哥伦比亚大学瓦格洛斯内科和外科医学院Hans-Willem Snoeck小组取得一项新突破。他们揭示了由多能性细胞衍生的人呼吸道祖细胞产生肺泡上皮细胞并模拟肺纤维化。2025年2月24日出版的《自然—生物技术》杂志发表了这项成果。

在这里，该研究组将人类多能干细胞（hPS细胞）转化为可扩展的球体，称为诱导呼吸道祖细胞（iRAPs），由~98%的RA/ TRBs相关细胞类型组成。一个hPS细胞可以产生10¹⁰个iRAP细胞。该课题组通过与过渡性2型肺泡上皮（AT2）细胞相一致的阶段将iRAPs分化为与成熟AT1细胞相对应的群体，纯度为95%。删除Hemansky-Pudlák综合征1 (HPS1)，引起人类肺纤维化，复制了在IPF中观察到的纤维化成纤维细胞的异常分化和募集，表明RA/ TRBs相关肺泡祖细胞的内在功能障碍有助于HPS1相关的IPF。iRAPs可以为IPF药物的发现和验证提供一个合适的系统。

据了解，人肺在远端呼吸道或终末呼吸细支气管（RA/TRBs）中含有独特的细胞群，这些细胞群在肺损伤和特发性肺纤维化（IPF）（一种致命的肺部疾病）患者中积累。由于这些种群在啮齿类动物中不存在，因此需要更深入的了解人类体外模型。

附：英文原文

Title: Human respiratory airway progenitors derived from pluripotent cells generate alveolar epithelial cells and model pulmonary fibrosis

Author: Pezet, Mikael G., Torres, Juan A., Thimraj, Tania A., Matkovic, Ivana, Schrode, Nadine, Murray, John W., Saqi, Anjali, Beaumont, Kristin G., Snoeck, Hans-Willem

Issue&Volume: 2025-02-24

Abstract: Human lungs contain unique cell populations in distal respiratory airways or terminal and respiratory bronchioles (RA/TRBs) that accumulate in persons with lung injury and idiopathic pulmonary fibrosis (IPF), a lethal lung disease. As these populations are absent in rodents, deeper understanding requires a human in vitro model. Here we convert human pluripotent stem cells (hPS cells) into expandable spheres, called induced respiratory airway progenitors (iRAPs), consisting of ~98% RA/TRB-associated cell types. One hPS cell can give rise to 10¹⁰ iRAP cells. We differentiate iRAPs through a stage consistent with transitional type 2 alveolar epithelial (AT2) cells into a population corresponding to mature AT1 cells with 95% purity. iRAPs with deletion of Hemansky–Pudlák Syndrome 1 (HPS1), which causes pulmonary fibrosis in humans, replicate the aberrant differentiation and recruitment of profibrotic fibroblasts observed in IPF, indicating that intrinsic dysfunction of RA/TRB-associated alveolar progenitors contributes to HPS1-related IPF. iRAPs may provide a system suitable for IPF drug discovery and validation.

DOI: 10.1038/s41587-025-02569-0

Source: https://www.nature.com/articles/s41587-025-02569-0