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Bulk RNA-sequencing of normal and Gls1 KO alveolar epithelial cells in mouse

ABSTRACT: Impaired alveolar regeneration underlies numerous chronic lung diseases, yet the metabolic determinants governing this process remain poorly understood. Effective alveolar repair depends on the differentiation of type 2 alveolar epithelial cells (AT2), the resident lung stem/progenitor cells, into type 1 alveolar epithelial cells (AT1) to restore gas exchange surfaces. Here, we reveal that glutaminolysis mediated by glutaminase 1 (GLS1) orchestrates a metabolic checkpoint essential for AT2 stem/progenitor cell differentiation. Using primary AT2 cells, alveolar organoids, and lineage-tracing mouse models, we demonstrate that GLS1 expression is upregulated during AT2-to-AT1 differentiation and is essential for this process. The differentiation program is accompanied by metabolic reprogramming characterized by increased glycolysis and enhanced glutamine flux into the TCA cycle. AT2-specific GLS1 deletion severely impairs differentiation both in vitro and in vivo, leading to defective alveolar repair and exacerbated pulmonary fibrosis following bleomycin injury. Mechanistically, GLS1 deletion triggers excessive autophagy and subsequent degradation of the Hippo pathway effectors YAP and TAZ, key transcriptional regulators governing progenitor cell fate decisions. Pharmacological inhibition of autophagy with chloroquine restores YAP/TAZ protein levels, rescues AT2-to-AT1 differentiation, and attenuates fibrosis while improving lung function. Consistent with our experimental findings, AT2 cells from patients with idiopathic pulmonary fibrosis exhibit reduced GLS expression, suggesting clinical relevance. These findings establish a previously unrecognized regulatory axis linking glutamine metabolism to alveolar stem/progenitor cell fate decisions and identify autophagy modulation as a potential therapeutic strategy for enhancing lung regeneration in fibrotic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE310645 | GEO | 2026/09/28

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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Bulk RNA-sequencing of normal and Gls1 KO alveolar epithelial cells in mouse

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