C-Kit Positive Cardiac Stem Cells and one Marrow Derived Mesenchymal Stem Cells Synergistically Enhance Angiogenesis and Improve Cardiac Function After Myocardial Infarction in a Paracrine Manner
C-Kit Positive Cardiac Stem Cells and one Marrow Derived Mesenchymal Stem Cells Synergistically Enhance Angiogenesis and Improve Cardiac Function After Myocardial Infarction in a Paracrine Manner
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C-Kit阳性心脏干细胞和骨髓衍生间充质干细胞以旁分泌方式协同增强血管生成并改善心肌梗死后的心脏功能
DOI：
10.1016/j.cardfail.2017.03.002
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发表时间：
2017-05-01
影响因子：
6
通讯作者：
Fan, Huimin
中科院分区：
文献类型：
--
作者：
Bao, Luer;Meng, Qingshu;Fan, Huimin
背景：干细胞移植为心力衰竭提供了一种有希望的治疗方法。近年来的研究表明，c-kit阳性的心脏干细胞（cardiac stem cells，CSCs）和骨髓间充质干细胞（bone marrow derived mesenchymal stem cells，BMMSCs）都是干细胞治疗心力衰竭的理想候选细胞，但干细胞治疗改善缺血性心肌病心功能的确切机制尚不完全清楚。我们的目的是测试我们的假设，CSCs和/或BM-MSCs修复受损的心脏，通过促进后心肌梗死（MI）血管生成的旁分泌mathematics.Methods和结果：我们分离和纯化大鼠CSCs和BM-MSCs。心肌梗死后28天进行心肌内注射CSC和/或BM-MSC。我们应用心脏超声和组织学分析来评价细胞治疗对心功能和心脏重构的影响。体内供体细胞移植实验表明，CSC和/或BM-MSC改善MI后的心脏功能并减少梗死面积。然而，体内细胞追踪实验表明，细胞移植后，极少量的供体细胞仍留在心肌中。我们进一步的体外和体内实验表明，CSC移植增强了促血管生成因子的表达，并以旁分泌的方式促进了心肌梗死后的血管生成，这在一定程度上有助于CSC对心肌梗死后心脏恢复的影响。CSC和BM-MSC协同抑制CSC/BM-MSC凋亡，并以旁分泌方式促进其增殖。这导致在共注射CSC和BM-MSC后，更多数量的移植细胞保留在MI后心肌中，因此与单独移植CSC或MSC相比，在心脏组织中积累了更多的促血管生成因子。结论：C-kit（+）CSC和/或BM-MSC联合移植上级通过旁分泌方式改善心肌梗死后心功能。CSC和BM-MSC两者的共注射通过改善供体细胞的植入和促进多种促血管生成因子的表达而比CSC或BM-MSC以旁分泌方式单独移植更显著地改善心脏功能。（J Cardiac Fail 2017;23：403-415）
Background: Stem cell transplantation offers a promising treatment for heart failure. Recent studies show that both c-kit positive cardiac stem cells (CSCs) and bone marrow derived mesenchymal stem cells (BMMSCs) are good candidates for stem cell therapy to treat heart failure; however, the exact mechanism of stem cell therapy in improving cardiac function of ischemic cardiomyopathy is not fully known. Our objective was to test our hypothesis that CSCs and/or BM-MSCs repair the damaged heart by boosting post myocardial infarction (MI) angiogenesis in a paracrine manner.Methods and Results: We isolated and purified CSCs and BM-MSCs from rats. Intramyocardial injections of CSCs and/or BM-MSCs were performed at 28 days after MI. We applied cardiac ultrasound and histological analysis to evaluate the effect of cell therapy on cardiac function and cardiac remodeling. In vivo donor cell transplantation experiments showed that CSCs and/or BM-MSCs improved cardiac function after MI and reduced infarct size. However, in vivo cell tracking experiments showed that minimal donor cells remained in the myocardium after cell transplantation. Our further in vitro and in vivo experiments showed that transplantation of CSCs enhanced the expression of pro-angiogenic factors and boosted post-MI angiogenesis in the myocardium in a paracrine manner, which in part contributed to the effect of CSCs on cardiac recovery after MI. CSCs and BM-MSCs synergistically inhibited CSC/BM-MSC apoptosis and enhanced their proliferation in a paracrine manner. This resulted in a larger number of transplanted cells remaining in the post-MI myocardium after coinjection of CSCs and BM-MSCs, and therefore the accumulation of more pro-angiogenic factors in the heart tissue compared to transplantation of CSCs or MSCs alone. Consequently, transplantation of both CSCs and BM-MSCs was superior to transplantation of either CSCs or BM-MSCs alone to boost post-MI angiogenesis and improve cardiac function after MI.Conclusion: C-kit(+) CSC and/or BM-MSC transplantation can improve cardiac function after MI in a paracrine manner. Coinjection of both CSCs and BM-MSCs improves cardiac function more significantly than CSC or BM-MSC transplantation alone in a paracrine manner by improving the engraftment of donor cells and boosting the expression of multiple pro-angiogenic factors. (J Cardiac Fail 2017;23:403-415)