Jiho Choi1-3,10, Soohyun Lee4,10, William Mallard5,6, Kendell Clement2,5,6, Guidantonio Malagoli Tagliazucchi4,7, Hotae Lim8, In Young Choi8, Francesco Ferrari4, Alexander M Tsankov2,5,6, Ramona Pop2,5,6, Gabsang Lee8, John L Rinn5,6,9, Alexander Meissner2,5,6, Peter J Park4 & Konrad Hochedlinger1-3
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
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.