Department of Internal Medicine V - Pulmonology, Allergology and Critical Care Medicine, Saarland University, 66421, Homburg, Germany.
Department of Clinical Medicine, Shanghai Tongji Hospital, School of Medicine, Tongji University, 200065, Shanghai, China.
Mol Med. 2024 Nov 23;30(1):227. doi: 10.1186/s10020-024-00990-w.
Impaired interaction of fibroblasts with pneumocytes contributes to the progression of chronic lung disease such as idiopathic pulmonary fibrosis (IPF). Mucin 5B (MUC5B) is associated with IPF. Here we analyzed the interaction of primary fibroblasts and alveolar type 2 (AT2) pneumocytes in the organoid model. Single-cell analysis, histology, and qRT-PCR revealed that fibroblasts expressing high levels of fibrosis markers regulate STAT3 signaling in AT2 cells, which is accompanied by cystic organoid growth and MUC5B expression. Cystic growth and MUC5B expression were also caused by the cytokine IL-6. The PI3K-Akt signaling pathway was activated in fibroblasts. The drug dasatinib prevented the formation of MUC5B-expressing cystic organoids. MUC5B associated with AT2 cells in samples obtained from IPF patients. Our model shows that fibrotic primary fibroblasts induce impaired differentiation of AT2 cells via STAT3 signaling pathways, as observed in IPF patients. It can be used for mechanistic studies and drug development.
成纤维细胞与肺泡 II 型细胞（AT2）相互作用受损会导致慢性肺部疾病（如特发性肺纤维化（IPF））的进展。黏蛋白 5B（MUC5B）与 IPF 相关。在这里，我们在类器官模型中分析了原代成纤维细胞和肺泡 II 型细胞的相互作用。单细胞分析、组织学和 qRT-PCR 显示，高表达纤维化标志物的成纤维细胞调节 AT2 细胞中的 STAT3 信号通路，这伴随着囊性类器官的生长和 MUC5B 的表达。细胞因子 IL-6 也会引起囊性生长和 MUC5B 的表达。PI3K-Akt 信号通路在成纤维细胞中被激活。药物达沙替尼可防止表达 MUC5B 的囊性类器官的形成。MUC5B 与从 IPF 患者中获得的样本中的 AT2 细胞相关。我们的模型表明，纤维化的原代成纤维细胞通过 STAT3 信号通路诱导 AT2 细胞的分化受损，这在 IPF 患者中观察到。它可以用于机制研究和药物开发。
