title: p53 Regulates Progenitor Cell Quiescence and Differentiation in the Airway.
abstract: Mechanisms that regulate progenitor cell quiescence and differentiation in slowly replacing tissues are not fully understood. Here, we demonstrate that the tumor suppressor p53 regulates both proliferation and differentiation of progenitors in the airway epithelium. p53 loss decreased ciliated cell differentiation and increased the self-renewal and proliferative capacity of club progenitors, increasing epithelial cell density. p53-deficient progenitors generated a pseudostratified epithelium containing basal-like cells in vitro and putative bronchioalveolar stem cells in vivo. Conversely, an additional copy of p53 increased quiescence and ciliated cell differentiation, highlighting the importance of tight regulation of p53 levels. Using single-cell RNA sequencing, we found that loss of p53 altered the molecular phenotype of progenitors and differentially modulated cell-cycle regulatory genes. Together, these findings reveal that p53 is an essential regulator of progenitor cell behavior, which shapes our understanding of stem cell quiescence during homeostasis and in cancer development.
authors.affiliation: Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27708, USA.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: McConnell
authors.affiliation: Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Changfu
authors.initials: C
authors.lastname: Yao
authors.affiliation: Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Alyson R
authors.initials: AR
authors.lastname: Yeckes
authors.affiliation: Genomics Core, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Yizhou
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Anna S
authors.initials: AS
authors.lastname: Selvaggio
authors.affiliation: Genomics Core, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.affiliation: Departments of Radiation Oncology and Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27708, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Lung and Regenerative Medicine Institutes, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC 27708, USA. Electronic address: barry.stripp@cshs.org.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Stripp
mesh_terms: D000818:Animals; D002452:Cell Count; D002453:Cell Cycle; D016923:Cell Death; D002454:Cell Differentiation; D049109:Cell Proliferation; D002999:Clone Cells; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D051379:Mice; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53
keywords: Trp53; airway epithelium; lung; progenitor cell; stem cell; tumor suppressor