Pulmonary alveolar type I cell population consists of two distinct subtypes that differ in cell fate

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-03, Vol.115 (10), p.2407-2412
• Main Authors: Wang, Yanjie, Tang, Zan, Huang, Huanwei, Li, Jiao, Wang, Zheng, Yu, Yuanyuan, Zhang, Chengwei, Li, Juan, Dai, Huaping, Wang, Fengchao, Cai, Tao, Tang, Nan
• Format: Article
• Language: English
• Subjects: Alveolar Epithelial Cells - cytology; Alveolar Epithelial Cells - metabolism; Alveolar Epithelial Cells - physiology; Alveoli; Animals; Biological Sciences; Cell Differentiation; Cell fate; Cell Lineage - physiology; Cells; Developmental plasticity; Genetic markers; Insulin; Insulin-Like Growth Factor Binding Protein 2 - genetics; Insulin-Like Growth Factor Binding Protein 2 - metabolism; Insulin-like growth factor-binding protein 2; Lungs; Mice; Mice, Transgenic; Molecules; Pulmonary Alveoli - cytology; Regeneration; Regeneration - physiology; Ribonucleic acid; RNA; RNA - analysis; RNA - genetics; RNA - metabolism; Rodents; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome - genetics; Transcriptome - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1719474115

Pulmonary alveolar type I (AT1) cells cover more than 95% of alveolar surface and are essential for the air–blood barrier function of lungs. AT1 cells have been shown to retain developmental plasticity during alveolar regeneration. However, the development and heterogeneity of AT1 cells remain largely unknown. Here, we conducted a single-cell RNA-seq analysis to characterize postnatal AT1 cell development and identified insulin-like growth factor-binding protein 2 (Igfbp2) as a genetic marker specifically expressed in postnatal AT1 cells. The portion of AT1 cells expressing Igfbp2 increases during alveologenesis and in post pneumonectomy (PNX) newly formed alveoli. We found that the adult AT1 cell population contains both Hopx⁺Igfbp2⁺ and Hopx⁺Igfbp2⁻ AT1 cells,which have distinct cell fates during alveolar regeneration. Using an Igfbp2-CreER mouse model, we demonstrate that Hopx⁺Igfbp2⁺ AT1 cells represent terminally differentiated AT1 cells that are not able to transdifferentiate into AT2 cells during post-PNX alveolar regeneration. Our study provides tools and insights that will guide future investigations into the molecular and cellular mechanism or mechanisms underlying AT1 cell fate during lung development and regeneration.