ORIGINAL RESEARCH article
Front. Med.
Sec. Pulmonary Medicine
Volume 12 - 2025 | doi: 10.3389/fmed.2025.1649108
Molecular signatures of alveolar type ii cell differentiation in acute respiratory distress syndrome
Provisionally accepted
- Fifth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
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Background Acute respiratory distress syndrome (ARDS) is a life-threatening lung condition with high morbidity and mortality. Methods We analyzed publicly available single-cell transcriptomic and microarray datasets from murine ARDS models to characterize AT2 cell differentiation trajectories following lipopolysaccharide (LPS)-induced injury. Computational mapping of cell "trajectories" identified distinct gene expression signatures associated with divergent repair outcomes. These findings were validated in bronchoalveolar lavage fluid (BALF) samples from ARDS patients and in an LPS-induced AT2-fibroblast co-culture model. Gene expression changes were examined at both the RNA and protein levels, and pathway enrichment analysis was used to explore underlying mechanisms. Results Trajectory analysis revealed two major differentiation branches of AT2 cells: one enriched for fibrotic programs (Igfbp6, Gstm1, Mgp, Lgals1) and the other linked to epithelial repair (Tgm2, Anxa1, Ankrd1, F3). Both branches exhibited distinct gene expression patterns in patient BALF, consistent with scRNA-seq findings. Functional enrichment highlighted the Wnt signaling pathway as a key regulator in the injury group, which was validated at protein levels in vitro. Co-culture models showed that prolonged LPS exposure induced AT2 cell apoptosis, fibroblast activation, and extracellular matrix protein upregulation. Conclusion This study highlights the important role of AT2 cell differentiation in shaping disease progression in ARDS and identifies potential molecular markers and signaling pathways involved in divergent repair outcomes. Our findings provide new insight into AT2 cell–driven lung repair and potential therapeutic targets.
Keywords: Acute Respiratory Distress Syndrome, type II alveolar epithelial cells, Cell Differentiation, trajectory analysis, Marker genes
Received: 22 Jun 2025; Accepted: 01 Sep 2025.
Copyright: © 2025 Zhang, Wang, Wen, Wang and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Liping Wang, Fifth Affiliated Hospital of Xinjiang Medical University, Ürümqi, China
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