Short Telomeres, even in the Presence of Telomerase, Limit Tissue Renewal Capacity

Hao, Ling; Armanios, Mary; Strong, Margaret A.; Karim, Baktiar O.; Feldser, David M.; Huso, David L.; Greider, Carol W.

doi:10.1016/j.cell.2005.11.020

Cited by 270 publications

(273 citation statements)

References 48 publications

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“…After the fourth generation, Terc knockout mice begin to exhibit abnormalities similar to the phenotype of human DKC (Samper et al, 2002). Wild-type mice derived from late generations of Terc þ /À mice with short telomeres and positive telomerase activity displayed a similar phonotype of DKC, indicating that short telomeres themselves, rather than lack of telomerase activity, cause stem cell failure (Hao et al, 2005). Recently, Cdkn1a deletion improved stem cell function and lifespan of mice with telomere dysfunction, indicating that upregulation of p21 (encoded by Cdkn1a) in response to shortened telomeres impairs repopulation capacity of stem cells in age-related diseases and senescence (Choudhury et al, 2007).…”

Section: Diseases Due To Lack Of Telomerase In Stem Cells: Dkc and Apmentioning

confidence: 99%

Telomere and telomerase in stem cells

2007

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Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells. Recently, the importance of telomere maintenance in human stem cells has been highlighted by studies on dyskeratosis congenital, which is a genetic disorder in the human telomerase component. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells. Here we review the role of telomeres and telomerase in the function and capacity of the human stem cells.

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Section: Diseases Due To Lack Of Telomerase In Stem Cells: Dkc and Apmentioning

confidence: 99%

Telomere and telomerase in stem cells

2007

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“…In contrast, heterozygous mutations of telomerase in C57BL/6J mice with long telomeres have little effect on stem cell function during aging . However, the heterozygous deletion of telomerase in a mouse strain with short telomeres (CAST/EjI) induced stem cell defects and impairment of organ maintenance similar to the human situation (Hao et al, 2005). Together, these results indicate that laboratory mouse strains with long telomeres lack telomere shortening, which represent one important aspect of human aging.…”

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confidence: 90%

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

Song¹,

Ju²,

Rudolph³

2009

Experimental Gerontology

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“…The data we present here highlight a contrast in the response to telomere dysfunction between high-and lowturnover tissues. In the hematopoietic system, telomere dysfunction causes stem cell failure because of replicative exhaustion, and this phenotype is clinically evident in mice and limits their survival (32)(33)(34)(35). In contrast, when telomere dysfunction is restricted to AEC2s, a population with a comparatively slow turnover, the clinical phenotype is fairly well tolerated de novo.…”

Section: Senescence Is a Preferred Response To Telomere Dysfunction Inmentioning

confidence: 99%

Telomere dysfunction causes alveolar stem cell failure

Alder

Barkauskas²,

Limjunyawong

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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271

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Telomere syndromes have their most common manifestation in lung disease that is recognized as idiopathic pulmonary fibrosis and emphysema. In both conditions, there is loss of alveolar integrity, but the underlying mechanisms are not known. We tested the capacity of alveolar epithelial and stromal cells from mice with short telomeres to support alveolar organoid colony formation and found that type 2 alveolar epithelial cells (AEC2s), the stem cell-containing population, were limiting. When telomere dysfunction was induced in adult AEC2s by conditional deletion of the shelterin component telomeric repeat-binding factor 2, cells survived but remained dormant and showed all the hallmarks of cellular senescence. Telomere dysfunction in AEC2s triggered an immune response, and this was associated with AEC2-derived up-regulation of cytokine signaling pathways that are known to provoke inflammation in the lung. Mice uniformly died after challenge with bleomycin, underscoring an essential role for telomere function in AEC2s for alveolar repair. Our data show that alveoloar progenitor senescence is sufficient to recapitulate the regenerative defects, inflammatory responses, and susceptibility to injury that are characteristic of telomere-mediated lung disease. They suggest alveolar stem cell failure is a driver of telomere-mediated lung disease and that efforts to reverse it may be clinically beneficial.

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Short Telomeres, even in the Presence of Telomerase, Limit Tissue Renewal Capacity

Cited by 270 publications

References 48 publications

Telomere and telomerase in stem cells

Telomere and telomerase in stem cells

Cell intrinsic and extrinsic mechanisms of stem cell aging depend on telomere status

Telomere dysfunction causes alveolar stem cell failure

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