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Intersectional genetic tracing reveals the origin of alveolar stem cells during lung repair and regeneration

ABSTRACT: Alveolar type 2 (AT2) cells are stem cells of the alveolar epithelia. Previous genetic lineage tracing studies reported multiple cellular origins for AT2 cells after injury. However, conventional lineage tracing based on Cre-loxP has the limitation of non-specific labeling. Thus, the exact contribution of various epithelial cells to the pools of AT2 cells under different conditions remains unclear. Here, we used dual recombinases-mediated intersectional genetic lineage tracing to investigate the cellular origins of AT2 cells during lung homeostasis, injury and repair. In contrast to previous studies, we found AT1 cells were terminally differentiated cells and did not contribute to AT2 cells after lung injury and repair. Distinctive, but simultaneous, labeling of club cells, bronchioalveolar stem cells (BASCs), and AT2 cells revealed the exact contribution of each to AT2 cells after lung injury. Moreover, we found that club cells have the potential to rebuild virtually all alveoli in some severely injured lung regions. Mechanistically, Notch signaling promotes a BASCs-to-AT2 cell transition, but it inhibits club cell-to-AT2 cell conversion during lung repair. This intersectional genetic lineage tracing strategy with enhanced precision allowed us to elucidate the physiological role of AT1, club, BASCs, and AT2 cells to alveolar regeneration after injury.

ORGANISM(S): Mus musculus

PROVIDER: GSE252588 | GEO | 2024/01/06

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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Intersectional genetic tracing reveals the origin of alveolar stem cells during lung repair and regeneration

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