Abnormal respiratory progenitors in fibrotic lung injury

Recent advances in single-cell RNA sequencing (scRNA-seq) and epithelium lineage labeling have yielded identification of multiple abnormal epithelial progenitor populations during alveolar type 2 (ATII) cell differentiation into alveolar type 1 (ATI) cells during regenerative lung post-fibrotic injury. These abnormal cells include basaloid/basal-like cells, ATII transition cells, and persistent epithelial progenitors (PEPs). These cells occurred and accumulated during the regeneration of distal airway and alveoli in response to both chronic and acute pulmonary injury. Among the alveolar epithelial progenitors, PEPs express a distinct Krt8⁺ phenotype that is rarely found in intact alveoli. However, post-injury, the Krt8⁺ phenotype is seen in dysplastic epithelial cells. Fully understanding the characteristics and functions of these newly found, injury-induced abnormal behavioral epithelial progenitors and the signaling pathways regulating their phenotype could potentially point the way to unique therapeutic targets for fibrosing lung diseases. This review summarizes recent advances in understanding these epithelial progenitors as they relate to uncovering regenerative mechanisms.