TY - JOUR
T1 - Dynamic variations in genetic integrity accompany changes in cell fate
AU - Chen, I. Chung
AU - Hernandez, Christine
AU - Xu, Xueping
AU - Cooney, Austin
AU - Wang, Yufeng
AU - McCarrey, John R.
N1 - Publisher Copyright:
© Copyright 2016, Mary Ann Liebert, Inc. 2016.
PY - 2016/11/15
Y1 - 2016/11/15
N2 - Pluripotent stem cells hold the potential to form the basis of novel approaches to treatment of disease in vivo as well as to facilitate the generation of models for human disease, providing powerful avenues to discovery of novel diagnostic biomarkers and/or innovative drug regimens in vitro. However, this will require extensive maintenance, expansion, and manipulation of these cells in culture, which raises a concern regarding the extent to which genetic integrity will be preserved throughout these manipulations. We used a mutation reporter (lacI) transgene approach to conduct direct comparisons of mutation frequencies in cell populations that shared a common origin and genetic identity, but were induced to undergo transitions in cell fate between pluripotent and differentiated states, or vice versa. We confirm that pluripotent cells normally maintain enhanced genetic integrity relative to that in differentiated cells, and we extend this finding to show that dynamic transformations in the relative stringency at which genetic integrity is maintained are associated with transitions between pluripotent and differentiated cellular states. These results provide insight into basic biological distinctions between pluripotent and differentiated cell types that impact genetic integrity in a manner that is directly relevant to the potential clinical use of these cell types.
AB - Pluripotent stem cells hold the potential to form the basis of novel approaches to treatment of disease in vivo as well as to facilitate the generation of models for human disease, providing powerful avenues to discovery of novel diagnostic biomarkers and/or innovative drug regimens in vitro. However, this will require extensive maintenance, expansion, and manipulation of these cells in culture, which raises a concern regarding the extent to which genetic integrity will be preserved throughout these manipulations. We used a mutation reporter (lacI) transgene approach to conduct direct comparisons of mutation frequencies in cell populations that shared a common origin and genetic identity, but were induced to undergo transitions in cell fate between pluripotent and differentiated states, or vice versa. We confirm that pluripotent cells normally maintain enhanced genetic integrity relative to that in differentiated cells, and we extend this finding to show that dynamic transformations in the relative stringency at which genetic integrity is maintained are associated with transitions between pluripotent and differentiated cellular states. These results provide insight into basic biological distinctions between pluripotent and differentiated cell types that impact genetic integrity in a manner that is directly relevant to the potential clinical use of these cell types.
KW - Cell fate transitions
KW - DNA repair
KW - Mutations
KW - Stem cells
UR - http://www.scopus.com/inward/record.url?scp=84994651137&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84994651137&partnerID=8YFLogxK
U2 - 10.1089/scd.2016.0221
DO - 10.1089/scd.2016.0221
M3 - Article
C2 - 27627671
AN - SCOPUS:84994651137
SN - 1547-3287
VL - 25
SP - 1698
EP - 1708
JO - Stem Cells and Development
JF - Stem Cells and Development
IS - 22
ER -