AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs
AKI Recovery Induced by Mesenchymal Stromal Cell-Derived Extracellular Vesicles Carrying MicroRNAs
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DOI：
10.1681/asn.2014070710
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发表时间：
2015-10-01
影响因子：
13.6
通讯作者：
Camussi, Giovanni
中科院分区：
文献类型：
--
作者：
Collino, Federica;Bruno, Stefania;Camussi, Giovanni
细胞外囊泡诱导的表型变化与间充质基质细胞促进的阿基恢复有关。microRNA是细胞重编程向proregenerative表型的潜在候选。本研究的目的是评估在严重联合免疫缺陷小鼠的甘油诱导阿基模型中，微小RNA失调是否会抑制间充质基质细胞和衍生的细胞外囊泡的再生潜力。我们产生了去除Drosha的间充质基质细胞以改变microRNA表达。Drosha敲低细胞产生的细胞外囊泡在数量、表面分子表达和肾小管上皮细胞内的内化方面与野生型细胞没有差异。然而，这些囊泡显示microRNA的整体下调。而野生型间充质基质细胞和衍生的囊泡静脉内给药诱导阿基的形态和功能恢复，Drosha敲除对应物无效。RNA测序分析表明，肾脏基因失调损伤后恢复治疗与间充质基质细胞和衍生囊泡，但不与Drosha敲低细胞和囊泡。基因本体分析显示阿基中下调的基因与脂肪酸代谢相关，上调的基因与炎症、基质-受体相互作用和细胞粘附分子相关。这些变化恢复后，治疗与野生型间充质基质细胞和细胞外囊泡，但没有治疗后与Drosha敲低的对应物。总之，间充质基质细胞和细胞外囊泡中的microRNA耗竭显著降低了阿基中的内在再生潜力，表明microRNA在阿基后的恢复中起着关键作用。
Phenotypic changes induced by extracellular vesicles have been implicated in mesenchymal stromal cell promoted recovery of AKI. MicroRNAs are potential candidates for cell reprogramming toward a proregenerative phenotype. The aim of this study was to evaluate whether microRNA deregulation inhibits the regenerative potential of mesenchymal stromal cells and derived extracellular vesicles in a model of glycerol-induced AKI in severe combined immunodeficient mice. We generated mesenchymal stromal cells depleted of Drosha to alter microRNA expression. Drosha-knockdown cells produced extracellular vesicles that did not differ from those of wild-type cells in quantity, surface molecule expression, and internalization within renal tubular epithelial cells. However, these vesicles showed global downregulation of microRNAs. Whereas wild-type mesenchymal stromal cells and derived vesicles administered intravenously induced morphologic and functional recovery in AKI, the Drosha-knockdown counterparts were ineffective. RNA sequencing analysis showed that kidney genes deregulated after injury were restored by treatment with mesenchymal stromal cells and derived vesicles but not with Drosha-knockdown cells and vesicles. Gene ontology analysis showed in AKI an association of downregulated genes with fatty acid metabolism and upregulated genes with inflammation, matrix-receptor interaction, and cell adhesion molecules. These alterations reverted after treatment with wild-type mesenchymal stromal cells and extracellular vesicles but not after treatment with the Drosha-knockdown counterparts. In conclusion, microRNA depletion in mesenchymal stromal cells and extracellular vesicles significantly reduced their intrinsic regenerative potential in AKI, suggesting a critical role of microRNAs in recovery after AKI.