HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2007-0677v1 26/4/850    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Yang, C. Articles by Lako, M. PubMed PubMed Citation Articles by Yang, C. Articles by Lako, M.

EMBRYONIC STEM CELLS

A Key Role for Telomerase Reverse Transcriptase Unit in Modulating Human Embryonic Stem Cell Proliferation, Cell Cycle Dynamics, and In Vitro Differentiation

^aNorth East Institute for Stem Cell Research,
^bInstitute of Human Genetics, and
^dCrucible Laboratory, Institute for Ageing and Health, University of Newcastle upon Tyne, International Centre for Life, Newcastle upon Tyne, United Kingdom;
^cSchool of Biological Sciences, University of Durham, Durham, United Kingdom

Key Words. Telomerase reverse transcriptase • Telomerase RNA component • Telomerase • Human embryonic stem cells • Cell cycle • In vitro differentiation

Correspondence: Majlinda Lako, B.Sc., Ph.D., International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom. Telephone: 00-44-191-241-8688; Fax: 00-44-191-241-8666; e-mail: Majlinda.Lako{at}ncl.ac.uk

Received August 20, 2007; accepted for publication January 8, 2008.
First published online in STEM CELLS EXPRESS   January 17, 2008.



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.

Disclosure of potential conflicts of interest is found at the end of this article.