Jiho Choi^1-3,10, Soohyun Lee^4,10, William Mallard^5,6, Kendell Clement^2,5,6, Guidantonio Malagoli Tagliazucchi^4,7, Hotae Lim⁸, In Young Choi⁸, Francesco Ferrari⁴, Alexander M Tsankov^2,5,6, Ramona Pop^2,5,6, Gabsang Lee⁸, John L Rinn^5,6,9, Alexander Meissner^2,5,6, Peter J Park⁴ & Konrad Hochedlinger^1-3

¹Department of Molecular Biology, Cancer Center and Center for Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA. ²Harvard Stem Cell Institute, Cambridge, Massachusetts, USA. ³Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. ⁴Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA. ⁵Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. ⁶Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA. ⁷Center for Genome Research, Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy. ⁸Institute for Cell Engineering, Department of Neurology, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ⁹Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA. ¹⁰These authors contributed equally to this work.

Correspondence to :  Peter J Park or Konrad Hochedlinger

 

Abstract
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.