Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice

Pulmonary premature ageing and fibrogenesis as in idiopathic pulmonary fibrosis (IPF) occur with the DNA damage response in lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that naturally occurring agei...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Kexiong Zhang, Lihui Wang, Xiaojing Hong, Hao Chen, Yao Shi, Yingying Liu, Jun Liu, Jun-Ping Liu
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	telomerase RNA component telomere shortening lung alveolar type 2 cells senescence apoptosis differentiation Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3e301ecbf0ea4147a29a613f97fe8786
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:3e301ecbf0ea4147a29a613f97fe8786
record_format	dspace
spelling	oai:doaj.org-article:3e301ecbf0ea4147a29a613f97fe87862021-11-25T17:08:34ZPulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice10.3390/cells101128922073-4409https://doaj.org/article/3e301ecbf0ea4147a29a613f97fe87862021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2892https://doaj.org/toc/2073-4409Pulmonary premature ageing and fibrogenesis as in idiopathic pulmonary fibrosis (IPF) occur with the DNA damage response in lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that naturally occurring ageing is associated with the DNA damage response (DDR) and activation of the p53 signalling pathway. Telomerase deficiency induced by telomerase RNA component (TERC) knockout (KO) accelerates not only replicative senescence but also altered differentiation and apoptosis of the pulmonary alveolar stem cells (AEC2) in association with increased innate immune natural killer (NK) cells in <i>TERC</i> KO mice. <i>TERC</i> KO results in increased senescence-associated heterochromatin foci (SAHF) marker HP1γ, p21, p16, and apoptosis-associated cleaved caspase-3 in AEC2. However, additional deficiency of the tumour suppressor p53 in the <i>Trp53</i><sup>−/−</sup> allele of the late generation of <i>TERC</i> KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of <i>T1α</i> (a marker of terminal differentiated AEC1) in AEC2 of the late generation of <i>TERC</i> KO mice. These findings demonstrate that, in natural ageing or premature ageing accelerated by telomere shortening, pulmonary senescence and IPF develop with alveolar stem cell p53-dependent premature replicative senescence, apoptosis, and p53-independent differentiation, resulting in pulmonary senescence-associated low-grade inflammation (SALI). Our studies indicate a natural ageing-associated molecular mechanism of telomerase deficiency-induced telomere DDR and SALI in pulmonary ageing and IPF.Kexiong ZhangLihui WangXiaojing HongHao ChenYao ShiYingying LiuJun LiuJun-Ping LiuMDPI AGarticletelomerase RNA componenttelomere shorteninglung alveolar type 2 cellssenescenceapoptosisdifferentiationBiology (General)QH301-705.5ENCells, Vol 10, Iss 2892, p 2892 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	telomerase RNA component telomere shortening lung alveolar type 2 cells senescence apoptosis differentiation Biology (General) QH301-705.5
spellingShingle	telomerase RNA component telomere shortening lung alveolar type 2 cells senescence apoptosis differentiation Biology (General) QH301-705.5 Kexiong Zhang Lihui Wang Xiaojing Hong Hao Chen Yao Shi Yingying Liu Jun Liu Jun-Ping Liu Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice
description	Pulmonary premature ageing and fibrogenesis as in idiopathic pulmonary fibrosis (IPF) occur with the DNA damage response in lungs deficient of telomerase. The molecular mechanism mediating pulmonary alveolar cell fates remains to be investigated. The present study shows that naturally occurring ageing is associated with the DNA damage response (DDR) and activation of the p53 signalling pathway. Telomerase deficiency induced by telomerase RNA component (TERC) knockout (KO) accelerates not only replicative senescence but also altered differentiation and apoptosis of the pulmonary alveolar stem cells (AEC2) in association with increased innate immune natural killer (NK) cells in <i>TERC</i> KO mice. <i>TERC</i> KO results in increased senescence-associated heterochromatin foci (SAHF) marker HP1γ, p21, p16, and apoptosis-associated cleaved caspase-3 in AEC2. However, additional deficiency of the tumour suppressor p53 in the <i>Trp53</i><sup>−/−</sup> allele of the late generation of <i>TERC</i> KO mice attenuates the increased senescent and apoptotic markers significantly. Moreover, p53 deficiency has no significant effect on the increased gene expression of <i>T1α</i> (a marker of terminal differentiated AEC1) in AEC2 of the late generation of <i>TERC</i> KO mice. These findings demonstrate that, in natural ageing or premature ageing accelerated by telomere shortening, pulmonary senescence and IPF develop with alveolar stem cell p53-dependent premature replicative senescence, apoptosis, and p53-independent differentiation, resulting in pulmonary senescence-associated low-grade inflammation (SALI). Our studies indicate a natural ageing-associated molecular mechanism of telomerase deficiency-induced telomere DDR and SALI in pulmonary ageing and IPF.
format	article
author	Kexiong Zhang Lihui Wang Xiaojing Hong Hao Chen Yao Shi Yingying Liu Jun Liu Jun-Ping Liu
author_facet	Kexiong Zhang Lihui Wang Xiaojing Hong Hao Chen Yao Shi Yingying Liu Jun Liu Jun-Ping Liu
author_sort	Kexiong Zhang
title	Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice
title_short	Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice
title_full	Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice
title_fullStr	Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice
title_full_unstemmed	Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice
title_sort	pulmonary alveolar stem cell senescence, apoptosis, and differentiation by p53-dependent and -independent mechanisms in telomerase-deficient mice
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3e301ecbf0ea4147a29a613f97fe8786
work_keys_str_mv	AT kexiongzhang pulmonaryalveolarstemcellsenescenceapoptosisanddifferentiationbyp53dependentandindependentmechanismsintelomerasedeficientmice AT lihuiwang pulmonaryalveolarstemcellsenescenceapoptosisanddifferentiationbyp53dependentandindependentmechanismsintelomerasedeficientmice AT xiaojinghong pulmonaryalveolarstemcellsenescenceapoptosisanddifferentiationbyp53dependentandindependentmechanismsintelomerasedeficientmice AT haochen pulmonaryalveolarstemcellsenescenceapoptosisanddifferentiationbyp53dependentandindependentmechanismsintelomerasedeficientmice AT yaoshi pulmonaryalveolarstemcellsenescenceapoptosisanddifferentiationbyp53dependentandindependentmechanismsintelomerasedeficientmice AT yingyingliu pulmonaryalveolarstemcellsenescenceapoptosisanddifferentiationbyp53dependentandindependentmechanismsintelomerasedeficientmice AT junliu pulmonaryalveolarstemcellsenescenceapoptosisanddifferentiationbyp53dependentandindependentmechanismsintelomerasedeficientmice AT junpingliu pulmonaryalveolarstemcellsenescenceapoptosisanddifferentiationbyp53dependentandindependentmechanismsintelomerasedeficientmice
_version_	1718412642541895680

Pulmonary Alveolar Stem Cell Senescence, Apoptosis, and Differentiation by p53-Dependent and -Independent Mechanisms in Telomerase-Deficient Mice

Ejemplares similares