障碍。有证据表明，铁螯合剂去铁胺（DFO）通过增加缺氧诱导因子1α（HIF-1α）蛋白的稳定性来增加祖细胞的动员和归巢。在这项研究中，研究了DFO对涉及骨髓源间充质干细胞归巢的某些因素的影响，并且该研究的其他目标是确定DFO是否能够增加迁移和随后的间充质干细胞归巢（链脲佐菌素-糖尿病大鼠体内和体外。研究设计和方法：在最小必需培养基α（αMEM）中用DFO处理MSC 24小时。通过Western印迹和免疫细胞化学评估HIF-1α的表达和定位。通过蛋白质印迹和RT-PCR评估C-X-C趋化因子受体4型（CXCR-4）和趋化因子受体2（CCR2）的表达。用明胶酶谱法测定基质金属蛋白酶（MMP）-2和-9的活性。最后，还评估了MSC向不同浓度的基质细胞衍生因子和单核细胞趋化蛋白1的体外迁移。为了证明MSC在体内的归巢，将DFO处理的氯甲基-苯甲酰胺基二烷基碳花青标记的MSC注射到大鼠的尾静脉中，并在24小时后确定到达胰腺的染色MSC的数量。结果：在经DFO处理的MSC中，HIF-1α（p <0.001），CXCR4（p <0.001），CCR2（p <0.001）和MMP-2（p <0.01）和MMP-9（与对照组相比，p <0.05）显着增加。 HIF-1α抑制剂2-甲氧基雌二醇（2-ME; 5μmol）逆转了DFO处理的MSC中HIF-1α的升高，CXCR4 / CCR2的上调和MMP-2 / MMP-9的较高活性。 DFO处理的MSC的体外迁移和体内归巢也显着高于对照组（p <0.05）。结论：在移植前通过DFO对MSC进行预处理可以通过影响某些趋化因子受体和相关蛋白酶来增加MSC的归巢，从而最终改善细胞疗法的疗效。

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