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A key role for telomerase reverse transcriptase unit in modulating human embryonic stem cell proliferation, cell cycle dynamics, and in vitro differentiation

Lookup NU author(s): Dr Chunbo Yang, Dr Rebecca Stewart, Dr George Anyfantis, Stuart Atkinson, Dr Gabriele Saretzki, Professor Lyle Armstrong, Professor Majlinda LakoORCiD


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Embryonic stem cells (ESC) are a unique cell population with the ability to self-renew and differentiate into all three germ layers. Human ESC express the telomerase reverse transcriptase (TERT) gene and the telomerase RNA (TR) and show telomerase activity, but TERT, TR, and telomerase are all downregulated during the differentiation process. To examine the role of telomerase in human ESC self-renewal and differentiation, we modulated the expression of TERT. Upregulation of TERT and increased telomerase activity enhanced the proliferation and colony-forming ability of human ESC, as well as increasing the S phase of the cell cycle at the expense of a reduced G1 phase. Upregulation of TERT expression was associated with increases in CYCLIN D1 and CDC6 expression, as well as hyperphosphorylation of RB. The differentiated progeny of control ESC showed shortening of telomeric DNA as a result of loss of telomerase activity. In contrast, the differentiated cells from TERT-overexpressing ESC maintained high telomerase activity and accumulated lower concentrations of peroxides than wild-type cells, implying greater resistance to oxidative stress. Although the TERT-overexpressing human ESC are able to form teratoma composed of three germ layers in vivo, their in vitro differentiation to all primitive and embryonic lineages was suppressed. In contrast, downregulation of TERT resulted in reduced ESC proliferation, increased G1, and reduced S phase. Most importantly, downregulation of TERT caused loss of pluripotency and human ESC differentiation to extraembryonic and embryonic lineages. Our results indicate for the first time an important role for TERT in the maintenance of human ESC pluripotency, cell cycle regulation, and in vitro differentiation capacity.

Publication metadata

Author(s): Yang C, Przyborski S, Cooke MJ, Zhang X, Stewart R, Anyfantis G, Atkinson SP, Saretzki GC, Armstrong L, Lako M

Publication type: Article

Publication status: Published

Journal: Stem Cells

Year: 2008

Volume: 26

Issue: 4

Pages: 850-863

ISSN (print): 1066-5099

ISSN (electronic): 1549-4918

Publisher: AlphaMed Press


DOI: 10.1634/stemcells.2007-0677


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Funder referenceFunder name
BB/E012841/1Biotechnology and Biological Sciences Research Council
BBS/B/14779Biotechnology and Biological Sciences Research Council
G0301182Medical Research Council