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Liver aging and pseudocapillarization in a Werner syndrome mouse model.

ABSTRACT: Werner syndrome is a progeric syndrome characterized by premature atherosclerosis, diabetes, cancer, and death in humans. The knockout mouse model created by deletion of the RecQ helicase domain of the mouse Wrn homologue gene (Wrn(?hel/?hel)) is of great interest because it develops atherosclerosis and hypertriglyceridemia, conditions associated with aging liver and sinusoidal changes. Here, we show that Wrn(?hel/?hel) mice exhibit increased extracellular matrix, defenestration, decreased fenestration diameter, and changes in markers of liver sinusoidal endothelial cell inflammation, consistent with age-related pseudocapilliarization. In addition, hepatocytes are larger, have increased lipofuscin deposition, more frequent nuclear morphological anomalies, decreased mitochondria number, and increased mitochondrial diameter compared to wild-type mice. The Wrn(?hel/?hel) mice also have altered mitochondrial function and altered nuclei. Microarray data revealed that the Wrn(?hel/?hel) genotype does not affect the expression of many genes within the isolated hepatocytes or liver sinusoidal endothelial cells. This study reveals that Wrn(?hel/?hel) mice have accelerated typical age-related liver changes including pseudocapillarization. This confirms that pseudocapillarization of the liver sinusoid is a consistent feature of various aging models. Moreover, it implies that DNA repair may be implicated in normal aging changes in the liver.

SUBMITTER: Cogger VC

PROVIDER: S-EPMC4158411 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Liver aging and pseudocapillarization in a Werner syndrome mouse model.

Cogger Victoria C VC Svistounov Dmitri D Warren Alessandra A Zykova Svetlana S Melvin Richard G RG Solon-Biet Samantha M SM O'Reilly Jennifer N JN McMahon Aisling C AC Ballard J William O JW De Cabo Rafa R De Cabo Rafa R Le Couteur David G DG Lebel Michel M

The journals of gerontology. Series A, Biological sciences and medical sciences 20131022 9

Werner syndrome is a progeric syndrome characterized by premature atherosclerosis, diabetes, cancer, and death in humans. The knockout mouse model created by deletion of the RecQ helicase domain of the mouse Wrn homologue gene (Wrn(∆hel/∆hel)) is of great interest because it develops atherosclerosis and hypertriglyceridemia, conditions associated with aging liver and sinusoidal changes. Here, we show that Wrn(∆hel/∆hel) mice exhibit increased extracellular matrix, defenestration, decreased fenes ...[more]

PMID: 24149428

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Project description:Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication, and/or DNA repair. The poly(ADP-ribose) polymerase-1 (PARP-1) enzyme is also involved in DNA repair and is known to affect transcription of several genes. In this study, we examined the expression profile of cells lacking the normal function of either or both enzymes. All mutant cells exhibited altered expression of genes normally responding to oxidative stress. Interestingly, more than 58% of misregulated genes identified in double mutant cells were not altered in cells with either the Wrn or PARP-1 mutation alone. Consequently, the impact on gene expression profile when both Wrn and PARP-1 are mutated was greater than a simple addition of individual mutant genotype. In addition, double mutant cultured cells showed major misregulation of genes involved in apoptosis, cell cycle control, embryonic development, metabolism, and signal transduction. More importantly, in vivo analyses of double mutant mice have confirmed the increased apoptosis and the developmental defects in embryos as well as the major increase in intracellular phosphorylation and oxidative DNA damage in adult tissues. They also exhibited a progressive increase in oxidative stress with age. Thus, a major result of this study is that changes in expression of several genes and physiological functions identified in vitro were confirmed in mouse embryonic and adult tissues. Experiment Overall Design: Microarray analyses were performed on cell cultures at the second passage (10 population doublings). For each genotype, asynchronously dividing cells derived from three healthy 15.5 day embryos from one litter were pooled at the second passage and cytoplasmic RNA was extracted. Cytoplasmic RNA was used in these experiments to avoid contamination with heterogeneous nuclear RNA and genomic DNA. (Note that DNAse treatment was also applied to all samples). This pool of RNA was labeled sample number 1 for each genotype. Pooling of embryonic cells was performed to minimize the effect of inter-individual biological differences. A second pool of embryonic cells was also created from a separate dam (second litter) for each genotype (called samples number 2). This strategy allowed obtaining samples in duplicate for each genotype. The cRNA from wild type cells were synthesized with Cy-5 labeled nucleotides and cRNAs from Wrn mutant, PARP-1 null, and PARP-1 null/Wrn mutant cells were synthesized with Cy-3 labeled nucleotides. Hybridization was performed on Mouse Agilent 60-mer Oligo Microarray chips by mixing wild type labeled cRNA (baseline expression levels) with either Wrn mutant, PARP-1 null, or PARP-1 null/Wrn mutant cRNA. Hybridization experiments were done in duplicates.

Dataset Information

Liver aging and pseudocapillarization in a Werner syndrome mouse model.

Publications

Liver aging and pseudocapillarization in a Werner syndrome mouse model.

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