MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation
MicroRNA-27a-3p Is a Negative Regulator of Lung Fibrosis by Targeting Myofibroblast Differentiation
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DOI：
10.1165/rcmb.2015-0205oc
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发表时间：
2016-06-01
影响因子：
6.4
通讯作者：
Liu, Gang
中科院分区：
文献类型：
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作者：
Cui, Huachun;Banerjee, Sami;Liu, Gang
虽然microRNAs（miRs）在器官纤维化的发病机制中起重要作用，但miRs是否直接调控肌成纤维细胞（病理性纤维化过程中的效应细胞）的分化尚缺乏证据。在这项研究中，我们发现，miR-27 a-3 p的水平上调转化生长因子β 1处理的人肺成纤维细胞中的Smad 2/3依赖性的方式，并从小鼠肺分离的成纤维细胞与实验性肺纤维化。然而，与正常对照组相比，特发性肺纤维化患者肺成纤维细胞中基础和转化生长因子β 1诱导的miR-27 a-3 p表达均降低。miR-27 a-3 p的过表达抑制肺成纤维细胞向肌成纤维细胞的分化，而miR-27 a-3 p的敲低增强肺成纤维细胞向肌成纤维细胞的分化。我们发现miR-27 a-3 p直接靶向肌成纤维细胞的表型标志物α-平滑肌肌动蛋白和两个关键的Smad转录因子Smad 2和Smad 4。更重要的是，我们发现通过慢病毒递送在小鼠肺中治疗性表达miR-27 a-3 p减少了博来霉素诱导的肺纤维化。总之，我们的数据表明，miR-27 a-3 p通过负反馈机制抑制肺纤维化。这项研究还表明，靶向miR-27 a-3 p是治疗纤维化器官疾病（包括肺纤维化）的一种新的治疗方法。
Although microRNAs (miRs) have been well recognized to play an important role in the pathogenesis of organ fibrosis, there is a lack of evidence as to whether miRs directly regulate the differentiation of myofibroblasts, the putative effector cells during pathological fibrogenesis. In this study, we found that levels of miR-27a-3p were up-regulated in transforming growth factor-beta 1-treated human lung fibroblasts in a Smad2/3-dependent manner and in fibroblasts isolated from lungs of mice with experimental pulmonary fibrosis. However, both basal and transforming growth factor-beta 1-induced expression of miR-27a-3p were reduced in lung fibroblasts from patients with idiopathic pulmonary fibrosis compared with that from normal control subjects. Overexpression of miR-27a-3p inhibited, whereas knockdown of miR-27a-3p enhanced, the differentiation of lung fibroblasts into myofibroblasts. We found that miR-27a-3p directly targeted the phenotypic marker of myofibroblasts, alpha-smooth muscle actin, and two key Smad transcription factors, Smad2 and Smad4. More importantly, we found that therapeutic expression of miR-27a-3p in mouse lungs through lentiviral delivery diminished bleomycin-induced lung fibrosis. In conclusion, our data suggest that miR-27a-3p functions via a negative-feedback mechanism in inhibiting lung fibrosis. This study also indicates that targeting miR-27a-3p is a novel therapeutic approach to treat fibrotic organ disorders, including lung fibrosis.