title: Telomerase protects werner syndrome lineage-specific stem cells from premature aging.
abstract: 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.
authors.affiliation: 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.
authors.forename: Hoi-Hung
authors.initials: HH
authors.lastname: Cheung
authors.affiliation: 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.
authors.forename: Xiaozhuo
authors.initials: X
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Lucile
authors.initials: L
authors.lastname: Canterel-Thouennon
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, N.T., 852 Hong Kong S.A.R.
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Catherine
authors.initials: C
authors.lastname: Edmonson
authors.affiliation: 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.
authors.forename: Owen M
authors.initials: OM
authors.lastname: Rennert
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics*; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D016922:Cellular Senescence / Q000235:genetics*; D016000:Cluster Analysis; D004249:DNA Damage / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014898:Werner Syndrome / Q000235:genetics*
chemical_list: D016159:Tumor Suppressor Protein p53; D019098:Telomerase
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