Lyz1-Expressing Alveolar Type II Cells Contribute to Lung Regeneration

Abstract

The alveolar units, composed of alveolar epithelial type II cells (AT2) and type I cells (AT1), are essential for efficient gas exchange. While AT2 cells are known to play critical roles in alveolar homeostasis and regeneration, the contribution of heterogeneous AT2 cells to lung repair remains poorly understood. Here, we identified a distinct AT2 subpopulation that exclusively expressed Lysozyme 1 (Lyz1) through single-cell RNA sequencing (scRNA-seq) analyses. Cell fate mapping revealed that the Lyz1^CreERT2 mouse strain specifically labeled Lyz1-expressing AT2 cells in vivo at homeostasis. Following lung injury, Lyz1⁺ AT2 cells expanded and contributed to alveolar regeneration by generating both self-renewing AT2 cells and differentiating AT1 cells. We further observed the emergence of de novo Lyz1-expressing cells in the airways after lung injury. Additionally, Lyz1⁺ AT2 cells displayed significantly enhanced proliferative capacity compared with general bulk AT2 cells in 3D organoid cultures. These findings define Lyz1⁺ AT2 cells as a previously unrecognized progenitor population, expanding the paradigm of alveolar regeneration and providing insight into how epithelial diversity supports lung regeneration.

Keywords

Lyz1 / AT2 subpopulation / Lung regeneration / scRNA-seq

Acknowledgement

We thank the colleagues in the Que Laboratory for their thoughtful discussion.

Author Contributions

Y.F. and J.Q. designed experiments, analyzed data and wrote the manuscript. Y.F. performed mouse genetics, mouse lung injury, histology and immunostaining. K.L. performed immunostaining and organoid culture. B.D. performed histology and immunostaining. N.G. and J.S. provided materials.

Ethics Statement

All mouse experiments and care were conducted in accordance with the procedures approved by the Institutional Animal Care and Use Committee at Columbia University (protocol number: AABM6565 and Date of IACUC approval: 14 May 2025).

Informed Consent Statement

Not applicable.

Data Availability Statement

The scRNA-seq datasets (GSE171571, GSE132910, GSE138585 and GSE202226) were publicly available in NCBI Gene Expression Omnibus (GEO).

Funding

This work is partly supported by NIH grants R01HL179522, R01HL177649, R01HL152293, R01HL159675 (to J.Q.). Flow cytometry was performed at the Columbia Center for Translational Immunology (CCTI) Flow Cytometry Core at Columbia University Medical Center, supported in part by the Office of the Director, National Institutes of Health under the awards S10RR027050 and S10OD020056. The CCHD microscopy core is supported by S10OD032447 from NIH. This research was also funded in part through the NIH/NCI Cancer Center Support Grant P30CA013696.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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