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P53 is a critical regulator of airway epithelial progenitor cell homeostasis.

ABSTRACT: How progenitor cells regulate quiescence and differentiation is poorly understood. Here, we demonstrate that the tumor suppressor p53 regulates both proliferation and differentiation of club progenitor cells in the airway epithelium. We show that p53 loss decreases ciliated cell differentiation and increases the proliferative capacity of club progenitors, increasing epithelial cell density. p53 deficient progenitors generated a pseudostratified epithelium containing basal-like cells in vitro and contained an increased proportion of BASCs in vivo, suggesting that p53 suppresses multipotency during homeostasis. Conversely, an additional copy of p53 decreases proliferation and increases ciliated cell differentiation. Using single cell RNA-Seq, we expose heterogeneity within airway epithelial progenitor cells and found that cell cycle regulators, particularly p21, are altered following p53 loss. Together, these findings reveal an essential role for p53 in regulating progenitor cell behavior, which has broad implications in understanding both stem cell and cancer biology

ORGANISM(S): Mus musculus

PROVIDER: GSE78045 | GEO | 2016/11/22

SECONDARY ACCESSION(S): PRJNA312408

REPOSITORIES: GEO

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Project description:Background. The human airway epithelium consists of 4 major cell types: ciliated, secretory, columnar and basal cells. During natural turnover and in response to injury, the airway basal cells function as stem / progenitor cells for the other airway cell types. The objective of this study is to better understand basal cell biology by defining the subset of expressed genes that characterize the signature of human airway epithelial basal cells. Methodology / Principal Findings. Microarrays were used to assess the transcriptome of basal cells purified from the airway epithelium of healthy nonsmokers obtained by bronchial brushings in comparison to the transcriptome of the complete differentiated airway epithelium. This analysis identified the “human airway basal cell signature” as 1,161 unique genes with >5-fold higher expression level in basal cells compared to the differentiated epithelium. The basal cell signature was suppressed when the basal cells differentiated into a ciliated airway epithelium in vitro. The human airway basal cell signature displayed extensive overlap with genes expressed in basal cells from other human tissues and murine airway basal cells. Consistent with self-modulation as well as signaling to other airway cell types, the airway basal cell signature was characterized by genes encoding extracellular matrix components, and growth factors and growth factor receptors, including genes related to EGFR and VEGFR signaling. However, while human airway basal cells share similarity with basal-like cells of other organs, the human airway basal cell signature has features not previously associated with this cell type, including a unique pattern of genes encoding extracellular matrix components, integrins, G protein-coupled receptors, neuroactive ligands and receptors, and ion channels. Conclusion / Significance. The human airway epithelial basal cells signature identified in the present study provides novel insights into the ontogeny, molecular phenotype and biology of the stem / progenitor cells of the human airway epithelium. This study was designed to distinguish the transcriptome of the airway epithelium basal cell from that of differentiated airway epithelium. A basal cell signature was derived and analyzed for functional significance. The signature was also evaluated as basal cells differentiated into ciliated epithelium in vitro.

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P53 is a critical regulator of airway epithelial progenitor cell homeostasis.

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