TY - JOUR
T1 - Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture
AU - Shimamoto, Akira
AU - Kagawa, Harunobu
AU - Zensho, Kazumasa
AU - Sera, Yukihiro
AU - Kazuki, Yasuhiro
AU - Osaki, Mitsuhiko
AU - Oshimura, Mitsuo
AU - Ishigaki, Yasuhito
AU - Hamasaki, Kanya
AU - Kodama, Yoshiaki
AU - Yuasa, Shinsuke
AU - Fukuda, Keiichi
AU - Hirashima, Kyotaro
AU - Seimiya, Hiroyuki
AU - Koyama, Hirofumi
AU - Shimizu, Takahiko
AU - Takemoto, Minoru
AU - Yokote, Koutaro
AU - Goto, Makoto
AU - Tahara, Hidetoshi
N1 - Publisher Copyright:
© 2014 Shimamoto et al.
PY - 2014/11/12
Y1 - 2014/11/12
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0112900
DO - 10.1371/journal.pone.0112900
M3 - Article
C2 - 25390333
AN - SCOPUS:84911457990
SN - 1932-6203
VL - 9
JO - PloS one
JF - PloS one
IS - 11
M1 - e112900
ER -