Telomere dynamics in dyskeratosis congenita: the long and the short of iPS

Agarwal, Suneet; Daley, George Q.

doi:10.1038/cr.2011.120

Cited by 20 publications

(19 citation statements)

References 16 publications

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“…The authors found that, even in the undifferentiated state, iPSCs derived from these DC patients exhibit the precise features of each form of the disease. Unlike an earlier study [54] , profound defects in telomere maintenance were observed [62] ; the reasons for the discrepancy between the studies are unclear but is likely due to possible differences in experimental conditions or statistical variations among the iPS clones [63] . In the Batista study [62] , iPSCs derived from the hTERT-mutated cells with telomerase haploinsufficiency exhibited blunted telomere elongation effect during reprogramming.…”

Section: Promises Obstacles and Challenges Of Ips Technologycontrasting

confidence: 49%

Telomere dynamics in induced pluripotent stem cells: Potentials for Human disease modeling

Ly¹

2011

WJG

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Recent advances in reprograming somatic cells from normal and diseased tissues into induced pluripotent stem cells (iPSCs) provide exciting possibilities for generating renewed tissues for disease modeling and therapy. However, questions remain on whether iPSCs still retain certain markers (e.g. aging) of the original somatic cells that could limit their replicative potential and utility. A reliable biological marker for measuring cellular aging is telomere length, which is maintained by a specialized form of cellular polymerase known as telomerase. Telomerase is composed of the cellular reverse transcriptase protein, its integral RNA component, and other cellular proteins (e.g. dyskerin). Mutations in any of these components of telomerase can lead to a severe form of marrow deficiency known as dyskeratosis congenita (DC). This review summarizes recent findings on the effect of cellular reprograming via iPS of normal or DC patient-derived tissues on telomerase function and consequently on telomere length maintenance and cellular aging. The potentials and challenges of using iPSCs in a clinical setting will also be discussed.

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Section: Promises Obstacles and Challenges Of Ips Technologycontrasting

confidence: 49%

Telomere dynamics in induced pluripotent stem cells: Potentials for Human disease modeling

Ly¹

2011

WJG

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“…While both groups observed increases in expression of multiple members of the core telomerase machinery in the reprogrammed iPS cells, there was clonal variation with respect to maintenance of telomere length. Agarwal et al observed that some iPSCs recovered enough telomerase activity to regrow telomeres, whereas in the study by Batista et al DC-specific iPSCs continued to show telomere decay [32]. Given these different outcomes, one must remain wary of the clonal variation that results from the technical inefficiency and infidelity of reprogramming when iPSC-based disease models are generated.…”

Section: Limitations Of Ipscsmentioning

confidence: 99%

New lessons learned from disease modeling with induced pluripotent stem cells

Önder

Daley

2012

Current Opinion in Genetics & Development

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Cellular reprogramming and generation of induced pluripotent stem cells (iPSCs) from adult cell types has enabled the creation of patient-specific stem cells for use in disease modeling. To date, many iPSC lines have been generated from a variety of disorders, which have then been differentiated into disease-relevant cell types. When a disease-specific phenotype is detectable in such differentiated cells, the reprogramming technology provides a new opportunity to identify aberrant disease-associated pathways and drugs that can block them. Here, we highlight recent progress as well as limitations in the use of iPSCs to recapitulate disease phenotypes and to screen for therapeutics in vitro.

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“…Increased levels of wild-type lamin A in normal human cells result in decreased replicative lifespan and nuclear membrane alterations that lead to apoptotic cell death and senescence in a manner that is strongly reminiscent of the phenotype shown by HGPS cells and that are also observed in cells from old-age individuals (Candelario et al, 2008), suggesting that the elevated levels of lamin A are associated with aging. Modeling of premature ageing syndromes by generation of induced pluripotent stem (iPS) cells from HGPS patients (Ho et al, 2011; Liu et al, 2011a; Liu et al, 2011b; Zhang et al, 2011), and from patients with dyskeratosis congenita (Agarwal and Daley, 2011; Agarwal et al, 2010), could provide in vitro model to understand the mechanisms of development of diseases and aging processes and help developing novel therapeutic drugs for interference of diseases.…”

Section: Introductionmentioning

confidence: 99%

Influences of lamin A levels on induction of pluripotent stem cells

et al. 2012

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SummaryLamin A is an inner nuclear membrane protein that maintains nuclear structure integrity, is involved in transcription, DNA damage response and genomic stability, and also links to cell differentiation, senescence, premature aging and associated diseases. Induced pluripotent stem (iPS) cells have been successfully generated from various types of cells and used to model human diseases. It remains unclear whether levels of lamin A influence reprogramming of somatic cells to pluripotent states during iPS induction. Consistently, lamin A is expressed more in differentiated than in relatively undifferentiated somatic cells, and increases in expression levels with age. Somatic cells with various expression levels of lamin A differ in their dynamics and efficiency during iPS cell induction. Cells with higher levels of lamin A show slower reprogramming and decreased efficiency to iPS cells. Furthermore, depletion of lamin A by transient shRNA accelerates iPS cell induction from fibroblasts. Reduced levels of lamin A are associated with increased expression of pluripotent genes Oct4 and Nanog, and telomerase genes Tert and Terc. On the contrary, overexpression of lamin A retards somatic cell reprogramming to iPS-like colony formation. Our data suggest that levels of lamin A influence reprogramming of somatic cells to pluripotent stem cells and that artificial silencing of lamin A facilitates iPS cell induction. These findings may have implications in enhancing rejuvenation of senescent or older cells by iPS technology and manipulating lamin A levels.

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Telomere dynamics in dyskeratosis congenita: the long and the short of iPS

Cited by 20 publications

References 16 publications

Telomere dynamics in induced pluripotent stem cells: Potentials for Human disease modeling

Telomere dynamics in induced pluripotent stem cells: Potentials for Human disease modeling

New lessons learned from disease modeling with induced pluripotent stem cells

Influences of lamin A levels on induction of pluripotent stem cells

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