Spontaneous Reversal of the Developmental Aging of Normal Human Cells Following Transcriptional Reprogramming

Vaziri, Homayoun; Chapman, KB; Guigova, Adriana; Teichroeb, Jonathan H.; Lacher,; Sternberg, Hal; Singeç, Ilyas; Briggs, Laura; Wheeler, JX; Sampathkumar, Janani; Gonzalez, Rodolfo; LaRocca, David; Murai, James T.; Snyder, Evan Y.; Andrews, W. H. H.; Funk, WD; West, Michael

doi:10.2217/rme.10.21

Cited by 60 publications

(59 citation statements)

References 63 publications

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“…Prematurely aged (shortened) telomeres are a common feature of human iPSCs created by current pluripotency protocols [24]. Together, in addition to routine methods for characterization of ESCs/iPSCs, such as ESC clone morphology, expression of ESC markers Oct4, Nanog, SSEAs, AP activity, and teratoma formation tests, our data show that telomere length and function are valuable to evaluate the developmental pluripotency of ESCs/iPSCs.…”

Section: Discussionmentioning

confidence: 74%

Association of telomere length with authentic pluripotency of ES/iPS cells

et al. 2011

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Telomerase and telomeres are important for indefinite replication of stem cells. Recently, telomeres of somatic cells were found to be reprogrammed to elongate in induced pluripotent stem cells (iPSCs). The role of telomeres in developmental pluripotency in vivo of embryonic stem cells (ESCs) or iPSCs, however, has not been directly addressed. We show that ESCs with long telomeres exhibit authentic developmental pluripotency, as evidenced by generation of complete ESC pups as well as germline-competent chimeras, the most stringent tests available in rodents. ESCs with short telomeres show reduced teratoma formation and chimera production, and fail to generate complete ESC pups. Telomere lengths are highly correlated (r > 0.8) with the developmental pluripotency of ESCs. Short telomeres decrease the proliferative rate or capacity of ESCs, alter the expression of genes related to telomere epigenetics, down-regulate genes important for embryogenesis and disrupt germ cell differentiation. Moreover, iPSCs with longer telomeres generate chimeras with higher efficiency than those with short telomeres. Our data show that functional telomeres are essential for the developmental pluripotency of ESCs/iPSCs and suggest that telomere length may provide a valuable marker to evaluate stem cell pluripotency, particularly when the stringent tests are not feasible.

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Section: Discussionmentioning

confidence: 74%

Association of telomere length with authentic pluripotency of ES/iPS cells

et al. 2011

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“…For example, reprogramming can trigger an increase in telomere length in cells of both old mice and humans, reversing the erosion characteristics of aged and senescent cells. However, whether the resulting iPSCs can maintain their telomere length over long‐term passages is still subject to debate (Marion et al ., 2009; Vaziri et al ., 2010). The epigenetic state of iPSCs derived from old donors is another aspect of reprogramming‐induced rejuvenation that has not been investigated thoroughly.…”

Section: Discussionmentioning

confidence: 99%

Blockade of senescence‐associated micro RNA ‐195 in aged skeletal muscle cells facilitates reprogramming to produce induced pluripotent stem cells.

et al. 2015

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SummaryThe low reprogramming efficiency in cells from elderly patients is a challenge that must be overcome. Recently, it has been reported that senescence‐associated microRNA (miR)‐195 targets Sirtuin 1 (SIRT1) to advance cellular senescence. Thus, we hypothesized that a blockade of miR‐195 expression could improve reprogramming efficiency in old skeletal myoblasts (SkMs). We found that miR‐195 expression was significantly higher in old SkMs (24 months) isolated from C57BL/6 mice as compared to young SkMs (2 months, 2.3‐fold). Expression of SIRT1 and telomerase reverse transcriptase (TERT) was downregulated in old SkMs, and transduction of old SkMs with lentiviral miR‐195 inhibitor significantly restored their expression. Furthermore, quantitative in situ hybridization analysis demonstrated significant telomere elongation in old SkMs transduced with anti‐miR‐195 (1.7‐fold increase). It is important to note that blocking miR‐195 expression markedly increased the reprogramming efficiency of old SkMs as compared to scramble (2.2‐fold increase). Transduction of anti‐miR‐195 did not alter karyotype or pluripotency marker expression. Induced pluripotent stem cells (iPSCs) from old SkMs transduced with anti‐miR‐195 successfully formed embryoid bodies that spontaneously differentiated into three germ layers, indicating that deletion of miR‐195 does not affect pluripotency in transformed SkMs. In conclusion, this study provided novel evidence that the blockade of age‐induced miR‐195 is a promising approach for efficient iPSC generation from aging donor subjects, which has the potential for autologous transplantation of iPSCs in elderly patients.

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“…Several npg possible and testable explanations exist, which reflect a number of concerns about uniformity in iPS cells as models of human disease. First, iPS cells show significant clonal variability, and recent studies show differences in telomerase activity and telomere elongation capacity even amongst wild-type iPS cells of the same genetic background [10,11]. Second, due to the inefficiency of the reprogramming process as usual and of DC iPS cells in particular, it is possible that additional genetic variation may have been selected during the reprogramming process (e.g., somatic mutations [12], copy number variations [13,14] ), and that these underlie differences in net telomere elongation or attrition in the cells.…”

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confidence: 99%