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 Ecker; Andrew Xiao; Richard A Young; Peter M Lansdorp; Rudolf Jaenisch

doi:10.1016/j.stem.2014.07.003

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

Cancer and Genomic Sciences

Research output: Contribution to journal › Article › peer-review

100 Citations (Scopus)

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.

Original language	English
Pages (from-to)	295-309
Number of pages	15
Journal	Cell stem cell
Volume	15
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2014.07.003
Publication status	Published - 4 Sept 2014

Keywords

Animals
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

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Buganim, Y., Markoulaki, S., van Wietmarschen, N., Hoke, H., Wu, T., Ganz, K., Akhtar-Zaidi, B., He, Y., Abraham, B. J., Porubsky, D., Kulenkampff, E., Faddah, D. A., Shi, L., Gao, Q., Sarkar, S., Cohen, M., Goldmann, J., Nery, J. R., Schultz, M. D., ... Jaenisch, R. (2014). The developmental potential of iPSCs is greatly influenced by reprogramming factor selection. Cell stem cell, 15(3), 295-309. https://doi.org/10.1016/j.stem.2014.07.003

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title = "The developmental potential of iPSCs is greatly influenced by reprogramming factor selection",

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.",

keywords = "Animals, 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",

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

year = "2014",

month = sep,

day = "4",

doi = "10.1016/j.stem.2014.07.003",

language = "English",

volume = "15",

pages = "295--309",

journal = "Cell stem cell",

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Buganim, 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 2014, 'The developmental potential of iPSCs is greatly influenced by reprogramming factor selection', Cell stem cell, vol. 15, no. 3, pp. 295-309. https://doi.org/10.1016/j.stem.2014.07.003

TY - JOUR

T1 - The developmental potential of iPSCs is greatly influenced by reprogramming factor selection

AU - Buganim, Yosef

AU - Markoulaki, Styliani

AU - van Wietmarschen, Niek

AU - Hoke, Heather

AU - Wu, Tao

AU - Ganz, Kibibi

AU - Akhtar-Zaidi, Batool

AU - He, Yupeng

AU - Abraham, Brian J

AU - Porubsky, David

AU - Kulenkampff, Elisabeth

AU - Faddah, Dina A

AU - Shi, Linyu

AU - Gao, Qing

AU - Sarkar, Sovan

AU - Cohen, Malkiel

AU - Goldmann, Johanna

AU - Nery, Joseph R

AU - Schultz, Matthew D

AU - Ecker, Joseph R

AU - Xiao, Andrew

AU - Young, Richard A

AU - Lansdorp, Peter M

AU - Jaenisch, Rudolf

PY - 2014/9/4

Y1 - 2014/9/4

N2 - 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.

AB - 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.

KW - Animals

KW - Cell Line

KW - Cellular Reprogramming

KW - Chimera

KW - Chromosomes, Human, Pair 8

KW - DNA Methylation

KW - Embryonic Stem Cells

KW - Enhancer Elements, Genetic

KW - Gene Expression Profiling

KW - Genome

KW - Histones

KW - Humans

KW - Induced Pluripotent Stem Cells

KW - Mice, Inbred C57BL

KW - Mice, Inbred DBA

KW - RNA, Messenger

KW - Transcription Factors

KW - Trisomy

U2 - 10.1016/j.stem.2014.07.003

DO - 10.1016/j.stem.2014.07.003

M3 - Article

C2 - 25192464

SN - 1934-5909

VL - 15

SP - 295

EP - 309

JO - Cell stem cell

JF - Cell stem cell

IS - 3

ER -

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

Abstract

Keywords

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