Unlocking Alveolar Regeneration: AT2 Stem Cells, Signaling Networks, and Therapeutic Frontiers

This review elucidates the pivotal role of alveolar type II epithelial cells (AT2) as key adult stem cells in lung homeostasis maintenance and post-injury repair, with molecular regulatory mechanisms. We synthesize current knowledge on AT2 self-renewal and differentiation into alveolar type I epithelial cells (AT1), and how their dysfunction drives refractory lung diseases such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. By evaluating findings from lineage tracing, single-cell transcriptomics, and three-dimensional organoid culture, this article outlines the cellular atlas of alveolar regeneration. This atlas encompasses not only AT2 cells and alveolar epithelial progenitors, but also auxiliary progenitor sources such as bronchioalveolar stem cells and lineage-negative epithelial progenitors. Notably, the review highlights the transitional plasticity stage—alveolar differentiation intermediate states—during AT2-to-AT1 differentiation. Mechanistically, the review delves into the intricate signaling networks governing AT2 cell fate, including key pathways such as Wnt/β-catenin, Hippo-YAP, Notch, and BMP. Crucially, it emphasizes that AT2 cell regenerative capacity relies on a multilayered quality control system involving epigenetic regulation, metabolic reprogramming, organelle homeostasis, and telomere maintenance. Furthermore, mesenchymal and immune cells within the alveolar stem cell niche engage in precise paracrine crosstalk with AT2 cells to collectively orchestrate regeneration. Finally, this review bridges fundamental biological discoveries with clinical prospects, illustrating how AT2 cells may serve as biomarkers for disease diagnosis, vehicles for gene-targeted therapy, and sources for cell replacement therapy. It outlooks novel treatments by modulating AT2 stem cell function—including small-molecule drugs, gene-editing nanoplatforms, and stem cell transplantation—heralding a transformative era in pulmonary regenerative medicine.