The role of epithelial Pten in programmed cellular senescence during lung development

Abstract

Introduction: Cellular senescence (CS) is a crucial anticancer mechanism that is defined by irreversible cell-cycle arrest and senescence-associated secretory phenotype (SASP). CS also participates in tissue remodeling during normal embryonic development (i.e., programmed CS): however, the roles of programmed CS in lung development and their intrinsic regulator(s) remain unknown. Aims: To determine the role of epithelial Pten, a tumor suppressor, in programmed CS and cell-fate decision during lung development. Methods: We conducted structural and biochemical analyses of two different types of lung epithelium-specific Pten-deleted mice (ShhGFPCre/PtenΔ/Δ mice and SPC-rtTA/(tetO)7Cre/PtenΔ/Δ; SOPtenΔ/Δ mice). Further mechanistic studies were performed in vitro and in vivo. Results: Both ShhGFPCre/PtenΔ/Δ and SOPtenΔ/Δ mice showed impaired development of mature alveoli. A microarray study identified attenuated expressions of alveolar type 2 markers whereas detected increased expressions of markers of neuroendocrine cells, Club cells, goblet cells, and alveolar type 1 in lung epithelial cells isolated from SOPtenΔ/Δ mice. Deletion of Pten in lung epithelium enhances NF-κB–Notch signaling pathway. Pten deficiency led to cell growth arrest of lung epithelial cells, increased number of senescent cells, and enhanced SASP at E18.5. Epithelial Pten ablation upregulated p53–p21 pathway and impaired bipolar spindle formation in vivo and in vitro. Conclusions: Our results demonstrate that epithelial Pten has an essential role in controlling programmed CS and cell-fate choices during lung development by regulating NF-κB–Notch pathway, p53–p21 pathway, and proper architectural integrity of the mitotic spindle.