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Phenotypic miRNA Screen Identifies miR-26b to Promote the Growth and Survival of Endothelial Cells
Molecular Therapy - Nucleic Acids ( IF 6.5 ) Pub Date : 2018-08-18 , DOI: 10.1016/j.omtn.2018.08.006
Andrea Martello 1 , David Mellis 1 , Marco Meloni 1 , Alison Howarth 2 , Daniel Ebner 2 , Andrea Caporali 1 , Ayman Al Haj Zen 3
Affiliation  

Endothelial cell (EC) proliferation is a crucial event in physiological and pathological angiogenesis. MicroRNAs (miRNAs) have emerged as important modulators of the angiogenic switch. Here we conducted high-content screening of a human miRNA mimic library to identify novel regulators of EC growth systematically. Several miRNAs were nominated that enhanced or inhibited EC growth. Of these, we focused on miR-26b, which is a conserved candidate and expressed in multiple human EC types. miR-26b overexpression enhanced EC proliferation, migration, and tube formation, while inhibition of miR-26b suppressed the proliferative and angiogenic capacity of ECs. A combinatory functional small interfering RNA (siRNA) screening of 48 predicted gene targets revealed that miR-26b enhanced EC growth and survival through inhibiting PTEN expression. Local administration of miR-26b mimics promoted the growth of new microvessels in the Matrigel plug model. In the mouse model of hindlimb ischemia, miR-26b was found to be downregulated in endothelium in the first week following ischemia, and local overexpression of miR-26b improved the survival of capillaries and muscle fibers in ischemic muscles. Our findings suggest that miR-26b enhances EC proliferation, survival, and angiogenesis. miR-26b is a potential target for developing novel pro-angiogenic therapeutics in ischemic disease.



中文翻译:


表型 miRNA 筛选鉴定 miR-26b 促进内皮细胞的生长和存活



内皮细胞(EC)增殖是生理和病理血管生成的关键事件。 MicroRNA (miRNA) 已成为血管生成开关的重要调节剂。在这里,我们对人类 miRNA 模拟库进行了高内涵筛选,以系统地识别 EC 生长的新型调节因子。一些 miRNA 被提名增强或抑制 EC 生长。其中,我们重点关注 miR-26b,它是一种保守的候选者,在多种人类 EC 类型中表达。 miR-26b 过表达增强了 EC 的增殖、迁移和管形成,而抑制 miR-26b 则抑制了 EC 的增殖和血管生成能力。对 48 个预测基因靶标的组合功能性小干扰 RNA (siRNA) 筛选表明,miR-26b 通过抑制 PTEN 表达来增强 EC 生长和存活。 miR-26b 模拟物的局部给药促进了 Matrigel 栓模型中新微血管的生长。在后肢缺血的小鼠模型中,发现缺血后第一周内皮细胞中的miR-26b下调,并且miR-26b的局部过表达改善了缺血肌肉中毛细血管和肌纤维的存活。我们的研究结果表明 miR-26b 增强 EC 增殖、存活和血管生成。 miR-26b 是开发缺血性疾病新型促血管生成疗法的潜在靶点。

更新日期:2018-08-18
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