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首页> 外文期刊>Drug Design, Development and Therapy >Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization
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Exosomes Derived from MicroRNA-146a-5p-Enriched Bone Marrow Mesenchymal Stem Cells Alleviate Intracerebral Hemorrhage by Inhibiting Neuronal Apoptosis and Microglial M1 Polarization

机译：通过抑制神经元细胞凋亡和微胶质M1偏振来缓解脑出血的微小RORNA-146A-5P富集骨髓间充质干细胞的外泌体

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Introduction: Intracerebral hemorrhage (ICH) is a devastating type of stroke with high mortality, and the effective therapies for ICH remain to be explored. Exosomes (Exos) have been found to play important roles in cell communication by transferring molecules, including microRNAs (miRNAs/miRs). MiRNAs are critical regulators of genes involved in many various biological processes and have been demonstrated to aggravate or alleviate brain damages induced by ICH. The aim of the present study was to investigate the effect of Exos derived from miR-146a-5p-enriched bone marrow mesenchymal stem cells (BMSCs-miR-146a-5p-Exos) on experimental ICH. Methods: ICH was induced in adult male Sprague-Dawley rats by an intrastriatal injection of collagenase type IV. At 24 h after surgery, Exos were administrated. For detecting apoptotic cells, TUNEL staining was performed using an in situ Cell Death Detection Kit. Fluoro-Jade B staining was performed to detect degenerating neurons. Immunofluorescence assay was performed to detect the expression of myeloperoxidase (MPO) and OX-42. The binding of miR-146a-5p and its target genes was confirmed by luciferase reporter assay. Results: At 24 h after surgery, BMSCs-miR-146a-5p-Exos administration significantly improved neurological function, reduced apoptotic and degenerative neurons, and inhibited inflammatory response. Furthermore, miR-146a-5p-enriched Exos obviously inhibited the M1 polarization of microglia after ICH in rats, accompanied by the reduced expression of pro-inflammatory mediators releasing by M1 microglia including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1). Finally, we observed that miR-146a-5p directly targeted interleukin-1 receptor-associated kinase1 (IRAK1) and nuclear factor of activated T cells 5 (NFAT5), which contributed to the inflammation response and the polarization of M1 microglia/macrophages. Conclusion: We demonstrated that miR-146a-5p-riched BMSCs-Exos could offer neuroprotection and functional improvements after ICH through reducing neuronal apoptosis, and inflammation associated with the inhibition of microglial M1 polarization by downregulating the expression of IRAK1 and NFAT5.
机译：简介：脑出血（ICH）是一种抗病性卒中，具有高死亡率，仍有待探索ICH的有效疗法。已发现外泌体（外壳）通过转移分子（包括MicroRNA）（miRNA / mir）来发挥细胞通信中的重要作用。 miRNA是涉及许多各种生物过程的基因的关键调节因素，并且已被证明是加重或缓解ICH诱导的脑损伤。本研究的目的是研究EXOS衍生自MiR-146A-5P富集的骨髓间充质干细胞（BMSCS-MIR-146A-5P-EXOS）对实验ICH的影响。方法：通过脑内注射胶原酶型胶原酶型胶原蛋白酶蛋白酶酶Ich诱导成年雄性Sprague-Dawley大鼠。在手术后24小时，给予EXOS。为了检测凋亡细胞，使用原位细胞死亡检测试剂盒进行TUNEL染色。进行氟代玉布B染色以检测退化神经元。进行免疫荧光测定以检测髓过氧化物酶（MPO）和OX-42的表达。通过荧光素酶报告结果证实miR-146a-5p及其靶基因的结合。结果：24小时手术后，BMSCS-MIR-146A-5P-EXOS给药显着改善神经功能，细胞凋亡和退行性神经元减少，抑制炎症反应。此外，富含MiR-146A-5P-5P的外壳显然抑制了大鼠中ICH后微胶质细胞的M1偏振，伴随着由M1微胶质细胞释放的促炎介质的表达减少，包括诱导的一氧化氮合酶（InOS），环氧化酶-2（COX -2）和单核细胞化学蛋白-1（MCP-1）。最后，我们观察到MiR-146A-5P直接靶向白细胞介素-1受体相关的激酶1（IRAK1）和活化T细胞5（NFAT5）的核因子，这有助于炎症反应和M1微胶质细胞的极化。结论：我们证明MIR-146A-5P-5P-5P-EXOS通过减少神经元细胞凋亡，通过降低伊拉克1和NFAT5的表达，通过减少神经元细胞凋亡和与微胶质M1偏振相关的炎症提供神经保护和功能改进。

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