| Regenerative Capacity of Alveolar Type 2 Cells Is Proportionally Reduced Following Disease Progression in Idiopathic Pulmonary Fibrosis-Derived Organoid Cultures |
Hyeon Kyu Choi, M.D.1 
, Gaeul Bang, M.S.2, Ju Hye Shin, M.S.3, Mi Hwa Shin, B.S.3, Ala Woo, M.D.3, Song Yee Kim, M.D., Ph.D.3, Sang Hoon Lee, M.D., Ph.D.3, Eun Young Kim, M.D., Ph.D.3, Hyo Sup Shim, M.D., Ph.D.4, Young Joo Suh, M.D., Ph.D.5, Ha Eun Kim, M.D.6, Jin Gu Lee, M.D., Ph.D.6, Jinwook Choi, Ph.D.2,7, Ju Hyeon Lee, Ph.D.7, Chul Hoon Kim, M.D., Ph.D.1, Moo Suk Park, M.D., Ph.D.3
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1Department of Pharmacology, Yonsei University College of Medicine, Seoul, Republic of Korea
2School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea
3Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
4Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
5Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
6Department of Thoracic and Cardiovascular Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
7Welcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, United Kingdom |
Correspondence:
Moo Suk Park, Tel: 82-2-2228-1955,
Email: pms70@yuhs.ac
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Received: 4 July 2024 • Revised: 14 September 2024 • Accepted: 22 September 2024 |
| Abstract |
Background
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease that culminates in respiratory failure and death due to irreversible scarring of the distal lung. While initially considered a chronic inflammatory disorder, the aberrant function of the alveolar epithelium is now acknowledged as playing a central role in the pathophysiology of IPF. This study aimed to investigate the regenerative capacity of alveolar type 2 (AT2) cells using IPF-derived alveolar organoids and to examine the effects of disease progression on this capacity.
Methods
Lung tissues from three pneumothorax patients and six IPF patients (early and advanced stages) were obtained through video-assisted thoracoscopic surgery and lung transplantation. HTII-280+ cells were isolated from CD31-CD45-epithelial cell adhesion molecule (EpCAM)+ cells in the distal lungs of IPF and pneumothorax patients using fluorescence-activated cell sorting (FACS) and resuspended in 48-well plates to establish IPF-derived alveolar organoids. Immunostaining was used to verify the presence of AT2 cells.
Results
FACS sorting yielded approximately 1% of AT2 cells in early IPF tissue, and the number decreased as the disease progressed, in contrast to 2.7% in pneumothorax. Additionally, the cultured organoids in the IPF groups were smaller and less numerous compared to those from pneumothorax patients. The colony forming efficiency decreased as the disease advanced. Immunostaining results showed that the IPF organoids expressed less surfactant protein C (SFTPC) compared to the pneumothorax group and contained keratin 5+ (KRT5+) cells.
Conclusion
This study confirmed that the regenerative capacity of AT2 cells in IPF decreases as the disease progresses, with IPF-derived AT2 cells inherently exhibiting functional abnormalities and altered differentiation plasticity. |
| Key Words:
Idiopathic Pulomonary Fibrosis, Alveolar Type 2 Cells, Patient-Derived Lung Organoid, Lung Regeneration |
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