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Airway-derived p63+ facultative progenitors contribute to alveolar regeneration after lung injury.

ABSTRACT: Lung injury activates potential stem cells or progenitors for alveolar repair and regeneration. However, the activation program and source of injury-induced facultative progenitors remain incompletely known. Here, we find that lung injury induces emergence of p63-expressing progenitors, which rapidly proliferate and differentiate into alveolar type-1 (AT1) and type-2 (AT2) cells. scRNA-seq analysis uncovers that a subset of p63+ progenitors exhibit two distinct parallele transient stages before differentiation into mature AT1 and AT2 cells, respectively. Dual recombinases-mediated sequential genetic tracing reveals that facultative p63+ progenitors originate from the distal airway secretory cells and subsequently regenerate alveoli. Functioanlly, secretory cell-specific knockout of p63 significantly impairs their contribution to alveolar epithelium during lung regeneration. Our study identified secretory cell-derived facultative p63+ progenitors that contribute to alveolar regeneration, indicating a potential therapeutic target for lung treatment after injuires.

ORGANISM(S): Mus musculus

PROVIDER: GSE225187 | GEO | 2023/02/20

REPOSITORIES: GEO

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Project description:Alveoli are thin-walled sacs that serve as the gas exchange units of the lung. They are affected in devastating lung diseases including COPD, Idiopathic Pulmonary Fibrosis, and the major form (adenocarcinoma) of lung cancer, the leading cause of cancer deaths. The alveolar epithelium is composed of two morphologically distinct cell types: alveolar type (AT) 1 cells, exquisitely thin cells across which oxygen diffuses to reach the blood, and AT2 cells, specialized surfactant-secreting cells. Classical studies suggested that AT1 cells arise from AT2 cells during development and following injury, but more recent studies suggest other sources. Here we use histological and marker analysis, lineage tracing, and clonal analysis in mice to identify alveolar progenitor and stem cells and map their locations and potential in vivo. The results show that AT1 and AT2 cells arise independently during development from a bipotential progenitor. After birth, new AT1 cells derive from rare, long-lived, self-renewing AT2 cells, each producing a slowly expanding clonal focus of regenerated alveoli contiguous with the founder AT2 cell. This stem cell function of AT2 cells is broadly activated by diffuse AT1 cell injury, and AT2 self-renewal can be induced in vitro by EGF ligands and permanently activated in vivo by AT2 cell-specific targeting of the oncogenic KrasG12D allele, efficiently transforming AT2 cells into monoclonal adenomatous tumors that rapidly enlarge and prove fatal. Thus, there is a developmental switch in alveolar progenitor cells after birth, when mature AT2 cells function as facultative stem cells that contribute to local alveolar renewal, repair, and cancer. We propose that short-range signals from dying AT1 cells regulate AT2 stem cell activity: a signal transduced by EGFR-KRAS controls AT2 self-renewal and is hijacked during oncogenic transformation, and a separate signal controls reprogramming to AT1 cell fate. To compare expression between ATII and E18 BP populations, RNA was isolated from either population purified by FACS. Two populations are analyzed with 3 biological replicates per population.

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Airway-derived p63+ facultative progenitors contribute to alveolar regeneration after lung injury.

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