Effects of Telomerase and Telomere Length on Epidermal Stem Cell Behavior

Flores, Ignacio; Cayuela, María L.; Blasco, Marı́a A.

doi:10.1126/science.1115025

Cited by 395 publications

(359 citation statements)

References 27 publications

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“…In mice, deletion of Terc results in decreased lifespan after several generations (Rudolph et al, 1999), implicating telomerase components as longevity factors. Interestingly, distinct from its action in telomere maintenance, TERT regulates the mobilization and proliferation of epidermal stem cells in the hair follicle (Flores et al, 2005;Sarin et al, 2005). Consistent with its prominent role in stem cell proliferation independent of its reverse transcriptase activity, TERT is a pivotal component of the transcriptional complex downstream of WNT signaling (Choi et al, 2008;Park et al, 2009).…”

Section: Foxo Transcription Factors In Adult Stem Cells: Integrating mentioning

confidence: 99%

Epigenetic regulation of aging stem cells

2011

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Section: Foxo Transcription Factors In Adult Stem Cells: Integrating mentioning

confidence: 99%

Epigenetic regulation of aging stem cells

2011

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“…Together, these data point out to a role of telomeres in the regulation of HSC homeostasis 102 . Two recent studies investigated the effects of telomerase and telomere length on epidermal stem cell behaviour 103,104 . Using different constitutive and inducible transgenic mouse models, authors demonstrated that telomere length and telomerase activity are independent determinants of the mobilization efficiency and proliferative capacity of epidermal stem cells.…”

Section: Telomerase Activity and Telomere Length Regulate Cancer Stemmentioning

confidence: 99%

“…Still, the idea of cancer as a consequence of stem cell niche mutations is hypothetical, although recent data support the role of the vascular niche in initiating metastasis 152 . In addition, skin tumors can be caused by telomerase activation, which promotes epidermal stem cell mobilization out of their niche together with increased cell proliferation 97,103 . The study of signalling pathways that control mobilization and homing of stem cells in the niche will enhance our understanding of cancer development, invasiveness, and metastasis.…”

Section: The Stem Cell Niche As a Master Regulator Of Cancer Formationmentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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“…The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .Here, we analysed the role of the molecular clock in fine-tuning the function of epidermal stem cells. The mammalian clock machinery anticipates and synchronizes vital functions related to the physiological circadian needs of the organism 21 .…”

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confidence: 99%

mentioning

confidence: 99%

The circadian molecular clock creates epidermal stem cell heterogeneity

Janich

Pascual

Merlos‐Suárez

et al. 2011

Nature

274

284

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Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.Epidermal stem cells ensure that skin homeostasis is maintained. Murine epidermal stem cells are located either at the permanent portion of the hair follicle-termed the bulge-and are exclusively responsible for hair cycling [1][2][3][4] ; or at the junction between the epidermis and the hair follicle (isthmus), and feed into the epidermis and sebaceous glands [5][6][7] . In addition, a continuous proliferation of basal interfollicular epidermal cells ensures daily epidermal maintenance 8 .Bulge stem cells undergo bouts of activation followed by periods of dormancy, to establish hair follicle cycling. Robust TGF-b and Bmp signals act as 'activation breaks', rendering bulge cells dormant during the resting phase of the hair cycle (telogen) [9][10][11] . At the onset of the growth phase (anagen), bulge cells respond to Wnt signals by migrating into the lower proliferative hair germ region, where they contribute to follicle growth [12][13][14][15] . Subsequently, at mid-anagen, the bulge undergoes a second round of activation, which replenishes cells lost at the onset of anagen 2,3 . However, the response of bulge stem cells to activating stimuli is a heterogeneous process, as only a subset of them become active during either stage of activation 12,13 . The nature of such niche heterogeneity is currently unknown. Importantly, perturbing the equilibrium between the responsive and non-responsive stem cell states causes tissue malfunction and increases the risk of carcinogenesis [16][17][18][19][20] .Here, we analysed the role of the molecular clock in fine-tuning the function of epidermal stem cells. The mammalian clock machinery anticipates and synchronizes vital functions related to the physiological circadian needs of the organism 21 . The core molecular clock is established by a positive limb, composed of heterodimers of the transcription fa...

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Effects of Telomerase and Telomere Length on Epidermal Stem Cell Behavior

Cited by 395 publications

References 27 publications

Epigenetic regulation of aging stem cells

Epigenetic regulation of aging stem cells

Somatic stem cells and the origin of cancer

The circadian molecular clock creates epidermal stem cell heterogeneity

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