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Cell Cycle. 2017;16(21):2119-2127. doi: 10.1080/15384101.2017.1371887. Epub 2017 Sep 14.

Post-irradiation promotes susceptibility to reprogramming to pluripotent state in human fibroblasts.

Author information

1
a Laboratory of Radiation Exposure & Therapeutics, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science , Seoul , Republic of Korea.
2
b Laboratory of Low Dose Risk Assessment, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science , Seoul , Republic of Korea.
3
c Laboratory of Biological Dosimetry, National Radiation Emergency Medical Center, Korea Institute of Radiological and Medical Science , Seoul , Republic of Korea.

Abstract

Ionizing radiation causes not only targeted effects in cells that have been directly irradiated but also non-targeted effects in several cell generations after initial exposure. Recent studies suggest that radiation can enrich for a population of stem cells, derived from differentiated cells, through cellular reprogramming. Here, we elucidate the effect of irradiation on reprogramming, subjected to two different responses, using an induced pluripotent stem cell (iPSC) model. iPSCs were generated from non-irradiated cells, directly-irradiated cells, or cells subsequently generated after initial radiation exposure. We found that direct irradiation negatively affected iPSC induction in a dose-dependent manner. However, in the post-irradiated group, after five subsequent generations, cells became increasingly sensitive to the induction of reprogramming compared to that in non-irradiated cells as observed by an increased number of Tra1-81-stained colonies as well as enhanced alkaline phosphatase and Oct4 promoter activity. Comparative analysis, based on reducing the number of defined factors utilized for reprogramming, also revealed enhanced efficiency of iPSC generation in post-irradiated cells. Furthermore, the phenotypic acquisition of characteristics of pluripotent stem cells was observed in all resulting iPSC lines, as shown by morphology, the expression of pluripotent markers, DNA methylation patterns of pluripotency genes, a normal diploid karyotype, and teratoma formation. Overall, these results suggested that reprogramming capability might be differentially modulated by altered radiation-induced responses. Our findings provide that susceptibility to reprogramming in somatic cells might be improved by the delayed effects of non-targeted response, and contribute to a better understanding of the biological effects of radiation exposure.

KEYWORDS:

induced pluripotent stem cells; non-targeted effects; pluripotency reprogramming; post-irradiation; targeted irradiation

PMID:
28902577
PMCID:
PMC5731415
DOI:
10.1080/15384101.2017.1371887
[Indexed for MEDLINE]
Free PMC Article

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