Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen 9713AV, The Netherlands; Lung Repair and Regeneration Unit, Helmholtz-Zentrum Munich, Ludwig-Maximilians-University, University Hospital Grosshadern, Member of the German Center of Lung Research (DZL), Munich 81377, Germany.
Department of Molecular Pharmacology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, Groningen 9713AV, The Netherlands.
EBioMedicine. 2018 Oct;36:461-474. doi: 10.1016/j.ebiom.2018.09.002. Epub 2018 Sep 17.
Despite compelling data describing pro-regenerative effects of all-trans retinoic acid (ATRA) in pre-clinical models of chronic obstructive pulmonary disease (COPD), clinical trials using retinoids for emphysema patients have failed. Crucial information about the specific role of RA signaling in adult rodent and human lung epithelial progenitor cells is largely missing.
Adult lung organoid cultures were generated from isolated primary mouse and human lung epithelial cells, and incubated with pharmacological pathway modulators and recombinant proteins. Organoid number and size were measured, and differentiation was assessed with quantitative immunofluorescence and gene expression analyses.
We unexpectedly found that ATRA decreased lung organoid size, whereas RA pathway inhibition increased mouse and human lung organoid size. RA pathway inhibition stimulated mouse lung epithelial proliferation via YAP pathway activation and epithelial-mesenchymal FGF signaling, while concomitantly suppressing alveolar and airway differentiation. HDAC inhibition rescued differentiation in growth-augmented lung organoids.
In contrast to prevailing notions, our study suggests that regenerative pharmacology using transient RA pathway inhibition followed by HDAC inhibition might hold promise to promote lung epithelial regeneration in diseased adult lung tissue. FUND: This project is funded by the Lung Foundation Netherlands (Longfonds) grant 6.1.14.009 (RG, MK, JS, PSH) and W2/W3 Professorship Award by the Helmholtz Association, Berlin, Germany (MK).
尽管有大量数据描述了全反式视黄酸（ATRA）在慢性阻塞性肺疾病（COPD）的临床前模型中具有促再生作用，但用于肺气肿患者的类视黄醇临床试验均以失败告终。关于 RA 信号在成年啮齿动物和人肺上皮祖细胞中的特定作用的关键信息在很大程度上仍然缺失。
从分离的原代小鼠和人肺上皮细胞中生成成年肺类器官培养物，并与药理学途径调节剂和重组蛋白孵育。测量类器官的数量和大小，并通过定量免疫荧光和基因表达分析评估分化。
我们出人意料地发现，ATRA 减小了肺类器官的大小，而 RA 途径抑制则增加了小鼠和人肺类器官的大小。RA 途径抑制通过 YAP 途径激活和上皮-间充质 FGF 信号转导刺激了小鼠肺上皮细胞的增殖，同时抑制了肺泡和气道的分化。HDAC 抑制挽救了生长增强的肺类器官中的分化。
与普遍的观点相反，我们的研究表明，使用短暂的 RA 途径抑制随后进行 HDAC 抑制的再生药理学可能有希望促进患病成年肺组织中的肺上皮再生。
本项目由荷兰肺基金会（Longfonds）授予 6.1.14.009 号补助金（RG、MK、JS、PSH）和德国柏林亥姆霍兹协会的 W2/W3 教授职位奖（MK）资助。
