Pulmonary alveolar stem cells undergo senescence, apoptosis and differentiation by p53‐dependent and ‐independent mechanisms in telomerase deficient mice. (25th February 2021)

• Record Type: Journal Article
• Authors: Zhang, Kexiong; Wang, Lihui; Chen, Hao; Shi, Yao; Liu, Yingying; Liu, Jun; Hong, Xiaojing; Liu, Jun‐Ping
• Is Part Of: Clinical and experimental pharmacology and physiology. Volume 48:Number 5(2021)
• Page Start: 651
• Page End: 659
• Publication Date: 2021-02-25
• Subjects: apoptosis -- differentiation -- lung alveolar type 2 cells -- p53 -- senescence -- telomerase RNA component -- telomere shortening; Clinical pharmacology -- Periodicals; Pharmacology, Experimental -- Periodicals; Physiology, Experimental -- Periodicals; Physiology, Pathological -- Periodicals; 615.1
• DOI: 10.1111/1440-1681.13472
• Languages: English
• ISSNs: 0305-1870

Abstract

Abstract: Pulmonary senescence and fibrosis occur with deoxyribonucleic acid (DNA) damage response in the lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that pulmonary alveolar epithelial type 2 cells (AEC2) (alveolar stem cells) undergo not only replicative senescence, but also apoptosis and differentiation in association with increased innate immune natural killer (NK) cells in telomerase knockout (KO) mice. Telomerase ribonucleic acid (RNA) component (TERC) deficiency results in increased senescence‐associated heterochromatin foci marker HP1γ, p21, p16 and apoptosis‐associated cleaved caspase‐3 in AEC2. However, p53 deficiency in the Trp53 −/− allele of the late generation of TERC KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of T1α (a marker of terminal differentiated alveolar epithelial type 1 cells [AEC1]) in AEC2 of the late generation of TERC KO mice. Collectively, our findings suggest that pulmonary senescence takes place in deficiency of telomerase RNA component with the alveolar stem cells undergoing p53‐dependent senescence and apoptosis as well as p53‐independent differentiation. Abstract : This study shows that pulmonary alveolar stem cells (AEC2) undergo either differentiation to AEC1, replicative senescence, or apoptosis in association with increased innate immune natural killer (NK) cells in telomerase knockout mice. With short telomeres in the late‐generation of TERC KO mice, p53 deficiency in the Trp53 −/− allele attenuates telomerase‐deficiency‐induced increases in AEC2 senescence and apoptosis, without significant effect on AEC2 differentiation to AEC1. These results indicate a p53‐dependent and independent mechanism in switching AEC2 cell fates from differentiation to replicative senescence and apoptosis when telomeres become shortened in the lung tissue stem cells of mice.