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

Yanjie Wang,Zan Tang,Huanwei Huang,Jiao Li,Zheng Wang,Yuanyuan Yu,Chengwei Zhang,Juan Li,H. Dai,Fengchao Wang,T. Cai,Nan Tang

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

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. Pulmonary alveolar type I (AT1) cells cover more than 95% of alveolar surface and are essential for the air–blood barrier function of lungs. AT1 cells have been shown to retain developmental plasticity during alveolar regeneration. However, the development and heterogeneity of AT1 cells remain largely unknown. Here, we conducted a single-cell RNA-seq analysis to characterize postnatal AT1 cell development and identified insulin-like growth factor-binding protein 2 (Igfbp2) as a genetic marker specifically expressed in postnatal AT1 cells. The portion of AT1 cells expressing Igfbp2 increases during alveologenesis and in post pneumonectomy (PNX) newly formed alveoli. We found that the adult AT1 cell population contains both Hopx+Igfbp2+ and Hopx+Igfbp2− AT1 cells, which have distinct cell fates during alveolar regeneration. Using an Igfbp2-CreER mouse model, we demonstrate that Hopx+Igfbp2+ AT1 cells represent terminally differentiated AT1 cells that are not able to transdifferentiate into AT2 cells during post-PNX alveolar regeneration. Our study provides tools and insights that will guide future investigations into the molecular and cellular mechanism or mechanisms underlying AT1 cell fate during lung development and regeneration.

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