Institute for Biomedical Technologies - National Research Council (ITB-CNR), F.lli Cervi 93, 20090 Segrate, Milan, Italy.
University of Verona, Center for BioMedical Computing (CBMC), Strada le Grazie 8, 37134 Verona, Italy.
Biochim Biophys Acta Gen Subj. 2017 May;1861(5 Pt A):1190-1199. doi: 10.1016/j.bbagen.2017.02.006. Epub 2017 Mar 7.
We have demonstrated that intramyocardial delivery of human mesenchymal stem cells preconditioned with a hyaluronan mixed ester of butyric and retinoic acid (MSCp) is more effective in preventing the decay of regional myocardial contractility in a swine model of myocardial infarction (MI). However, the understanding of the role of MSCp in proteomic remodeling of cardiac infarcted tissue is not complete. We therefore sought to perform a comprehensive analysis of the proteome of infarct remote (RZ) and border zone (BZ) of pigs treated with MSCp or unconditioned stem cells.
Heart tissues were analyzed by MudPIT and differentially expressed proteins were selected by a label-free approach based on spectral counting. Protein profiles were evaluated by using PPI networks and their topological analysis.
The proteomic remodeling was largely prevented in MSCp group. Extracellular proteins involved in fibrosis were down-regulated, while energetic pathways were globally up-regulated. Cardioprotectant pathways involved in the production of keto acid metabolites were also activated. Additionally, we found that new hub proteins support the cardioprotective phenotype characterizing the left ventricular BZ treated with MSCp. In fact, the up-regulation of angiogenic proteins NCL and RAC1 can be explained by the increase of capillary density induced by MSCp.
Our results show that angiogenic pathways appear to be uniquely positioned to integrate signaling with energetic pathways involving cardiac repair.
Our findings prompt the use of proteomics-based network analysis to optimize new approaches preventing the post-ischemic proteomic remodeling that may underlie the limited self-repair ability of adult heart.
我们已经证明，用透明质酸丁酸和视黄酸混合酯预处理的人间充质干细胞（MSCp）进行心肌内给药，在猪心肌梗死（MI）模型中更能有效防止区域性心肌收缩力的衰减。然而，对于 MSCp 在心脏梗死组织蛋白质组重塑中的作用的理解并不完全。因此，我们试图对接受 MSCp 或未处理的干细胞治疗的猪的梗死远区（RZ）和边界区（BZ）的心脏组织进行蛋白质组的全面分析。
通过 MudPIT 对心脏组织进行分析，并通过基于光谱计数的无标记方法选择差异表达的蛋白质。使用 PPI 网络及其拓扑分析评估蛋白质图谱。
在 MSCp 组中，蛋白质组的重塑在很大程度上得到了预防。涉及纤维化的细胞外蛋白质被下调，而能量途径则被全面上调。涉及酮酸代谢产物产生的心脏保护途径也被激活。此外，我们发现，新的枢纽蛋白质支持 MSCp 治疗的左心室 BZ 的心脏保护表型。事实上，血管生成蛋白 NCL 和 RAC1 的上调可以通过 MSCp 诱导的毛细血管密度增加来解释。
我们的结果表明，血管生成途径似乎处于独特的位置，能够将信号与涉及心脏修复的能量途径整合在一起。
我们的发现促使使用基于蛋白质组学的网络分析来优化新的方法，以防止可能是成年心脏自我修复能力有限的缺血后蛋白质组重塑。
