Flores, I. et al. The longest telomeres: a general signature of adult stem cell compartments. Genes Dev. 22, 654-667

Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid E-28029, Spain.
Genes & Development (Impact Factor: 10.8). 04/2008; 22(5):654-67. DOI: 10.1101/gad.451008
Source: PubMed


Identification of adult stem cells and their location (niches) is of great relevance for regenerative medicine. However, stem cell niches are still poorly defined in most adult tissues. Here, we show that the longest telomeres are a general feature of adult stem cell compartments. Using confocal telomere quantitative fluorescence in situ hybridization (telomapping), we find gradients of telomere length within tissues, with the longest telomeres mapping to the known stem cell compartments. In mouse hair follicles, we show that cells with the longest telomeres map to the known stem cell compartments, colocalize with stem cell markers, and behave as stem cells upon treatment with mitogenic stimuli. Using K15-EGFP reporter mice, which mark hair follicle stem cells, we show that GFP-positive cells have the longest telomeres. The stem cell compartments in small intestine, testis, cornea, and brain of the mouse are also enriched in cells with the longest telomeres. This constitutes the description of a novel general property of adult stem cell compartments. Finally, we make the novel finding that telomeres shorten with age in different mouse stem cell compartments, which parallels a decline in stem cell functionality, suggesting that telomere loss may contribute to stem cell dysfunction with age.

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Available from: Maria A Blasco, Mar 22, 2014
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    • "Telomerase is responsible for maintaining the telomere length. The elevated activity of telomerases in proliferation cells, such as cancer cells and stem cells (3), makes the telomerase a potential therapeutic target in cancers and aging-associated disease (4,5). "
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    ABSTRACT: Telomerase, a ribonucleoprotein complex, is responsible for maintaining the telomere length at chromosome ends. Using its RNA component as a template, telomerase uses its reverse transcriptase activity to extend the 3′-end single-stranded, repetitive telomeric DNA sequence. Pif1, a 5′-to-3′ helicase, has been suggested to regulate telomerase activity. We used single-molecule experiments to directly show that Pif1 helicase regulates telomerase activity by removing telomerase from telomere ends, allowing the cycling of the telomerase for additional extension processes. This telomerase removal efficiency increases at longer ssDNA gaps and at higher Pif1 concentrations. The enhanced telomerase removal efficiency by Pif1 at the longer single-stranded telomeric DNA suggests a way of how Pif1 regulates telomerase activity and maintains telomere length.
    Nucleic Acids Research 06/2014; 42(13). DOI:10.1093/nar/gku541 · 9.11 Impact Factor
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    • "Age-associated telomere reduction has been shown to threaten chromosome integrity of highly proliferative aging tissues (Vaziri & Benchimol, 1996). A gradual decline of telo-mere length with age has been observed in mouse (Flores et al., 2008) and human tissues (Harley, Futcher, & Greider, 1990). Further evidence supports the notion that age-related decrease in telomere length could occur through loss of telomerase, which maintains telomere length. "
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    ABSTRACT: Tissue homeostasis and regenerative capacity rely on rare populations of somatic stem cells endowed with the potential to self-renew and differentiate. During aging, many tissues show a decline in regenerative potential coupled with a loss of stem cell function. Cells including somatic stem cells have evolved a series of checks and balances to sense and repair cellular damage to maximize tissue function. However, during aging the mechanisms that protect normal cell function begin to fail. In this review, we will discuss how common cellular mechanisms that maintain tissue fidelity and organismal lifespan impact somatic stem cell function. We will highlight context-dependent changes and commonalities that define aging, by focusing on three age-sensitive stem cell compartments: blood, neural, and muscle. Understanding the interaction between extrinsic regulators and intrinsic effectors that operate within different stem cell compartments is likely to have important implications for identifying strategies to improve health span and treat age-related degenerative diseases.
    Current Topics in Developmental Biology 01/2014; 107C:405-438. DOI:10.1016/B978-0-12-416022-4.00014-7 · 4.68 Impact Factor
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    • "ging and declining organ function with age ( Rudolph et al . 2000 ; Cristofalo et al . 2004 ) . Indeed , senescent markers , in - cluding SA - b - Gal , DDR , telomere dysfunction , and p16 , have been detected in various tissues from old individuals ( Dimri et al . 1995 ; Krishnamurthy et al . 2004 ; Herbig et al . 2006 ; Jeyapalan et al . 2007 ; Flores et al . 2008 ) and age - related diseased organs in mammals ( Minamino et al . 2002 ; Price et al . 2002 ) . Such age - dependent up - regulation of p16 was also confirmed using p16 reporter mouse models ( Yamakoshi et al . 2009 ; Burd et al . 2013 ) . But does senescence play a causative role in aging ? A series of studies in 2006 touched on this i"
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    ABSTRACT: Cellular senescence is a stress response that accompanies stable exit from the cell cycle. Classically, senescence, particularly in human cells, involves the p53 and p16/Rb pathways, and often both of these tumor suppressor pathways need to be abrogated to bypass senescence. In parallel, a number of effector mechanisms of senescence have been identified and characterized. These studies suggest that senescence is a collective phenotype of these multiple effectors, and their intensity and combination can be different depending on triggers and cell types, conferring a complex and diverse nature to senescence. Series of studies on senescence-associated secretory phenotype (SASP) in particular have revealed various layers of functionality of senescent cells in vivo. Here we discuss some key features of senescence effectors and attempt to functionally link them when it is possible.
    Genes & development 01/2014; 28(2):99-114. DOI:10.1101/gad.235184.113 · 10.80 Impact Factor
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