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

TitleThe developmental potential of iPSCs is greatly influenced by reprogramming factor selection.
Publication TypeJournal Article
Year of Publication2014
AuthorsBuganim Y, Markoulaki S, van Wietmarschen N, Hoke H, Wu T, Ganz K, Akhtar-Zaidi B, He Y, Abraham BJ, Porubsky D, Kulenkampff E, Faddah DA, Shi L, Gao Q, Sarkar S, Cohen M, Goldmann J, Nery JR, Schultz MD, Ecker JR, Xiao A, Young RA, Lansdorp PM, Jaenisch R
JournalCell Stem Cell
Date Published2014 Sep 4
KeywordsAnimals, Cell Line, Cellular Reprogramming, Chimera, Chromosomes, Human, Pair 8, DNA Methylation, Embryonic Stem Cells, Enhancer Elements, Genetic, Gene Expression Profiling, Genome, Histones, Humans, Induced Pluripotent Stem Cells, Mice, Inbred C57BL, Mice, Inbred DBA, RNA, Messenger, Transcription Factors, Trisomy

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.

PubMed URL
Alternate TitleCell Stem Cell
PubMed ID25192464
PubMed Central IDPMC4170792
Grant List1 F32GM099153-01A1 / GM / NIGMS NIH HHS / United States
HD 045022 / HD / NICHD NIH HHS / United States
R01 CA084198 / CA / NCI NIH HHS / United States
R01 HD045022 / HD / NICHD NIH HHS / United States
R37 HD045022 / HD / NICHD NIH HHS / United States
R37CA084198 / CA / NCI NIH HHS / United States
UL1 TR000142 / TR / NCATS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
Bioinformatics and Systems Biology