Ageing-associated regenerative failure in the lung: stem cell senescence and transitional cell persistence in...

Alveolar regeneration failure due to alveolar stem cell senescence is a defining feature of idiopathic pulmonary fibrosis (IPF), yet the epithelial mechanisms underlying this dysfunction remain incompletely understood. Recent single-cell and lineage-tracing studies have identified distinct transitional epithelial states, such as pre-alveolar type-1 transitional cells, damage-associated transient progenitors, and alveolar-basal intermediates, which normally serve as intermediates during type 2 alveolar cell (AT2) to type 1 alveolar cell (AT1) differentiation. While these states are transient and successfully resolved during acute lung injury, these populations persist abnormally in IPF lungs, exhibiting features of senescence, cell-cycle arrest, and impaired differentiation.We review recent evidence showing how premature alveolar epithelial senescence, suppression of developmental regenerative programmes, and sustained transforming growth factor-β signalling within the fibrotic niche contribute to this disruption. These factors promote the accumulation of dysfunctional transitional cells, such as cytokeratin (KRT)8⁺/KRT17⁺ basaloid cells, which fail to regenerate alveolar epithelium and instead contribute to fibrosis and bronchiolisation through pathological crosstalk with macrophages and fibroblasts. Notably, similar transitional states appear in COVID-19-associated acute respiratory distress syndrome, but they typically exhibit minimal features of senescence and resolve during regeneration, underscoring the pathological importance of accelerated epithelial senescence in IPF.Understanding the molecular checkpoints that regulate transitional cell fate may offer novel strategies to restore regenerative capacity in fibrosing lung diseases.