Reprogramming suppresses premature senescence phenotypes of Werner syndrome cells and maintains chromosomal stability over long-term culture.
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.
Department of Cellular and Molecular Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Akira
A
Shimamoto
Department of Cellular and Molecular Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Harunobu
H
Kagawa
Department of Cellular and Molecular Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Kazumasa
K
Zensho
Department of Cellular and Molecular Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Yukihiro
Y
Sera
Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan.
Yasuhiro
Y
Kazuki
Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan; Division of Pathological Biochemistry, Faculty of Medicine, Tottori University, Yonago, Japan.
Mitsuhiko
M
Osaki
Department of Biomedical Science, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Science, Tottori University, Yonago, Japan.
Mitsuo
M
Oshimura
Medical Research Institute, Kanazawa Medical University, Kahoku, Ishikawa, Japan.
Yasuhito
Y
Ishigaki
Department of Genetics, Radiation Effects Research Foundation, Hiroshima, Japan.
Kanya
K
Hamasaki
Department of Genetics, Radiation Effects Research Foundation, Hiroshima, Japan.
Yoshiaki
Y
Kodama
Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
Shinsuke
S
Yuasa
Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.
Keiichi
K
Fukuda
Division of Molecular Biotherapy, The Cancer Chemotherapy Center, Japanese Foundation For Cancer Research, Tokyo, Japan.
Kyotaro
K
Hirashima
Division of Molecular Biotherapy, The Cancer Chemotherapy Center, Japanese Foundation For Cancer Research, Tokyo, Japan.
Hiroyuki
H
Seimiya
Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Hirofumi
H
Koyama
Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Takahiko
T
Shimizu
Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Minoru
M
Takemoto
Department of Clinical Cell Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Koutaro
K
Yokote
Division of Orthopedic Surgery & Rheumatology, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
Makoto
M
Goto
Department of Cellular and Molecular Biology, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Hidetoshi
H
Tahara
D000328:Adult; D019588:Aging, Premature / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D065150:Cellular Reprogramming / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics*; D043171:Chromosomal Instability / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics; D010641:Phenotype; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D014898:Werner Syndrome / Q000235:genetics* / Q000378:metabolism
D019098:Telomerase