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Single-cell transcriptomics of mouse alveolar type 2 cells after bleomycin treatment

ABSTRACT: Aging-related impairment in alveolar regeneration has been identified in a variety of acute and chronic lung diseases. As the aging population increases, understanding the mechanisms involved in age-dependent deterioration in alveolar stem cell function can support the development of new therapies for lung diseases. In this study, we investigated the cellular and molecular mechanisms underlying AT2 cell differentiation and how aging affected post-injury alveolar regeneration. We discovered that the process of AT2 cells differentiating into AT1 cells is an energetically costly process. During the differentiation of AT2 cells, activated AMPK-PFKFB2 signaling up-regulates glycolysis, which is essential to enhance cellular ATP production and to support the intracellular energy expenditure that is required for cell shape change and cytoskeletal remodeling during AT2 cells differentiating into AT1 cells. AT2 cells in aging lungs show reduced AMPK-PFKFB2 signaling and decreased ATP production, resulting in impaired AT2 cell differentiation. Activating AMPK-PFKFB2 signaling in aged AT2 cells can rescue defects in alveolar regeneration. Thus, beyond demonstrating that the activation of AMPK-PFKFB2 signaling facilitates the great energy demands of AT2 cells during alveolar regeneration, our study suggests that modulating these pathways could promote the alveolar repair in aged lungs.

ORGANISM(S): Mus musculus

PROVIDER: GSE186246 | GEO | 2022/05/01

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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Single-cell transcriptomics of mouse alveolar type 2 cells after bleomycin treatment

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