Extracellular Vesicles Released from Mesenchymal Stromal Cells Modulate miRNA in Renal Tubular Cells and Inhibit ATP Depletion Injury
Extracellular Vesicles Released from Mesenchymal Stromal Cells Modulate miRNA in Renal Tubular Cells and Inhibit ATP Depletion Injury
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DOI：
10.1089/scd.2013.0618
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发表时间：
2014-08-01
影响因子：
4
通讯作者：
Camussi, Giovanni
中科院分区：
文献类型：
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作者：
Lindoso, Rafael S.;Collino, Federica;Camussi, Giovanni
间充质基质细胞(MSCs)参与肾脏修复的机制尚未完全阐明。生物活性分子的旁分泌与保护作用有关。除了可溶性介质外，MSCs还能释放细胞外小泡(EV)，参与不同损伤模型的肾脏修复过程。EV通过蛋白质、生物活性脂类、mRNA和microRNAs(MiRNAs)等几种分子的转移来调节细胞之间的通讯。MiRNAs是转录后调节基因表达的非编码RNA，参与多种细胞过程的调节，包括与修复相关的过程。本研究旨在探讨MSC-EVS在ATP耗竭所致的体外肾小管上皮细胞(PTECs)内miRNAs调控中的作用。在这个模型中，我们评估了miRNA表达的变化是依赖于miRNA的直接转移还是依赖于MSC-EVS的转录诱导。结果表明，在损伤的PTECs中，MSC-EVS的掺入增强，并保护细胞免于死亡。这种生物学效应与EV介导的miRNA转移和损伤的PTECs表达的miRNAs的转录调控有关。对miRNA靶点的预测表明，PTECs中调控的miRNAs参与了肾脏的修复过程，与细胞凋亡、细胞骨架重组和缺氧相关的编码基因下调，如CASP3和7、SHC1和Smad4。综上所述，这些结果表明，MSC-EVS可能转移和调控参与PTECs修复和恢复过程的几个miRNAs的表达。
The mechanisms involved in renal repair by mesenchymal stromal cells (MSCs) are not entirely elucidated. The paracrine secretion of bioactive molecules has been implicated in the protective effects. Besides soluble mediators, MSCs have been shown to release extracellular vesicles (EVs), involved in renal repair process for different injury models. EVs have been shown to mediate communication between cells through the transference of several molecules, like protein, bioactive lipids, mRNA, and microRNAs (miRNAs). The miRNAs are noncoding RNAs that posttranscriptionally modulate gene expression and are involved in the regulation of several cellular processes, including those related to repair. The aim of the present study was to investigate the role of MSC-EVs in the modulation of miRNAs inside renal proximal tubular epithelial cells (PTECs) in an in vitro model of ischemia-reperfusion injury induced by ATP depletion. In this model we evaluated whether changes in miRNA expression were dependent on direct miRNA transfer or on transcription induction by MSC-EVs. The obtained results showed an enhanced incorporation of MSC-EVs in injured PTECs with protection from cell death. This biological effect was associated with EV-mediated miRNA transfer and with transcriptional modulation of miRNAs expressed by injured PTECs. Prediction of miRNA targets showed that miRNAs modulated in PTECs are involved in process of renal recovery with downregulation of coding-mRNAs associated with apoptosis, cytoskeleton reorganization, and hypoxia, such as CASP3 and 7, SHC1 and SMAD4. In conclusion, these results indicate that MSC-EVs may transfer and modulate the expression of several miRNAs involved in the repair and recovery process in PTECs.