Preconditioning of bone marrow mesenchymal stem cells by prolyl hydroxylase inhibition enhances cell survival and angiogenesis in vitro and after transplantation into the ischemic heart of rats.
Preconditioning of bone marrow mesenchymal stem cells by prolyl hydroxylase inhibition enhances cell survival and angiogenesis in vitro and after transplantation into the ischemic heart of rats.
复制标题
通过脯氨酰羟化酶抑制对骨髓间充质干细胞进行预处理，可增强体外和移植到大鼠缺血心脏后的细胞存活和血管生成。
DOI：
10.1186/scrt499
复制
发表时间：
2014-09-25
影响因子：
7.5
通讯作者：
Wei L
中科院分区：
文献类型：
--
作者：
Liu XB;Wang JA;Ji XY;Yu SP;Wei L
骨髓间充质干细胞（BMSCs）在心肌梗死治疗中的作用受到细胞存活率低和功能获益有限的限制。我们最近发现，移植前对骨髓间充质干细胞和神经前体细胞进行缺氧预处理可以提高这些细胞在缺血脑和心脏中的存活和治疗性能。本研究旨在探讨缺氧诱导因子1α（HIF-α）脯氨酰羟化酶抑制剂二甲基草酰甘氨酸（DMOG）预处理BMSCs的新策略，以提高BMSCs移植到梗死心肌后的存活率和治疗效果。在移植前，将来自绿色荧光蛋白转基因大鼠的BMSC在有或没有1 mM DMOG的情况下在完全培养基中培养24小时。通过台盼蓝染色、蛋白质印迹和试管形成试验在体外评估存活和血管生成因子。在大鼠缺血性心脏模型中，在永久性心肌缺血30分钟后，将经DMOG预处理和未经DMOG预处理的BMSCs心肌内移植到梗死周围区域。在植入后24小时测量细胞死亡。4周后检测心功能、血管生成和梗死面积。DMOG预处理的BMSCs（DMOG-BMSCs）中HIF-1α、血管内皮生长因子、葡萄糖转运蛋白1和磷酸化Akt等存活因子和血管生成因子的表达明显增加。与对照细胞相比，DMOG-BMSCs在体外和体内试验中都显示出更高的活力和增强的血管生成。DMOG-BMSCs移植减少了心肌梗死面积，促进了细胞治疗的功能益处。我们认为DMOG预处理增强了骨髓基质细胞的存活能力和旁分泌效应，并增加了分化潜能。抑制脯氨酰羟化酶是提高心肌缺血后骨髓间充质干细胞移植治疗效果和效率的有效可行策略。
Poor cell survival and limited functional benefits have restricted the efficacy of bone marrow mesenchymal stem cells (BMSCs) in the treatment of myocardial infarction. We showed recently that hypoxia preconditioning of BMSCs and neural progenitor cells before transplantation can enhance the survival and therapeutic properties of these cells in the ischemic brain and heart. The present investigation explores a novel strategy of preconditioning BMSCs using the Hypoxia-inducible factor 1α (HIF-α) prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) to enhance their survival and therapeutic efficacy after transplantation into infarcted myocardium. BMSCs from green fluorescent protein transgenic rats were cultured with or without 1 mM DMOG for 24 hours in complete culture medium before transplantation. Survival and angiogenic factors were evaluated in vitro by trypan blue staining, Western blotting, and tube formation test. In an ischemic heart model of rats, BMSCs with and without DMOG preconditioning were intramyocardially transplanted into the peri-infarct region 30 minutes after permanent myocardial ischemia. Cell death was measured 24 hours after engraftment. Heart function, angiogenesis and infarct size were measured 4 weeks later. In DMOG preconditioned BMSCs (DMOG-BMSCs), the expression of survival and angiogenic factors including HIF-1α, vascular endothelial growth factor, glucose transporter 1 and phospho-Akt were significantly increased. In comparison with control cells, DMOG-BMSCs showed higher viability and enhanced angiogenesis in both in vitro and in vivo assays. Transplantation of DMOG-BMSCs reduced heart infarct size and promoted functional benefits of the cell therapy. We suggest that DMOG preconditioning enhances the survival capability of BMSCs and paracrine effects with increased differentiation potential. Prolyl hydroxylase inhibition is an effective and feasible strategy to enhance therapeutic efficacy and efficiency of BMSC transplantation therapy after heart ischemia.