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

Yosef Buganim*, Styliani Markoulaki, Niek Van Wietmarschen, Heather Hoke, Tao Wu, Kibibi Ganz, Batool Akhtar-Zaidi, Yupeng He, Brian J. Abraham, David Porubsky, Elisabeth Kulenkampff, Dina A. Faddah, Linyu Shi, Qing Gao, Sovan Sarkar, Malkiel Cohen, Johanna Goldmann, Joseph R. Nery, Matthew D. Schultz, Joseph R. EckerAndrew Xiao, Richard A. Young, Peter M. Lansdorp, Rudolf Jaenisch

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

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 highquality 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 highand 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.

Original languageAmerican English
Pages (from-to)295-309
Number of pages15
JournalCell Stem Cell
Volume15
Issue number3
DOIs
StatePublished - 2014

Bibliographical note

Funding Information:
We thank Biology and Research Computing (BaRC), especially Prathapan Thiru at the Whitehead Institute’s Center for Microarray Technology, for computational and technical assistance. Y.B. was supported by an NIH Kirschstein National Research Service Award (1 F32GM099153-01A1). D.A.F. is a Vertex Scholar and was supported by a National Science Foundation (NSF) Graduate Research Fellowship and Jerome and Florence Brill Graduate Student Fellowship. R.J. is an adviser to Stemgent and a cofounder of Fate Therapeutics. J.R.E. is an investigator of the Howard Hughes Medical Institute. This research project was supported by NIH grants HD 045022 and R37CA084198 to R.J., the Gordon and Betty Moore Foundation (GMBF3034) and Chapman Foundation grants to J.R.E., and the Israeli Centers of Research Excellence (I-CORE) program (Center No. 41/11) grant to Y.B.

Publisher Copyright:
© 2014 Elsevier Inc.

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