Nitric oxide releasing hydrogel enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.
Nitric oxide releasing hydrogel enhances the therapeutic efficacy of mesenchymal stem cells for myocardial infarction.
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DOI：
10.1016/j.biomaterials.2015.04.046
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发表时间：
2015-08
期刊：
影响因子：
14
通讯作者：
X. Yao;Yi Liu;Jie Gao;Liang Yang;Duo Mao;C. Stefanitsch;Yang Li;Jun Zhang;L. Ou;D. K
中科院分区：
文献类型：
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作者：
X. Yao;Yi Liu;Jie Gao;Liang Yang;Duo Mao;C. Stefanitsch;Yang Li;Jun Zhang;L. Ou;D. K
干细胞治疗已被证明是改善心肌梗死后心脏重构的有效途径。然而，缺血心肌细胞移植和存活率差限制了细胞疗法治疗MI的成功应用。在这里，我们试图用水凝胶（NapFF-NO）、萘共价结合的短肽、FFGGG和β-半乳糖笼状一氧化氮（NO）供体移植脂肪来源的间充质干细胞（AD-MSC），所述β-半乳糖笼状一氧化氮（NO）供体可以响应于β-半乳糖苷酶释放NO分子。将AD-MSC（来自组成型表达GFP和萤火虫荧光素酶（Fluc）的转基因小鼠或在VEGFR 2启动子控制下表达Fluc的转基因小鼠）与NapFF-NO水凝胶共移植到鼠MI模型中。分别通过生物发光成像（BLI）和超声心动图证实了细胞存活率的提高和心脏功能的增强。此外，在体内也实时追踪了VEGFR 2-luc表达的增加，表明NapFF-NO水凝胶刺激AD-MSCs分泌VEGF。为探讨NapFF-NO水凝胶的治疗机制，进行了细胞迁移试验、AD-MSCs的旁分泌作用和组织学分析。我们的结果显示，条件培养基从AD-MSCs培养与NapFF-NO水凝胶可以促进内皮细胞迁移。此外，在NapFF-NO水凝胶存在下，AD-MSCs显示出血管生成因子VEGF和SDF-1α的分泌显著增加。最后，死后分析证实，移植AD-MSCs与NapFF-NO水凝胶可以改善心功能，促进血管生成和减轻心室重构。结论：NapFF-NO水凝胶可通过增加细胞植入和血管生成旁分泌作用，明显提高AD-MSCs治疗MI的疗效。
Stem cell therapy has been proved to be an effective approach to ameliorate the heart remodeling post myocardial infarction (MI). However, poor cell engraftment and survival in ischemic myocardium limits the successful use of cellular therapy for treating MI. Here, we sought to transplant adipose derived-mesenchymal stem cells (AD-MSCs) with a hydrogel (NapFF-NO), naphthalene covalently conjugated a short peptide, FFGGG, and β-galactose caged nitric oxide (NO) donor, which can release NO molecule in response to β-galactosidase. AD-MSCs, either from transgenic mice that constitutively express GFP and firefly luciferase (Fluc), or express Fluc under the control of VEGFR2 promoter, were co-transplanted with NapFF-NO hydrogel into murine MI models. Improved cell survival and enhanced cardiac function were confirmed by bioluminescence imaging (BLI) and echocardiogram respectively. Moreover, increasing VEGFR2-luc expression was also tracked in real-timein vivo, indicating NapFF-NO hydrogel stimulated VEGF secretion of AD-MSCs. To investigate the therapeutic mechanism of NapFF-NO hydrogel, cell migration assay, paracrine action of AD-MSCs, and histology analysis were carried out. Our results revealed that condition medium from AD-MSCs cultured with NapFF-NO hydrogel could promote endothelial cell migration. Additionally, AD-MSCs showed significant improvement secretion of angiogenic factors VEGF and SDF-1α in the presence of NapFF-NO hydrogel. Finally, postmortem analysis confirmed that transplanted AD-MSCs with NapFF-NO hydrogel could ameliorate heart function by promoting angiogenesis and attenuating ventricular remodeling. In conclusion, NapFF-NO hydrogel can obviously improve therapeutic efficacy of AD-MSCs for MI by increasing cell engraftment and angiogenic paracrine action.