Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity

• Published in: Nature communications 2024-07, Vol.15 (1), p.5898-24, Article 5898
• Main Authors: Quach, Henry, Farrell, Spencer, Wu, Ming Jia Michael, Kanagarajah, Kayshani, Leung, Joseph Wai-Hin, Xu, Xiaoqiao, Kallurkar, Prajkta, Turinsky, Andrei L., Bear, Christine E., Ratjen, Felix, Kalish, Brian, Goyal, Sidhartha, Moraes, Theo J., Wong, Amy P.
• Format: Article
• Language: English
• Subjects: 13/100; 13/51; 38/39; 45/91; 631/136/142; 631/136/1660/1986; 631/136/532/1360; 631/532/2064/2158; Benchmarks; Cell culture; Cell Differentiation; Cell Lineage; Cell Plasticity; Cystic fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Differentiation (biology); Epithelial cells; Epithelial Cells - cytology; Epithelial Cells - metabolism; Epithelium; Female; Fetus - cytology; Fetus - embryology; Fetuses; Gene Expression Regulation, Developmental; Humanities and Social Sciences; Humans; Lung - cytology; Lung - embryology; Lung diseases; Lungs; multidisciplinary; Neuroendocrine system; Pluripotency; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - metabolism; Progenitor cells; Science; Science (multidisciplinary); Signal Transduction; Single-Cell Analysis; Stem cells; Trajectory analysis; Transcriptome; Transcriptomics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-50281-5

Studying human fetal lungs can inform how developmental defects and disease states alter the function of the lungs. Here, we sequenced >150,000 single cells from 19 healthy human pseudoglandular fetal lung tissues ranging between gestational weeks 10–19. We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator ( CFTR ). These cells give rise to multiple specialized epithelial cell types. Combined with spatial transcriptomics, we show temporal regulation of key signalling pathways that may drive the temporal and spatial emergence of specialized epithelial cells including ciliated and pulmonary neuroendocrine cells. Finally, we show that human pluripotent stem cell-derived fetal lung models contain CFTR -expressing progenitor cells that capture similar lineage developmental trajectories as identified in the native tissue. Overall, this study provides a comprehensive single-cell atlas of the developing human lung, outlining the temporal and spatial complexities of cell lineage development and benchmarks fetal lung cultures from human pluripotent stem cell differentiations to similar developmental window. Quach and Farrell et al. report single-cell transcriptomic analysis of over 150,000 cell from 19 human fetal lung tissues and describe the temporal and spatial dynamics of epithelial lineage development. These epithelial lineage trajectories were further identified in human pluripotent stem cell-based models of lung cell differentiation.