miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1.
miR-199a-5p Is upregulated during fibrogenic response to tissue injury and mediates TGFbeta-induced lung fibroblast activation by targeting caveolin-1.
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DOI：
10.1371/journal.pgen.1003291
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Pottier N
中科院分区：
文献类型：
--
作者：
Lino Cardenas CL;Henaoui IS;Courcot E;Roderburg C;Cauffiez C;Aubert S;Copin MC;Wallaert B;Glowacki F;Dewaeles E;Milosevic J;Maurizio J;Tedrow J;Marcet B;Lo-Guidice JM;Kaminski N;Barbry P;Luedde T;Perrais M;Mari B;Pottier N
由于miRNAs与正常的细胞过程有关，miRNAs的解除调控被认为在许多复杂疾病中起到了致病作用。然而，miRNAs在纤维化肺疾病，特别是特发性肺疾病(IPF)中的确切作用仍然知之甚少。鉴于IPF患者对当前治疗的反应率较低，对控制肺成纤维细胞激活的致病机制的新见解对于开发这种毁灭性疾病的新治疗策略至关重要。肺成纤维细胞是推动纤维化过程的关键细胞类型。为了确定在肺纤维化形成中具有潜在作用的miRNAs，我们对两个不同品系的小鼠肺中miRNA的表达进行了全基因组评估，这两个品系已知它们在博莱霉素暴露后发生肺纤维化的不同易感性。这导致了miR-199a-5p被确定为与博莱霉素反应相关的最佳miRNA候选。重要的是，miR-199a-5p在IPF患者肺组织中的表达也显著增加(94例IPF与83例对照)。特别是，在受损的小鼠肺和成纤维细胞灶中，miR-199a-5p的水平选择性地增加，这是与IPF相关的组织学特征。因此，我们进一步研究了miR-199a-5p在培养的肺成纤维细胞中的促纤维化作用：转化生长因子β诱导miR-199a-5p表达，异位表达miR-199a-5p足以促进肺成纤维细胞的病理性激活，包括增殖、迁移、侵袭和分化为肌成纤维细胞。此外，我们还证实了miR-199a-5p是肺成纤维细胞转化生长因子β信号转导的关键效应因子，它通过调节肺纤维化的关键介质CAV1而发挥作用。值得注意的是，miR-199a-5p在单侧输尿管梗阻小鼠肾纤维化模型中也有异常表达，在胆管结扎和CCl4诱导的小鼠肝纤维化模型中也发现了异常表达，提示miR-199a-5p的异常调节是导致纤维化过程的一般机制。因此，MIR-199a-5P是组织纤维化的主要调节剂，具有治疗纤维增生性疾病的疗效。纤维化是几乎所有形式的慢性器官衰竭的最终共同途径，包括肺、肝和肾，是全世界发病率和死亡率的主要原因。纤维化的原因是成纤维细胞的过度活动，特别是一种被称为肌成纤维细胞的分化形式，它导致瘢痕组织的过度和持续积累，最终导致器官衰竭。特发性肺纤维化(IPF)是一种慢性且常迅速致死的不明原因肺部疾病，其特征是肺的支持框架(间质)纤维化。鉴于IPF患者预后较差，对(Myo)成纤维细胞生物学的新见解对开发旨在降低(Myo)成纤维细胞活性以减缓甚至逆转疾病进展从而保护器官功能和延长生命的新疗法具有重要意义。MicroRNAs(MiRNAs)是新近发现的一类非编码RNA，与正常的细胞过程有关，miRNAs的解除调控在一系列复杂的疾病中起着致病作用。在这项研究中，我们鉴定了一种特殊的miRNA：miR-199a-5p，它调控肺成纤维细胞的激活，最终导致肺纤维化。总体而言，我们表明miR-199a-5p是一种主要的纤维化调节因子，在治疗纤维增生性疾病如IPF方面具有很强的治疗能力。
As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of miR-199a-5p represents a general mechanism contributing to the fibrotic process. MiR-199a-5p thus behaves as a major regulator of tissue fibrosis with therapeutic potency to treat fibroproliferative diseases. Fibrosis is the final common pathway in virtually all forms of chronic organ failure, including lung, liver, and kidney, and is a leading cause of morbidity and mortality worldwide. Fibrosis results from the excessive activity of fibroblasts, in particular a differentiated form known as myofibroblast that is responsible for the excessive and persistent accumulation of scar tissue and ultimately organ failure. Idiopathic Lung Fibrosis (IPF) is a chronic and often rapidly fatal pulmonary disorder of unknown origin characterized by fibrosis of the supporting framework (interstitium) of the lungs. Given the poor prognosis of IPF patients, new insights into the biology of (myo)fibroblasts is of major interest to develop new therapeutics aimed at reducing (myo)fibroblast activity to slow or even reverse disease progression, thereby preserving organ function and prolonging life. MicroRNAs (miRNAs), a class of non-coding RNA recently identified, are associated with normal cellular processes; and deregulation of miRNAs plays a causative role in a vast array of complex diseases. In this study, we identified a particular miRNA: miR-199a-5p that governs lung fibroblast activation and ultimately lung fibrosis. Overall we showed that miR-199a-5p is a major regulator of fibrosis with strong therapeutic potency to treat fibroproliferative diseases such as IPF.
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