Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome
Zeming WuWeiqi ZhangMoshi SongWei WangGang WeiWei LiJinghui LeiYu HuangYanmei SangPiu ChanChang ChenJing QuKeiichiro SuzukiJuan Carlos Izpisúa BelmonteGuang‐Hui Liu
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Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product—progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.Keywords:
Progeria
LMNA
Premature aging
Werner syndrome
Senescence
Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product—progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
Progeria
LMNA
Premature aging
Werner syndrome
Senescence
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Aging is a complex process that is not completely understood. The study of segmental
progeroid syndromes such as Hutchinson-Gilford progeria syndrome (HGPS) has allowed
us to connect the common genetic mechanisms that occur in normal physiological aging,
with the cellular alterations presented by this severe premature aging syndrome. Since the
identification of mutations in the lamin A/C coding LMNA gene that cause HGPS and
other laminopathies, there has been an increasing interest in the potential role of lamins in
the normal aging process. Progerin, a mutant form of lamin A, has attracted particular
great attention. LMNA mutations in HGPS activate a cryptic splice site, leading to an
aberrant splicing of lamin A, which results in a lamin AΔ150 transcript and progerin.
Recent research data, including the results presented in this thesis, provide support for the
possibility of a shared mechanism between natural physiological aging and pathological
aging occurring in HGPS. This shared mechanism could contribute to solving part of the
aging puzzle. The overall aim of this thesis was to gain an increased understanding of
potential common genetic mechanisms behind Hutchinson-Gilford progeria syndrome
and normal physiological aging. For this purpose, the research was primarily designed to
study the expression of LMNA and the global genome differential splicing in aging cells
to investigate the potential relationships that link the genetic mechanisms found in HGPS
to those occurring in normal physiological aging.
In paper I, we develop an absolute quantification method to determine the overall
expression levels of the LMNA gene transcripts lamin A, lamin C and lamin AΔ150
(progerin) during the in vitro cell aging of primary dermal fibroblasts from HGPS patients
and from age-matched and parent controls. We show that lamin C is the most highly
expressed transcript and that the lamin AΔ150 transcript is present in unaffected controls
at an approximately 160-fold lower expression level compared with HGPS patients.
While the levels of lamin A and lamin C transcripts remained unchanged during in vitro
cell aging, the lamin AΔ150 transcript increased in late passage cells from HGPS patients
and parental controls, suggesting a similar mechanism in HGPS patients and unaffected
donors during cellular aging.
In paper II, we expand on the first study and continue to investigate the expression of
progerin in unaffected cells from different age groups, evaluating progerin as an aging
biomarker for cellular senescence. We utilize a newly developed progerin antibody and
quantify the percentage of progerin-expressing cells in the early and late passages of cells
aged in vitro. We found that well-defined nuclear expression of progerin in primary
dermal fibroblasts that were aged in vitro is an extremely rare event (or below the
detection limit of an immunofluorescence assay). Our results do not rule out the
possibility of progerin being expressed during normal cellular aging but…
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More than 20 mutations in the gene encoding A-type lamins (LMNA) cause progeria, a rare premature aging disorder. The major pathognomonic hallmarks of progeria cells are seen as nuclear deformations or blebs that are related to the redistribution of A- and B-type lamins within the nuclear lamina. However, the functional significance of these progeria-associated blebs remains unknown. We have carried out an analysis of the structural and functional consequences of progeria-associated nuclear blebs in dermal fibroblasts from a progeria patient carrying a rare point mutation p.S143F (C428T) in lamin A/C. These blebs form microdomains that are devoid of major structural components of the nuclear envelope (NE)/lamina including B-type lamins and nuclear pore complexes (NPCs) and are enriched in A-type lamins. Using laser capture microdissection and comparative genomic hybridization (CGH) analyses, we show that, while these domains are devoid of centromeric heterochromatin and gene-poor regions of chromosomes, they are enriched in gene-rich chromosomal regions. The active form of RNA polymerase II is also greatly enriched in blebs as well as nascent RNA but the nuclear co-activator SKIP is significantly reduced in blebs compared to other transcription factors. Our results suggest that the p.S143F progeria mutation has a severe impact not only on the structure of the lamina but also on the organization of interphase chromatin domains and transcription. These structural defects are likely to contribute to gene expression changes reported in progeria and other types of laminopathies.
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The A‐and B‐type nuclear lamins (LA/C, LB1 and LB2) form separate but interconnecting networks within the nuclear lamina and nucleoplasm. Hundreds of mutations in the LMNA gene cause a wide range of diseases including the premature aging disease, Hutchinson‐Gilford Progeria Syndrome (HGPS). The nuclei of HGPS patients’ cells exhibit a wide range of changes in the architecture of their nuclei, including the formation of LA/C rich nuclear envelope blebs, a loss of peripheral heterochromatin, alterations in epigenetic modifications of chromatin, and changes in the RNA pol II transcriptional machinery. Recently we have focused our attention on the mechanisms responsible for the premature senescenece of cells derived from HGPS patients. The results demonstrate that the nuclear lamins are critical factors in the proliferation and senescence of both normal diploid and HGPS cells. Supported by the NCI and the Progeria Research Foundation.
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Hutchinson–Gilford progeria syndrome (HGPS; Online Mendelian Inheritance in Man accession no. 176670 ) is a rare disorder that is characterized by segmental premature aging and death between 7 and 20 years of age from severe premature atherosclerosis. Mutations in the LMNA gene are responsible for this syndrome. Approximately 80% of HGPS cases are caused by a G608 (GGC→GGT) mutation within exon 11 of LMNA , which elicits a deletion of 50 aa near the C terminus of prelamin A. In this article, we present evidence that the mutant lamin A (progerin) accumulates in the nucleus in a cellular age-dependent manner. In human HGPS fibroblast cultures, we observed, concomitantly to nuclear progerin accumulation, severe nuclear envelope deformations and invaginations preventable by farnesyltransferase inhibition. Nuclear alterations affect cell-cycle progression and cell migration and elicit premature senescence. Strikingly, skin biopsy sections from a subject with HGPS showed that the truncated lamin A accumulates primarily in the nuclei of vascular cells. This finding suggests that accumulation of progerin is directly involved in vascular disease in progeria.
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Hutchinson–Gilford progeria syndrome (HGPS) is an extremely rare premature aging disease presenting many features resembling the normal aging process. HGPS patients die before the age of 20 years due to cardiovascular problems and heart failure. HGPS is linked to mutations in the LMNA gene encoding the intermediate filament protein lamin A. Lamin A is a major component of the nuclear lamina, a scaffold structure at the nuclear envelope that defines mechanochemical properties of the nucleus and is involved in chromatin organization and epigenetic regulation. Lamin A is also present in the nuclear interior where it fulfills lamina-independent functions in cell signaling and gene regulation. The most common LMNA mutation linked to HGPS leads to mis-splicing of the LMNA mRNA and produces a mutant lamin A protein called progerin that tightly associates with the inner nuclear membrane and affects the dynamic properties of lamins. Progerin expression impairs many important cellular processes providing insight into potential disease mechanisms. These include changes in mechanosignaling, altered chromatin organization and impaired genome stability, and changes in signaling pathways, leading to impaired regulation of adult stem cells, defective extracellular matrix production and premature cell senescence. In this review, we discuss these pathways and their potential contribution to the disease pathologies as well as therapeutic approaches used in preclinical and clinical tests.
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Many studies have shown that abnormal expression and modification of lamin are closely related to aging.Hutchinson-Gilford progeria syndrome(HGPS)is a rare and severe premature aging disease caused by mutations in the gene encoding nuclear envelope proteins of A-type lamins(LMNA). The pathogenesis of HGPS is similar to the aging process of normal individuals, thus research on HGPS will be helpful for understanding the mechanisms of senescence and developing anti-aging drugs.This paper reviews recent advances in lamin and the pathogenesis and treatment of HGPS, in order to provide a reference for further basic and clinical research on HGPS.
Key words:
Aging; Lamin; Hutchinson-Gilford progeria syndrome
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Senescence
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