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Differential stem cell aging kinetics in Hutchinson-Gilford progeria syndrome and Werner syndrome
Authors:Zeming Wu  Weiqi Zhang  Moshi Song  Wei Wang  Gang Wei  Wei Li  Jinghui Lei  Yu Huang  Yanmei Sang  Piu Chan  Chang Chen  Jing Jing  Keiichiro Suzuki  Juan Carlos Izpisua Belmonte  Guang-Hui Liu
Abstract:Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product—progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNAmutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem cells (MSCs) showed aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature aging phenotypes while HGPS-MSCs exhibited late-onset acute premature aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature aging disorders, and provides reliable stem-cell based models to identify new therapeutic strategies for pathological and physiological aging.
Keywords:WRN  lamin  HGPS  Werner syndrome  stem cell  aging  
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