Dataset Information

Regulation of lung progenitor plasticity and repair by fatty acid oxidation

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes significantly diminishes in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1, and SCGB3A2. Further, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283885 | GEO | 2025/02/25

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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.

Dataset Information

Regulation of lung progenitor plasticity and repair by fatty acid oxidation

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets