Zhao Yu, Zhou Yueqing, Zhang Weipan, Liu Mingzhe, Duan Jun, Zhang Xiaopeng, Ma Qiwang, Wang Yujia, Zhang Yuzhen, Guo Zhongliang, Zhang Ting, Zuo Wei
Institute for Regenerative Medicine, State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
Tongji Stem Cell Center, School of Medicine, Tongji University, Shanghai, China.
Nat Commun. 2025 Feb 3;16(1):1303. doi: 10.1038/s41467-025-56501-w.
Irreversible damage of the lung epithelium in idiopathic pulmonary fibrosis (IPF) patients causes high mortality worldwide, with no lung repair approaches available currently. Here we show that in murine and monkey models, the KRT5 P63 progenitor cells in airway basal layer can enter the alveolar area post fibrotic injury. Aided with an automated culture system, we clone and characterize airway basal progenitor cells from 44 donors with various lung conditions. Transplantation of human progenitor cells into the mouse lung efficiently re-epithelializes the injured alveolar area, forms new respiratory tract and saccule-like structures, which ameliorates fibrotic lesions and improves survival of mice. Mechanistically, the engrafted human progenitor cells do not function by differentiating into mature alveolar cells in mouse lung; instead, they differentiate into saccular cells expressing multiple tight junction proteins such as CLDN4, which help the lung to re-establish epithelial barriers. Furthermore, by cloning P63 airway basal progenitors from larger mammals and birds, we construct multiple lung-chimerism animals and uncover the evolutionarily conserved roles of these progenitor cells in lung repair. Overall, our data highlight the fate of airway basal progenitor cells in fibrotic lung and provide a potential therapeutic strategy for pulmonary diseases that lack inherent recovery mechanisms.
特发性肺纤维化（IPF）患者的肺上皮发生不可逆损伤，在全球范围内导致高死亡率，目前尚无肺部修复方法。在此我们表明，在小鼠和猴子模型中，气道基底层的KRT5⁺P63⁺祖细胞在纤维化损伤后可进入肺泡区域。借助自动化培养系统，我们从44名患有各种肺部疾病的供体中克隆并鉴定了气道基底祖细胞。将人祖细胞移植到小鼠肺中可有效地使受损的肺泡区域重新上皮化，形成新的呼吸道和囊状结构，从而改善纤维化病变并提高小鼠的存活率。从机制上讲，移植的人祖细胞在小鼠肺中并非通过分化为成熟的肺泡细胞发挥作用；相反，它们分化为表达多种紧密连接蛋白（如CLDN4）的囊状细胞，这有助于肺重新建立上皮屏障。此外，通过从大型哺乳动物和鸟类中克隆P63⁺气道基底祖细胞，我们构建了多种肺嵌合体动物，并揭示了这些祖细胞在肺修复中进化上保守的作用。总体而言，我们的数据突出了纤维化肺中气道基底祖细胞的命运，并为缺乏内在恢复机制的肺部疾病提供了一种潜在的治疗策略。
