Effects of Telomerase and Telomere Length on Epidermal Stem Cell Behavior

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Melchor Fernández Almagro 3, Madrid E-28029, Spain.
Science (Impact Factor: 33.61). 09/2005; 309(5738):1253-6. DOI: 10.1126/science.1115025
Source: PubMed


A key process in organ homeostasis is the mobilization of stem cells out of their niches. We show through analysis of mouse
models that telomere length, as well as the catalytic component of telomerase, Tert, are critical determinants in the mobilization
of epidermal stem cells. Telomere shortening inhibited mobilization of stem cells out of their niche, impaired hair growth,
and resulted in suppression of stem cell proliferative capacity in vitro. In contrast, Tert overexpression in the absence
of changes in telomere length promoted stem cell mobilization, hair growth, and stem cell proliferation in vitro. The effects
of telomeres and telomerase on stem cell biology anticipate their role in cancer and aging.

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Available from: Maria A Blasco, Mar 21, 2014
    • "As DNA polymerases cannot copy the end of the DNA strand, telomeres progressively shorten with each cell division. When telomeres become critically short this causes chromosomal instability (Chan & Blackburn, 2002) and cellular senescence (Flores et al. 2005). Consequently, TL is considered a biological marker of ageing (Harley et al. 1990). "
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    ABSTRACT: Telomere attrition might be one of the mechanisms through which psychosocial stress leads to somatic disease. To date it is unknown if exposure to adverse life events in adulthood is associated with telomere shortening prospectively. In the current study we investigated whether life events are associated with shortening of telomere length (TL). Participants were 1094 adults (mean age 53.1, range 33-79 years) from the PREVEND cohort. Data were collected at baseline (T1) and at two follow-up visits after 4 years (T2) and 6 years (T3). Life events were assessed with an adjusted version of the List of Threatening Events (LTE). TL was measured by monochrome multiplex quantitative PCR at T1, T2, and T3. A linear mixed model was used to assess the effect of recent life events on TL prospectively. Multivariable regression analyses were performed to assess whether the lifetime life events score or the score of life events experienced before the age of 12 predicted TL cross-sectionally. All final models were adjusted for age, sex, body mass index, presence of chronic diseases, frequency of sports, smoking status, and level of education. Recent life events significantly predicted telomere attrition prospectively (B = -0.031, p = 0.007). We were not able to demonstrate a significant cross-sectional relationship between the lifetime LTE score and TL. Nor did we find exposure to adverse life events before the age of 12 to be associated with TL in adulthood. Exposure to recent adverse life events in adulthood is associated with telomere attrition prospectively.
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    • "sco , 2007 ) and has become a cellular marker of aging . However , some cell types , such as most adult stem cells , express telomerase , a specific enzyme able to replicate telomeric sequences , counteracting their shortening ( Vaziri et al . , 1994 ; Chiu et al . , 1996 ; Morrison et al . , 1996 ; Espejel et al . , 2004 ; Ferrón et al . , 2004 ; Flores et al . , 2005 ) ."
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    ABSTRACT: Myotonic dystrophy type 1 (DM1 or Steinert’s disease) and type 2 (DM2) are multisystem disorders of genetic origin. Progressive muscular weakness, atrophy and myotonia are the most prominent neuromuscular features of these diseases, while other clinical manifestations such as cardiomyopathy, insulin resistance and cataracts are also common. From a clinical perspective, most DM symptoms are interpreted as a result of an accelerated aging (cataracts, muscular weakness and atrophy, cognitive decline, metabolic dysfunction, etc.), including an increased risk of developing tumors. From this point of view, DM1 could be described as a progeroid syndrome since a notable age-dependent dysfunction of all systems occurs. The underlying molecular disorder in DM1 consists of the existence of a pathological (CTG) triplet expansion in the 3′ untranslated region (UTR) of the Dystrophia Myotonica Protein Kinase (DMPK) gene, whereas (CCTG)n repeats in the first intron of the Cellular Nucleic acid Binding Protein/Zinc Finger Protein 9 (CNBP/ZNF9) gene cause DM2. The expansions are transcribed into (CUG)n and (CCUG)n-containing RNA, respectively, which form secondary structures and sequester RNA-binding proteins, such as the splicing factor muscleblind-like protein (MBNL), forming nuclear aggregates known as foci. Other splicing factors, such as CUGBP, are also disrupted, leading to a spliceopathy of a large number of downstream genes linked to the clinical features of these diseases. Skeletal muscle regeneration relies on muscle progenitor cells, known as satellite cells, which are activated after muscle damage, and which proliferate and differentiate to muscle cells, thus regenerating the damaged tissue. Satellite cell dysfunction seems to be a common feature of both age-dependent muscle degeneration (sarcopenia) and muscle wasting in DM and other muscle degenerative diseases. This review aims to describe the cellular, molecular and macrostructural processes involved in the muscular degeneration seen in DM patients, highlighting the similarities found with muscle aging.
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    • "When telomeres reach a critically short length, this triggers activation of a persistent DNA damage response at telomeres and the subsequent induction of cellular senescence or apoptosis. In the case of adult stem cells, critical telomere shortening impairs their ability to regenerate tissues both in mice and humans, leading to many different age-related pathologies (Flores et al., 2005). Interestingly, telomere shortening has been shown to be influenced both by genetic factors (ie., mutations in genes necessary for telomere maintenance) and environmental factors (ie., cigarette smoke has a negative effect) (Armanios, 2013; King et al., 2011). "
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a degenerative disease of the lungs with an average survival post-diagnosis of 2-3 years. New therapeutic targets and treatments are necessary. Mutations in components of the telomere-maintenance enzyme telomerase or in proteins important for telomere protection are found in both familial and sporadic IPF cases. However, the lack of mouse models that faithfully recapitulate the human disease has hampered new advances. Here, we generate two independent mouse models that develop IPF owing to either critically short telomeres (telomerase-deficient mice) or severe telomere dysfunction in the absence of telomere shortening (mice with Trf1 deletion in type II alveolar cells). We show that both mouse models develop pulmonary fibrosis through induction of telomere damage, thus providing proof of principle of the causal role of DNA damage stemming from dysfunctional telomeres in IPF development and identifying telomeres as promising targets for new treatments. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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