Overexpression of protein kinase C ɛ improves retention and survival of transplanted mesenchymal stem cells in rat acute myocardial infarction.
Overexpression of protein kinase C ɛ improves retention and survival of transplanted mesenchymal stem cells in rat acute myocardial infarction.
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DOI：
10.1038/cddis.2015.417
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发表时间：
2016-01-21
影响因子：
9
通讯作者：
Zeng YJ
中科院分区：
文献类型：
--
作者：
He H;Zhao ZH;Han FS;Liu XH;Wang R;Zeng YJ
我们评估了蛋白激酶C β（PKC β）在改善急性心肌梗死（AMI）干细胞治疗中的作用。从大鼠骨髓中收获原代间充质干细胞（MSC）。将PKC β过表达的MSCs和对照MSCs移植到大鼠AMI模型的梗死边缘区。移植后第1天，通过免疫荧光和western blot分析MSC和PKC β的分布以及通过基质细胞衍生因子1（SDF-1）/CXC趋化因子受体4型（CXCR 4）轴和磷脂酰肌醇3激酶（PI 3 K）/蛋白激酶B（AKT）途径参与PKC β信号传导的主要蛋白的表达。移植后4周行超声心动图和组织学检查，观察MSC存活率、血管内皮生长因子（VEGF）、碱性成纤维细胞生长因子（bFGF）、转化生长因子β（TGFβ）、心肌肌钙蛋白I（cTnI）、血管性血友病因子（vWF）、平滑肌肌动蛋白（SMA）和因子VIII的表达以及梗死边缘区细胞凋亡情况。移植后第1天，心肌组织中的MSCs数量增加，SDF-1、CXCR 4、PI 3 K和磷酸化AKT增加，PKC β过表达。在移植后4周，PKC β过表达的MSC的动物中MSC存活和VEGF、bFGF、TGFβ、cTnI、vWF、SMA和因子VIII的表达增加，心功能不全和重构改善。细胞体积和细胞凋亡也减少。CXCR 4或PI 3 K的抑制作用部分减弱了PKC β的作用。PKC β的激活可提高移植MSCs在心肌中的滞留、存活和分化。增加PKC β的表达可能增强干细胞治疗AMI的疗效。
We assessed the effects of protein kinase C ɛ (PKCɛ) for improving stem cell therapy for acute myocardial infarction (AMI). Primary mesenchymal stem cells (MSCs) were harvested from rat bone marrow. PKCɛ-overexpressed MSCs and control MSCs were transplanted into infarct border zones in a rat AMI model. MSCs and PKCɛ distribution and expression of principal proteins involved in PKCɛ signaling through the stromal cell-derived factor 1 (SDF-1)/CXC chemokine receptor type 4 (CXCR4) axis and the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT) pathway were analyzed by immunofluorescence and western blot 1 day after transplantation. Echocardiographic measurements and histologic studies were performed at 4 weeks after transplantation, and MSC survival, expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor β (TGFβ), cardiac troponin I (cTnI), von Willebrand factor (vWF), smooth muscle actin (SMA) and factor VIII and apoptosis in infarct border zones were assessed. Rat heart muscles retained more MSCs and SDF-1, CXCR4, PI3K and phosphorylated AKT increased with PKCɛ overexpression 1 day after transplantation. MSC survival and VEGF, bFGF, TGFβ, cTnI, vWF, SMA and factor VIII expression increased in animals with PKCɛ-overexpressed MSCs at 4 weeks after transplantation and cardiac dysfunction and remodeling improved. Infarct size and apoptosis decreased as well. Inhibitory actions of CXCR4 or PI3K partly attenuated the effects of PKCɛ. Activation of PKCɛ may improve retention, survival and differentiation of transplanted MSCs in myocardia. Augmentation of PKCɛ expression may enhance the therapeutic effects of stem cell therapy for AMI.