Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosisResearch in context
Summary: Background: 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 o...
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Elsevier
2025-02-01
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| author | Zeyu Liu Qi Zheng Zhoubin Li Moli Huang Cheng Zhong Ruize Yu Rong Jiang Haotian Dai Jingyuan Zhang Xiaohua Gu Yongle Xu Chunwei Li Shan Shan Feng Xu Yue Hong Tao Ren |
| author_facet | Zeyu Liu Qi Zheng Zhoubin Li Moli Huang Cheng Zhong Ruize Yu Rong Jiang Haotian Dai Jingyuan Zhang Xiaohua Gu Yongle Xu Chunwei Li Shan Shan Feng Xu Yue Hong Tao Ren |
| author_sort | Zeyu Liu |
| collection | DOAJ |
| description | Summary: Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: 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). |
| format | Article |
| id | doaj-art-0ca778bd59c54e42aeb50bf3e328a640 |
| institution | Kabale University |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-0ca778bd59c54e42aeb50bf3e328a6402025-01-03T04:08:46ZengElsevierEBioMedicine2352-39642025-02-01112105538Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosisResearch in contextZeyu Liu0Qi Zheng1Zhoubin Li2Moli Huang3Cheng Zhong4Ruize Yu5Rong Jiang6Haotian Dai7Jingyuan Zhang8Xiaohua Gu9Yongle Xu10Chunwei Li11Shan Shan12Feng Xu13Yue Hong14Tao Ren15Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, ChinaDepartment of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, ChinaDepartment of Lung Transplantation and Thoracic Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, PR ChinaDepartment of Bioinformatics, School of Biological and Basic Medical Sciences, Soochow University, Suzhou, 215123, ChinaDepartment of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, ChinaKey Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, ChinaDepartment of Bioinformatics, School of Biological and Basic Medical Sciences, Soochow University, Suzhou, 215123, ChinaDepartment of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, ChinaDepartment of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, ChinaDepartment of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, ChinaDepartment of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, ChinaDepartment of Otolaryngology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, ChinaDepartment of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China; Corresponding author.Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China; Shandong Engineering Laboratory of Prevention and Control for Endocrine and Metabolic Diseases, Jinan, 250021, Shandong, China; Corresponding author. Key Laboratory of Endocrine Glucose & Lipids Metabolism and Brain Aging, Ministry of Education, Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.School of Life and Health Sciences, Hainan University, Haikou, Hainan 570228, China; Hainan Province Key Laboratory of One Health, Collaborative Innovation Center of One Health, Hainan University, Haikou, Hainan 570228, China; Corresponding author.Department of Respiratory and Clinical Care Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China; Corresponding author.Summary: Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: 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).http://www.sciencedirect.com/science/article/pii/S2352396424005747Basal stem cellsHuman small bronchiTherapy of idiopathic pulmonary fibrosisBronchoscopic implantationSenescent phenotype |
| spellingShingle | Zeyu Liu Qi Zheng Zhoubin Li Moli Huang Cheng Zhong Ruize Yu Rong Jiang Haotian Dai Jingyuan Zhang Xiaohua Gu Yongle Xu Chunwei Li Shan Shan Feng Xu Yue Hong Tao Ren Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosisResearch in context EBioMedicine Basal stem cells Human small bronchi Therapy of idiopathic pulmonary fibrosis Bronchoscopic implantation Senescent phenotype |
| title | Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosisResearch in context |
| title_full | Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosisResearch in context |
| title_fullStr | Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosisResearch in context |
| title_full_unstemmed | Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosisResearch in context |
| title_short | Epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosisResearch in context |
| title_sort | epithelial stem cells from human small bronchi offer a potential for therapy of idiopathic pulmonary fibrosisresearch in context |
| topic | Basal stem cells Human small bronchi Therapy of idiopathic pulmonary fibrosis Bronchoscopic implantation Senescent phenotype |
| url | http://www.sciencedirect.com/science/article/pii/S2352396424005747 |
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