Pulmonary alveolar type I cell population consists of two distinct subtypes that differ in cell fate

TLDR

Pulmonary alveolar type I cells are essential for gas exchange and retain plasticity during injury‑induced regeneration, yet their developmental heterogeneity remains poorly understood. Using insulin‑like growth factor‑binding protein 2 as a robust marker, the study shows that postnatal AT1 cells comprise two subtypes—Hopx⁺Igfbp2⁺ and Hopx⁺Igfbp2⁻—with distinct regenerative fates. Most adult AT1 cells express Igfbp2 and cannot transdifferentiate into AT2 cells after pneumonectomy, indicating that Hopx⁺Igfbp2⁺ AT1 cells are terminally differentiated.

Abstract

Significance Pulmonary alveolar type I (AT1) cells are essential for the gas-exchange function of lungs. AT1 cells retain their cellular plasticity during injury-induced alveolar regeneration. However, we know very little about the developmental heterogeneity of the AT1 cell population. Our study identified a robust genetic marker of postnatal AT1 cells, insulin-like growth factor-binding protein 2 (Igfbp2). We use this marker to demonstrate that the postnatal AT1 cell population actually consists of two AT1 cell subtypes (Hopx + Igfbp2 + and Hopx + Igfbp2 − AT1 cells) with distinct cell fates during alveolar regeneration. The large majority of adult AT1 cells expresses Igfbp2 and cannot transdifferentiate into AT2 cells during post pneumonectomy formation of new alveoli. Therefore, Hopx + Igfbp2 + AT1 cells represent the terminally differentiated population of AT1 cells.