Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture

Akira Shimamoto, Harunobu Kagawa, Kazumasa Zensho, Yukihiro Sera, Yasuhiro Kazuki, Mitsuhiko Osaki, Mitsuo Oshimura, Yasuhito Ishigaki, Kanya Hamasaki, Yoshiaki Kodama, Shinsuke Yuasa, Keiichi Fukuda, Kyotaro Hirashima, Hiroyuki Seimiya, Hirofumi Koyama, Takahiko Shimizu, Minoru Takemoto, Koutaro Yokote, Makoto Goto, Hidetoshi Tahara

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Abstract

Werner syndrome (WS) is a premature aging disorder characterized by chromosomal instability and cancer predisposition. Mutations in WRN are responsible for the disease and cause telomere dysfunction, resulting in accelerated aging. Recent studies have revealed that cells from WS patients can be successfully reprogrammed into induced pluripotent stem cells (iPSCs). In the present study, we describe the effects of long-term culture on WS iPSCs, which acquired and maintained infinite proliferative potential for self-renewal over 2 years. After long-term cultures, WS iPSCs exhibited stable undifferentiated states and differentiation capacity, and premature upregulation of senescence-associated genes in WS cells was completely suppressed in WS iPSCs despite WRN deficiency. WS iPSCs also showed recapitulation of the phenotypes during differentiation. Furthermore, karyotype analysis indicated that WS iPSCs were stable, and half of the descendant clones had chromosomal profiles that were similar to those of parental cells. These unexpected properties might be achieved by induced expression of endogenous telomerase gene during reprogramming, which trigger telomerase reactivation leading to suppression of both replicative senescence and telomere dysfunction in WS cells. These findings demonstrated that reprogramming suppressed premature senescence phenotypes in WS cells and WS iPSCs could lead to chromosomal stability over the long term. WS iPSCs will provide opportunities to identify affected lineages in WS and to develop a new strategy for the treatment of WS.

Original languageEnglish
Article numbere112900
JournalPloS one
Volume9
Issue number11
DOIs
Publication statusPublished - 2014 Nov 12

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Shimamoto, A., Kagawa, H., Zensho, K., Sera, Y., Kazuki, Y., Osaki, M., Oshimura, M., Ishigaki, Y., Hamasaki, K., Kodama, Y., Yuasa, S., Fukuda, K., Hirashima, K., Seimiya, H., Koyama, H., Shimizu, T., Takemoto, M., Yokote, K., Goto, M., & Tahara, H. (2014). Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture. PloS one, 9(11), [e112900]. https://doi.org/10.1371/journal.pone.0112900