Liu Zeyu, Zheng Qi, Li Zhoubin, Huang Moli, Zhong Cheng, Yu Ruize, Jiang Rong, Dai Haotian, Zhang Jingyuan, Gu Xiaohua, Xu Yongle, Li Chunwei, Shan Shan, Xu Feng, Hong Yue, Ren Tao
Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
Department of Lung Transplantation and Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, PR China.
EBioMedicine. 2025 Feb;112:105538. doi: 10.1016/j.ebiom.2024.105538. Epub 2025 Jan 2.
Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial pneumonia with restrictive ventilation. Recently, the structural and functional defects of small airways have received attention in the early pathogenesis of IPF. This study aimed to elucidate the characteristics of small airway epithelial dysfunction in patients with IPF and explore novel therapeutic interventions to impede IPF progression by targeting the dysfunctional small airways.
Airway trees spanning the proximal-distal axis were harvested from control lungs and explanted lungs with end-stage IPF undergoing transplant. Qualified basal cells (BCs, p63/Krt5/ITGA6/NGFR) were expanded, and their cellular functions, feasibility, safety and efficacy for transplantation therapy in IPF were validated with experiments in vitro and mouse model. Single-cell RNA-sequencing was employed to elucidate the underlying mechanisms governing the BCs based therapy. Based upon these evidences, three patients with advanced IPF and small airway dysfunction received autologous-BCs transplantation. Post-transplantation assessments included lung function, exercise capacity and high resolution computed tomography (HRCT) scans were analyzed to quantify the clinical benefits conferred by the BCs transplantation.
An overall landscape of senescent phenotype in airway epithelial cells and airway stem/progenitor cells along the proximal-distal axis of the airway tree in IPF were outlined. In contrast to the cells situated in distal airways, BCs located in small bronchi in IPF displayed a non-senescent phenotype, with comparable proliferative, differentiative capabilities, and similar transcriptomic profiles to normal controls. In a mouse model of pulmonary fibrosis, BCs exhibited promising protective efficacy and safety for transplantation therapy. Autologous BCs transplantation in three advanced IPF patients with small airway dysfunction yielded significant clinical improvements in pulmonary function, particularly evidence in lung volume and small airway function.
Epithelia of small bronchi in IPF contain functional and expandable basal stem cells, which exert therapeutic benefits via bronchoscopic implantation. Our findings offer a potential for IPF treatment by targeting small airways.
National Natural Science Foundation of China (82430001, 81930001, and 81900059), Shanghai Shenkang Hospital Development Center (SHDC2020CR3063B), Department of Science and Technology of Shandong Province (2024HWYQ-058).
特发性肺纤维化（IPF）是一种具有限制性通气的纤维化间质性肺炎。近年来，小气道的结构和功能缺陷在IPF的早期发病机制中受到关注。本研究旨在阐明IPF患者小气道上皮功能障碍的特征，并探索通过靶向功能失调的小气道来阻止IPF进展的新型治疗干预措施。
从对照肺和接受移植的终末期IPF移植肺中获取跨越近端-远端轴的气道树。扩增合格的基底细胞（BCs，p63/Krt5/ITGA6/NGFR），并通过体外实验和小鼠模型验证其细胞功能、移植治疗IPF的可行性、安全性和有效性。采用单细胞RNA测序来阐明基于BCs治疗的潜在机制。基于这些证据，3例晚期IPF和小气道功能障碍患者接受了自体BCs移植。移植后评估包括肺功能、运动能力，并分析高分辨率计算机断层扫描（HRCT）扫描结果以量化BCs移植带来的临床益处。
勾勒出IPF气道树近端-远端轴上气道上皮细胞和气道干/祖细胞衰老表型的总体情况。与位于远端气道的细胞不同，IPF中小支气管中的BCs表现出非衰老表型，其增殖、分化能力与正常对照相当，转录组谱也相似。在肺纤维化小鼠模型中，BCs在移植治疗中显示出有前景的保护效果和安全性。对3例晚期IPF合并小气道功能障碍患者进行自体BCs移植后，肺功能有显著临床改善，尤其是肺容积和小气道功能方面的证据。
IPF中小支气管上皮含有功能性且可扩增的基底干细胞，可通过支气管镜植入发挥治疗作用。我们的研究结果为靶向小气道治疗IPF提供了可能性。
中国国家自然科学基金（82430001、81930001和8190005９）、上海申康医院发展中心（SHDC2020CR3063B）、山东省科学技术厅（2024HWYQ-058）
