A comparison of genetically matched cell lines reveals the equivalence of human iPSCs and ESCs.
The equivalence of human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) remains controversial. Here we use genetically matched hESC and hiPSC lines to assess the contribution of cellular origin (hESC vs. hiPSC), the Sendai virus (SeV) reprogramming method and genetic background to transcriptional and DNA methylation patterns while controlling for cell line clonality and sex. We find that transcriptional and epigenetic variation originating from genetic background dominates over variation due to cellular origin or SeV infection. Moreover, the 49 differentially expressed genes we detect between genetically matched hESCs and hiPSCs neither predict functional outcome nor distinguish an independently derived, larger set of unmatched hESC and hiPSC lines. We conclude that hESCs and hiPSCs are molecularly and functionally equivalent and cannot be distinguished by a consistent gene expression signature. Our data further imply that genetic background variation is a major confounding factor for transcriptional and epigenetic comparisons of pluripotent cell lines, explaining some of the previously observed differences between genetically unmatched hESCs and hiPSCs.
Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Jiho
J
Choi
Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
Soohyun
S
Lee
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
William
W
Mallard
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Kendell
K
Clement
Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.|Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Guidantonio Malagoli
GM
Tagliazucchi
Institute for Cell Engineering, Department of Neurology, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Hotae
H
Lim
Institute for Cell Engineering, Department of Neurology, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
In Young
IY
Choi
Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
Francesco
F
Ferrari
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Alexander M
AM
Tsankov
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Ramona
R
Pop
Institute for Cell Engineering, Department of Neurology, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Gabsang
http://orcid.org/0000-0002-5052-5927
G
Lee
Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.|Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
John L
JL
Rinn
Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.|Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.
Alexander
A
Meissner
Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA.
Peter J
http://orcid.org/0000-0001-9378-960X
PJ
Park
Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts, USA.|Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
Konrad
K
Hochedlinger
D016000:Cluster Analysis; D019295:Computational Biology; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000502:physiology; D020869:Gene Expression Profiling; D005796:Genes / Q000235:genetics*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000502:physiology; D008297:Male