Interleukin-10 deficiency impairs bone marrow-derived endothelial progenitor cell survival and function in ischemic myocardium.
Interleukin-10 deficiency impairs bone marrow-derived endothelial progenitor cell survival and function in ischemic myocardium.
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DOI：
10.1161/circresaha.111.248369
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发表时间：
2011-11-11
影响因子：
20.1
通讯作者：
Kishore R
中科院分区：
文献类型：
--
作者：
Krishnamurthy P;Thal M;Verma S;Hoxha E;Lambers E;Ramirez V;Qin G;Losordo D;Kishore R
受损心肌中的内皮祖细胞 (EPC) 的存活和功能受到缺血、缺氧和炎症反应等不利微环境的不利影响，从而损害 EPC 介导的心肌修复的全部益处。我们假设白介素 10 (IL-10) 调节 EPC 生物学，从而提高缺血心肌移植后的存活率和功能。 IL-10 KO 小鼠中，心肌梗死 (MI) 诱导的骨髓 EPC（Sca-1+Flk1+ 细胞）动员进入循环系统显着受损。用 WT 骨髓替代 IL-10 KO 骨髓的骨髓移植 (BMT) 减弱了这些影响。运动受损与 KO 小鼠心肌中较低的 SDF-1 表达水平相关。有趣的是，SDF-1 给药逆转了 KO 小鼠的动员缺陷。在体外，在 IL-10 缺陷型 EPC 中，缺氧介导的 CXCR4 表达增加和细胞存活率较低。此外，SDF-1 诱导的 WT-EPC 迁移受到 CXCR4 抑制剂 AMD3100 的抑制。为了进一步研究 IL-10 对体内 EPC 存活和植入血管结构的影响，在诱导 MI 后将 GFP 标记的 EPC 注射到心肌内，并用盐水或重组 IL-10 治疗小鼠。 IL-10治疗组显示移植的EPC在心肌中的保留增加，并且与MI后EPC细胞凋亡显着减少相关。有趣的是，在 IL-10 处理的小鼠中观察到 EPC 保留增加及其与血管结构的关联。 IL-10 治疗小鼠心肌中 EPC 存活率和血管生成增加，证实了左心室功能改善、梗塞面积减少和心肌纤维化。在体外，IL-10 诱导的 WT-EPC 中 VEGF 表达的增加被 STAT3 抑制剂消除，表明 IL-10 信号通过 STAT3 激活。综上所述，我们的研究表明，IL-10 KO 小鼠中 MI 诱导的 EPC 动员受损，IL-10 可能通过激活 STAT3/VEGF 信号级联来增加 EPC 存活和功能，从而减弱 MI 诱导的左室功能障碍和重塑。
Endothelial progenitor cell (EPC) survival and function in the injured myocardium is adversely influenced by hostile microenvironment like ischemia, hypoxia and inflammatory response, thereby compromising full benefits of EPC-mediated myocardial repair. We hypothesized that interleukin-10 (IL-10) modulates EPC biology leading to enhanced survival and function following transplantation in the ischemic myocardium. Myocardial infarction (MI)-induced mobilization of bone marrow EPC (Sca-1+Flk1+ cells) into the circulation was significantly impaired in IL-10 KO-mice. Bone marrow transplantation (BMT) to replace IL-10 KO-marrow with WT-marrow attenuated these effects. Impaired mobilization was associated with lower SDF-1 expression levels in the myocardium of KO-mice. Interestingly, SDF-1 administration reversed mobilization defect in KO-mice. In vitro, hypoxia-mediated increases in CXCR4 expression and cell survival were lower in IL-10-deficient-EPCs. Furthermore, SDF-1-induced migration of WT-EPCs was inhibited by AMD3100, an inhibitor of CXCR4. To further study the effect of IL-10 on in vivo EPC survival and engraftment into vascular structures, GFP-labeled EPC were injected intramyocardially after induction of MI, and the mice were treated with either saline or recombinant IL-10. IL-10-treated group showed increased retention of transplanted EPCs in the myocardium and was associated with significantly reduced EPC apoptosis post-MI. Interestingly, increased EPC retention and their association with the vascular structures was observed in IL-10 treated mice. Increased EPC survival and angiogenesis in the myocardium of IL-10-treated mice corroborated with improved LV function, reduced infarct size and fibrosis in the myocardium. In vitro, IL-10-induced increase in VEGF expression in WT-EPC was abrogated by STAT3 inhibitor suggesting IL-10 signals via STAT3 activation. Taken together, our studies demonstrate that MI-induced EPC mobilization was impaired in IL-10 KO-mice and that IL-10 increases EPC survival and function possibly via activation of STAT3/VEGF signaling cascades, leading to attenuation of MI-induced LV dysfunction and remodeling.