Abstract
The ability to reprogram adult cells into stem cells has raised hopes for novel therapies for many human diseases. Typical stem cell reprogramming protocols involve expression of a small number of genes in differentiated somatic cells with the c-Myc and Klf4 proto-oncogenes typically included in this mix. We have previously shown that expression of oncogenes leads to DNA replication stress and genomic instability, explaining the high frequency of p53 mutations in human cancers. Consequently, we wondered whether stem cell reprogramming also leads to genomic instability. To test this hypothesis, we examined stem cells induced by a variety of protocols. The first protocol, developed specifically for this study, reprogrammed primary mouse mammary cells into mammary stem cells by expressing c-Myc. Two other previously established protocols reprogrammed mouse embryo fibroblasts into induced pluripotent stem cells by expressing either three genes, Oct4, Sox2 and Klf4, or four genes, OSK plus c-Myc. Comparative genomic hybridization analysis of stem cells derived by these protocols revealed the presence of genomic deletions and amplifications, whose signature was suggestive of oncogene-induced DNA replication stress. The genomic aberrations were to a significant degree dependent on c-Myc expression and their presence could explain why p53 inactivation facilitates stem cell reprogramming.
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Abbreviations
- iPS:
-
induced pluripotent stem
- OSK:
-
Oct4, Sox2, Klf4
- OSKC:
-
Oct4, Sox2, Klf4, c-Myc
- TAM:
-
4-hydroxytamoxifen
- MEF:
-
mouse embryo fibroblast
- CFS:
-
common fragile site
- cGH:
-
comparative genomic hybridization
- CNC:
-
copy number change
- Rora :
-
retinoic acid receptor-related orphan receptor A
- Pde4D :
-
phosphodiesterase 4D
- Ptprg :
-
protein tyrosine phosphatase receptor type G
- Fhit :
-
fragile histidine triad
- Jarid2 :
-
jumonji AT rich interactive domain 2
- Dtnbp1 :
-
dystrobrevin-binding protein 1
- Odz3 :
-
odd Oz/ten-m homolog 3
- Cdh13 :
-
cadherin 13
- Fto :
-
fat mass and obesity associated
- Dock3 :
-
dedicator of cytokinesis3
- Cadm2 :
-
cell adhesion molecule 2
- Lsamp :
-
limbic system-associated membrane protein
- Naaladl2 :
-
N-acetylated alpha-linked acidic dipeptidase-like 2
- Erc2 :
-
ELKS–RAB6-interacting/CAST family member 2
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Acknowledgements
Financial support for this project was provided by the Swiss National Foundation to TDH and DT, the National Institutes of Health, USA to TDH, the European Commission Seventh Framework Programme (GENICA) to TDH and PGP, and the Italian Ministry of Health, Project Giovanni Ricercatori to SC and GT.
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Pasi, C., Dereli-Öz, A., Negrini, S. et al. Genomic instability in induced stem cells. Cell Death Differ 18, 745–753 (2011). https://doi.org/10.1038/cdd.2011.9
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DOI: https://doi.org/10.1038/cdd.2011.9
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