Abstract
Club cells are known to function as regional progenitor cells to repair the bronchiolar epithelium in response to lung damage. By lineage tracing in mice, we have shown recently that club cells also give rise to alveolar type 2 cells (AT2s) and alveolar type 1 cells (AT1s) during the repair of the damaged alveolar epithelium. Here, we show that when highly purified, anatomically and phenotypically confirmed club cells are seeded in 3-dimensional culture either in bulk or individually, they proliferate and differentiate into both AT2- and AT1-like cells and form alveolar-like structures. This differentiation was further confirmed by transcriptomic analysis of freshly isolated club cells and their cultured progeny. Freshly isolated club cells express Sca-1 and integrin α6, markers commonly used to characterize lung stem/progenitor cells. Together, current study for the first time isolated highly purified club cells for in vitro study and demonstrated club cells’ capacity to differentiate into alveolar epithelial cells at the single-cell level.
Highlights
The lung is a branching structure of trachea, bronchioles and alveoli, evolved for efficient gas exchange
By lineage tracing in secretoglobin family 1A member 1 (Scgb1a1)-CreER: ACTB-Tm-enhanced green fluorescent protein (EGFP) transgenic mice we have shown previously that club cells can give rise to alveolar type 2 cells (AT2s) and alveolar type 1 cells (AT1s) during the repair of severe lung damage following either influenza virus infection or bleomycin treatment[23]
We further show that club cell to AT2 and AT1 differentiation goes through a process involving an intermediate stage of pro-surfactant protein C (pro-SPC)+ bronchiolar epithelial cells
Summary
The lung is a branching structure of trachea, bronchioles and alveoli, evolved for efficient gas exchange. Lung progenitor cells quickly proliferate and differentiate to repair the damaged structures in order to maintain lung function. Among the reported lung stem/progenitor cell populations are CD31−CD45−CD34+Sca-1+ cells[18], CD45−CD31−EpCAMhiCD49f+CD104+CD24low cells[19], and integrin α6β4+ (or CD49fCD104+) cells[20], some of which express CD200 and CD14 and are suggested as lineage negative epithelial progenitor cells (LNEPs)[21] Despite these progresses, the relationship between stem/progenitor cells identified by lineage tracing and surface staining has yet to be delineated, so as the full differentiation potential of various cell types during the lung damage repair. Our quantitative and transcriptomic analyses provide further evidence for club cell to AT2 and AT1 cell differentiation
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