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Cited by 16Pluripotent Stem Cells ResearchMicrotubule and mitosis dynamicsTelomeres, Telomerase, and Senescence

Reprogramming to pluripotency can conceal somatic cell chromosomal instability

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Hamada, Masakazu, Malureanu, Liviu A., Wijshake, Tobias, Zhou, Wei, van Deursen, Jan M.·2012·PLoS Genetics
DOI 10.1371/journal.pgen.1002913PMC PMC3431347
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Abstract

The discovery that somatic cells are reprogrammable to pluripotency by ectopic expression of a small subset of transcription factors has created great potential for the development of broadly applicable stem-cell-based therapies. One of the concerns regarding the safe use of induced pluripotent stem cells (iPSCs) in therapeutic applications is loss of genomic integrity, a hallmark of various human conditions and diseases, including cancer. Structural chromosome defects such as short telomeres and double-strand breaks are known to limit reprogramming of somatic cells into iPSCs, but whether defects that cause whole-chromosome instability (W-CIN) preclude reprogramming is unknown. Here we demonstrate, using aneuploidy-prone mouse embryonic fibroblasts (MEFs) in which chromosome missegregation is driven by BubR1 or RanBP2 insufficiency, that W-CIN is not a barrier to reprogramming. Unexpectedly, the two W-CIN defects had contrasting effects on iPSC genomic integrity, with BubR1 hypomorphic MEFs almost exclusively yielding aneuploid iPSC clones and RanBP2 hypomorphic MEFs karyotypically normal iPSC clones. Moreover, BubR1-insufficient iPSC clones were karyotypically unstable, whereas RanBP2-insufficient iPSC clones were rather stable. These findings suggest that aneuploid cells can be selected for or against during reprogramming depending on the W-CIN gene defect and present the novel concept that somatic cell W-CIN can be concealed in the pluripotent state. Thus, karyotypic analysis of somatic cells of origin in addition to iPSC lines is necessary for safe application of reprogramming technology.

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Cited by

Sorted by citations

Authors
Hamada, M., Malureanu, L. A., Wijshake, T., Zhou, W., & van Deursen, J. M.
Affiliations
Mayo Clinic (US)
ORCID
Venue
PLoS Genetics
Publisher
Public Library of Science (PLoS)
Published
2012-08-30
Volume
8
Issue
8
Pages
e1002913
ISSN
  • 1553-7390 (ISSN-L)
  • 1553-7404
DOI
10.1371/journal.pgen.1002913
PMC
PMC3431347
OpenAlex
W2136623804
Cited by
16
References
7
Citations by year
2021: 3 · 2020: 2 · 2019: 1 · 2017: 5 · 2015: 1 · 2013: 3 · 2012: 1
FWCI
0.64
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
National Cancer Institute (R01-CA77262, R01CA077262, R01CA096985, R01CA96985)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Keywords
induced pluripotent stem cells, somatic cell reprogramming, aneuploidy, karyotype stability, BubR1, RanBP2, chromosome missegregation, mouse embryonic fibroblasts, genome stability, iPSC safety
MeSH terms
Aneuploidy, Animals, Cell Differentiation, Cell Line, Fibroblasts, Humans, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Molecular Chaperones, Nuclear Pore Complex Proteins, Chromosomal Instability, Mice, Induced Pluripotent Stem Cells

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