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Cell Stem Cell. 2014 Sep 4;15(3):295-309. doi: 10.1016/j.stem.2014.07.003.

The developmental potential of iPSCs is greatly influenced by reprogramming factor selection.

Author information

1
Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. Electronic address: yossibug@ekmd.huji.ac.il.
2
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
3
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, AV Groningen 9713, the Netherlands.
4
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5
Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
6
Genomic Analysis Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
7
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Skolkovo Institute of Science and Technology (Skoltech), Novaya strazha 100, Skolkovo Moscow Region 143025, Russia.
8
European Research Institute for the Biology of Ageing, University Medical Center Groningen, University of Groningen, Antonius Deusinglaan 1, AV Groningen 9713, the Netherlands; Skolkovo Institute of Science and Technology (Skoltech), Novaya strazha 100, Skolkovo Moscow Region 143025, Russia.
9
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Skolkovo Institute of Science and Technology (Skoltech), Novaya strazha 100, Skolkovo Moscow Region 143025, Russia. Electronic address: jaenisch@wi.mit.edu.

Abstract

Induced pluripotent stem cells (iPSCs) are commonly generated by transduction of Oct4, Sox2, Klf4, and Myc (OSKM) into cells. Although iPSCs are pluripotent, they frequently exhibit high variation in terms of quality, as measured in mice by chimera contribution and tetraploid complementation. Reliably high-quality iPSCs will be needed for future therapeutic applications. Here, we show that one major determinant of iPSC quality is the combination of reprogramming factors used. Based on tetraploid complementation, we found that ectopic expression of Sall4, Nanog, Esrrb, and Lin28 (SNEL) in mouse embryonic fibroblasts (MEFs) generated high-quality iPSCs more efficiently than other combinations of factors including OSKM. Although differentially methylated regions, transcript number of master regulators, establishment of specific superenhancers, and global aneuploidy were comparable between high- and low-quality lines, aberrant gene expression, trisomy of chromosome 8, and abnormal H2A.X deposition were distinguishing features that could potentially also be applicable to human.

PMID:
25192464
PMCID:
PMC4170792
DOI:
10.1016/j.stem.2014.07.003
[Indexed for MEDLINE]
Free PMC Article
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