Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis.
Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis.
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DOI：
10.1016/j.stem.2016.10.004
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发表时间：
2017-02-02
期刊：
影响因子：
23.9
通讯作者：
Bellusci S
中科院分区：
文献类型：
--
作者：
El Agha E;Moiseenko A;Kheirollahi V;De Langhe S;Crnkovic S;Kwapiszewska G;Szibor M;Kosanovic D;Schwind F;Schermuly RT;Henneke I;MacKenzie B;Quantius J;Herold S;Ntokou A;Ahlbrecht K;Braun T;Morty RE;Günther A;Seeger W;Bellusci S
特发性肺纤维化（IPF）是一种病因不明的进行性间质性肺病。由于缺乏有效治疗，IPF与高死亡率相关。这种疾病的标志性特征是过度存款细胞外基质蛋白的活化肌成纤维细胞的积累，从而损害肺结构和功能并阻碍气体交换。在这里，我们研究了激活的肌成纤维细胞的起源和纤维化形成和解决的分子机制。在小鼠中的基因工程使得能够在纤维化形成和消退期间对肺成纤维细胞的脂肪生成或肌生成群体进行时间控制的标记和监测。我们的数据表明，在纤维化形成过程中，成纤维细胞表型中存在脂肪生成到肌生成的转换。相反，我们在纤维化消退期间观察到肌生成到脂肪生成的转换。对人肺组织和原代人肺成纤维细胞的分析表明，这种命运转换参与IPF发病机制，为治疗患者开辟了潜在的治疗途径。El Agha等人在小鼠中使用基因工程来鉴定活化的肌成纤维细胞的前体细胞，并在肺纤维化的可逆模型中研究它们的命运。他们的发现强调了脂肪生成和肌生成肺成纤维细胞的表型可塑性，并表明PPARγ激动剂可能有益于治疗IPF。
Idiopathic pulmonary fibrosis (IPF) is a form of progressive interstitial lung disease with unknown etiology. Due to a lack of effective treatment, IPF is associated with a high mortality rate. The hallmark feature of this disease is the accumulation of activated myofibroblasts that excessively deposit extracellular matrix proteins, thus compromising lung architecture and function and hindering gas exchange. Here we investigated the origin of activated myofibroblasts and the molecular mechanisms governing fibrosis formation and resolution. Genetic engineering in mice enables the time-controlled labeling and monitoring of lipogenic or myogenic populations of lung fibroblasts during fibrosis formation and resolution. Our data demonstrate a lipogenic-to-myogenic switch in fibroblastic phenotype during fibrosis formation. Conversely, we observed a myogenic-to-lipogenic switch during fibrosis resolution. Analysis of human lung tissues and primary human lung fibroblasts indicates that this fate switching is involved in IPF pathogenesis, opening potential therapeutic avenues to treat patients. El Agha et al. use genetic engineering in mice to identify precursor cells for activated myofibroblasts and investigate their fate in a reversible model of lung fibrosis. Their findings emphasize the phenotypic plasticity of lipogenic and myogenic lung fibroblasts and indicate that PPARγ agonists might be beneficial in treating IPF.