Lim Kyungtae, Rutherford Eimear N, Sun Dawei, Van den Boomen Dick J H, Edgar James R, Bang Jae Hak, Matesic Lydia E, Lee Joo-Hyeon, Lehner Paul J, Marciniak Stefan J, Rawlins Emma L, Dickens Jennifer A
Wellcome Trust/CRUK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3DY, UK.
bioRxiv. 2023 Sep 4:2023.08.30.555522. doi: 10.1101/2023.08.30.555522.
Alveolar type 2 (AT2) cells maintain lung health by acting as stem cells and producing pulmonary surfactant. AT2 dysfunction underlies many lung diseases including interstitial lung disease (ILD), in which some inherited forms result from mislocalisation of surfactant protein C (SFTPC) variants. Disease modelling and dissection of mechanisms remains challenging due to complexities in deriving and maintaining AT2 cells Here, we describe the development of expandable adult AT2-like organoids derived from human fetal lung which are phenotypically stable, can differentiate into AT1-like cells and are genetically manipulable. We use these organoids to test key effectors of SFTPC maturation identified in a forward genetic screen including the E3 ligase ITCH, demonstrating that their depletion phenocopies the pathological SFTPC redistribution seen for the SFTPC-I73T variant. In summary, we demonstrate the development of a novel alveolar organoid model and use it to identify effectors of SFTPC maturation necessary for AT2 health.
2型肺泡（AT2）细胞作为干细胞并产生肺表面活性物质，从而维持肺部健康。AT2功能障碍是包括间质性肺病（ILD）在内的许多肺部疾病的基础，其中一些遗传性形式是由表面活性物质蛋白C（SFTPC）变体的定位错误导致的。由于获取和维持AT2细胞的复杂性，疾病建模和机制剖析仍然具有挑战性。在这里，我们描述了从人胎儿肺中衍生出的可扩增的成年AT2样类器官的发育，这些类器官表型稳定，可分化为AT1样细胞，并且可进行基因操作。我们使用这些类器官来测试在前向遗传筛选中确定的SFTPC成熟的关键效应器，包括E3连接酶ITCH，证明它们的缺失模拟了SFTPC - I73T变体所见的病理性SFTPC重新分布。总之，我们展示了一种新型肺泡类器官模型的开发，并使用它来鉴定AT2健康所需的SFTPC成熟的效应器。
