Journal article
Robust activation of the human but not mouse telomerase gene during the induction of pluripotency
The FASEB journal, Vol.24(8), pp.2702-2715
08/2010
Handle:
https://hdl.handle.net/2376/108025
PMCID: PMC2909285
PMID: 20354136
Abstract
Pluripotent stem cells (PSCs) express telomerase and have unlimited proliferative potential. To study telomerase activation during reprogramming, 3 classes of embryonic stem cell (ESC)-like clones were isolated from mouse fibroblasts containing a transgenic hTERT reporter. Class I expressed few pluripotency markers, whereas class II contained many, but not Oct4, Nanog, and Sox2. Neither class of cells differentiated efficiently. Class III cells, the fully reprogrammed induced PSCs (iPSCs), expressed all pluripotency markers, formed teratomas indistinguishable from those of mESCs, and underwent efficient osteogenic differentiation
in vitro
. Interestingly, whereas the endogenous
mTERT
gene expression was only moderately increased during reprogramming, the hTERT promoter was strongly activated in class II cells and was further elevated in class III cells. Treatment of class II cells with chemical inhibitors of MEKs and glycogen synthase kinase 3 resulted in their further reprogramming into class III cells, accompanied by a strong activation of hTERT promoter. In reprogrammed human cells, the endogenous telomerase level, although variable among different clones, was dramatically elevated. Only in cells with the highest telomerase were telomeres restored to the lengths in hESCs. Our data, for the first time, demonstrated that the hTERT promoter was strongly activated in discrete steps, revealing a critical difference in human and mouse cell reprogramming. Because telomere elongation is crucial for self-renewal of hPSCs and replicative aging of their differentiated progeny, these findings have important implications in the generation and applications of iPSCs.—Mathew, R., Jia, W., Sharma, A., Zhao, Y., Clarke, L. E., Cheng, X., Wang, H., Salli, U., Vrana, K. E., Robertson, G. P., Zhu, J., Wang, S. Robust activation of the human but not mouse telomerase gene during the induction of pluripotency.
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Details
- Title
- Robust activation of the human but not mouse telomerase gene during the induction of pluripotency
- Creators
- Renjith Mathew - Department of Cellular and Molecular PhysiologyWenwen Jia - Department of Cellular and Molecular PhysiologyArati Sharma - Department of Pharmacology, andYuanjun Zhao - Department of Cellular and Molecular PhysiologyLoren E Clarke - Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA; andXiang Cheng - Shaanxi Branch, National Stem Cell Engineering and Technology Centre, Animal Medicine College, Northwest University of Agriculture and Forestry, Yangling, ChinaHuayan Wang - Department of Cellular and Molecular PhysiologyUgur Salli - Department of Pharmacology, andKent E Vrana - Department of Pharmacology, andGavin P Robertson - Department of Pharmacology, andJiyue Zhu - Department of Cellular and Molecular PhysiologyShuwen Wang - Department of Cellular and Molecular Physiology
- Publication Details
- The FASEB journal, Vol.24(8), pp.2702-2715
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- The Federation of American Societies for Experimental Biology
- Identifiers
- 99900547502201842
- Language
- English
- Resource Type
- Journal article