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Telomerase Protects Werner Syndrome Lineage-Specific Stem Cells from Premature Aging
Stem cell reports, Issue: 4, Volume: 2, Pages: 534-546. | 2014-01-04
0 Patent citations    29 Scholarly citations     Reference Count: 51
Hoi-Hung Cheung;Xiaozhuo Liu;Lucile Canterel-Thouennon;Lu Li;Catherine Edmonson;Owen M Rennert

摘要

Werner syndrome (WS) patients exhibit premature aging predominantly in mesenchyme-derived tissues, but not in neural lineages, a consequence of telomere dysfunction and accelerated senescence. The cause of this lineage-specific aging remains unknown. Here, we document that reprogramming of WS fibroblasts to pluripotency elongated telomere length and prevented telomere dysfunction. To obtain mechanistic insight into the origin of tissue-specific aging, we differentiated iPSCs to mesenchymal stem cells (MSCs) and neural stem/progenitor cells (NPCs). We observed recurrence of premature senescence associated with accelerated telomere attrition and defective synthesis of the lagging strand telomeres in MSCs, but not in NPCs. We postulate this “aging” discrepancy is regulated by telomerase. Expression of hTERT or p53 knockdown ameliorated the accelerated aging phenotypein MSC, whereas inhibition of telomerase sensitized NPCs to DNA damage. Our findings unveil a role for telomerase in the protection of accelerated aging in a specific lineage of stem cells.


机构

National Institutes of Health;Laboratory of Clinical and Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA ; School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, N.T., 852 Hong Kong S.A.R.National Institutes of Health;Laboratory of Clinical and Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA ; School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, N.T., 852 Hong Kong S.A.R.National Institutes of Health;Laboratory of Clinical and Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.The Chinese University of Hong Kong;School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, N.T., 852 Hong Kong S.A.R.National Institutes of Health;Laboratory of Clinical and Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.National Institutes of Health;Laboratory of Clinical and Developmental Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.


文献类型:

journal article;research support, non-u.s. gov't;

出版商:

Cell Press

发表时间:

2014-01-04

基金信息