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Comparing isogenic pairs of hESC and hiPSC lines reveals genetic background and reprogramming method as primary sources of transcriptional variation

ABSTRACT: The equivalency of human induced pluripotent stem cells (hiPSCs) with human embryonic stem cells (hESCs) remains controversial. Here, we devised a strategy to assess the contribution of clonal growth, reprogramming method and genetic background to transcriptional patterns in hESCs and hiPSCs. Surprisingly, transcriptional variation originating from two different genetic backgrounds was dominant over variation due to the reprogramming method or cell type of origin of pluripotent cell lines. Moreover, the few differences we detected between isogenic hESCs and hiPSCs neither predicted functional outcome, nor distinguished an independently derived, larger set of unmatched hESC/hiPSC lines. We conclude that hESCs and hiPSCs are transcriptionally and functionally highly similar 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 comparisons of pluripotent cell lines, explaining some of the previously observed expression differences between unmatched hESCs and hiPSCs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE73211 | GEO | 2015/10/26

SECONDARY ACCESSION(S): PRJNA296379

REPOSITORIES: GEO

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Comparing isogenic pairs of hESC and hiPSC lines reveals genetic background and reprogramming method as primary sources of transcriptional variation

Project description:The equivalency of human induced pluripotent stem cells (hiPSCs) with human embryonic stem cells (hESCs) remains controversial. Here, we devised a strategy to assess the contribution of clonal growth, reprogramming method and genetic background to transcriptional patterns in hESCs and hiPSCs. Surprisingly, transcriptional variation originating from two different genetic backgrounds was dominant over variation due to the reprogramming method or cell type of origin of pluripotent cell lines. Moreover, the few differences we detected between isogenic hESCs and hiPSCs neither predicted functional outcome, nor distinguished an independently derived, larger set of unmatched hESC/hiPSC lines. We conclude that hESCs and hiPSCs are transcriptionally and functionally highly similar 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 comparisons of pluripotent cell lines, explaining some of the previously observed expression differences between unmatched hESCs and hiPSCs. Expression profiling of human embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and fibroblasts, mostly in triplicates.

2015-10-26 | E-GEOD-73211 | biostudies-arrayexpress

The quantitative proteomes of human-induced pluripotent stem cells and embryonic stem cells

Project description:Assessing relevant molecular differences between human-induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) is important, given that such differences may impact their potential therapeutic use. Controversy surrounds recent gene expression studies comparing hiPSCs and hESCs. Here, we present an in-depth quantitative mass spectrometry-based analysis of hESCs, two different hiPSCs and their precursor fibroblast cell lines. Our comparisons confirmed the high similarity of hESCs and hiPSCS at the proteome level as 97.8% of the proteins were found unchanged. Nevertheless, a small group of 58 proteins, mainly related to metabolism, antigen processing and cell adhesion, was found significantly differentially expressed between hiPSCs and hESCs. A comparison of the regulated proteins with previously published transcriptomic studies showed a low overlap, highlighting the emerging notion that differences between both pluripotent cell lines rather reflect experimental conditions than a recurrent molecular signature. See the Data Processing section of the published paper concerning the bioinformatics pipeline used. PMCID: PMC3261715 PMID: 22108792 Mol Syst Biol. 2011 Nov 22;7:550. doi: 10.1038/msb.2011.84. The quantitative proteomes of human-induced pluripotent stem cells and embryonic stem cells. Munoz J, Low TY, Kok YJ, Chin A, Frese CK, Ding V, Choo A, Heck AJ. Biomolecular Mass Spectrometry and Proteomics Group, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.

2013-02-01 | PXD000134 | Pride

Integrated Transcriptomic and Epigenomic Comparison of Human Induced Pluripotent Stem Cells Generated from Various Reprogramming Methods

Project description:Within the last decade, multiple reprogramming methods have been developed to generate human induced pluripotent stem cells (hiPSCs) which closely resemble human embryonic stem cells (hESCs). This has led to studies which assess how similar hiPSCs are to hESCs, by evaluating the differences in gene expression, epigenetic marks, and differentiation potential. However, these studies were all performed using hiPSCs acquired from different laboratories, passage numbers, culturing conditions, genetic backgrounds, and reprogramming methods which may contribute to the reported differences. In this study, we reprogrammed the same primary fibroblast population with six different reprogramming methods (episomal vectors, mRNA, microRNA/mRNA transfections (microRNA), minicircle vectors, lentivirus, and Sendai virus) and performed high-throughput sequencing on the hiPSCs with standardized cell culturing conditions and passage number. RNA-sequencing on all of our lines determined that clones derived from the same reprogramming method clustered together, which may indicate the reprogramming method could influence the resulting gene expression profile of the hiPSCs. In comparison to hESCs, a significant proportion of differentially expressed and spliced genes could be attributed to polycomb repressive complex (PRC) targets and the activity of HDAC2, SOX2, NANOG, LEF1, TCF3, and c-MYC transcription factors. Differences in epigenetic signatures (H3K4me3, H3K27me3, and HDAC2 ChIP-seq profiles) also corresponded to the activity of these factors. In addition, some hiPSC lines displayed a more similar PRC transcriptome profile to that of hESCs, and these lines also produced a higher percentage of cardiac troponin-T positive cells after cardiomyocyte differentiations were performed in parallel. Collectively, differential PRC activity contributes to the differences between hESCs and hiPSCs and likely impacts the differentiation potential of hiPSCs.

2017-10-09 | GSE69626 | GEO

Comparison of DNA methylation profilings between hESCs and hiPSCs

Project description:It remains controversial whether human induced pluripotent stem cells (hiPSCs) are distinct from human embryonic stem cells (hESCs) in their molecular signatures and differentiation properties. We examined the gene expression and DNA methylation of 49 hiPSC and 10 hESC lines and identified no molecular signatures that distinguished hiPSCs from hESCs. Comparisons of the in vitro directed neural differentiation of 40 hiPSC and four hESC lines showed that most hiPSC clones were comparable to hESCs. However, in seven hiPSC clones, significant amount of undifferentiated cells persisted even after neural differentiation and resulted in teratoma formation when transplantated into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression of several genes, including those expressed from long terminal repeats of human endogenous retroviruses. These data demonstrated that many hiPSC clones are indistinguishable from hESCs, while some defective hiPSC clones need to be eliminated prior to their application for regenerative medicine. Bisulphite converted DNA from 10 hESCs, 49 hiPSCs, 2 hECCs, 6 somatic cells and 3 cancer cell lines were hybridized to the Illumina Infinium 27k Human Methylation Beadchip.

2013-12-03 | E-GEOD-42448 | biostudies-arrayexpress

Comparison of miRNA expression profilings between hESCs and hiPSCs

Project description:It remains controversial whether human induced pluripotent stem cells (hiPSCs) are distinct from human embryonic stem cells (hESCs) in their molecular signatures and differentiation properties. We examined the gene expression and DNA methylation of 49 hiPSC and 10 hESC lines and identified no molecular signatures that distinguished hiPSCs from hESCs. Comparisons of the in vitro directed neural differentiation of 40 hiPSC and four hESC lines showed that most hiPSC clones were comparable to hESCs. However, in seven hiPSC clones, significant amount of undifferentiated cells persisted even after neural differentiation and resulted in teratoma formation when transplantated into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression of several genes, including those expressed from long terminal repeats of human endogenous retroviruses. These data demonstrated that many hiPSC clones are indistinguishable from hESCs, while some defective hiPSC clones need to be eliminated prior to their application for regenerative medicine. We extracted total RNA from 10 hESCs, 49 hiPSCs, 2 hECCs, 6 somatic cells and 3 cancer cell lines and hybridized them to Agilent miRNA expression microarrays.

2013-12-03 | E-GEOD-42446 | biostudies-arrayexpress

Comparison of gene expression profilings between hESCs and hiPSCs

Project description:It remains controversial whether human induced pluripotent stem cells (hiPSCs) are distinct from human embryonic stem cells (hESCs) in their molecular signatures and differentiation properties. We examined the gene expression and DNA methylation of 49 hiPSC and 10 hESC lines and identified no molecular signatures that distinguished hiPSCs from hESCs. Comparisons of the in vitro directed neural differentiation of 40 hiPSC and four hESC lines showed that most hiPSC clones were comparable to hESCs. However, in seven hiPSC clones, significant amount of undifferentiated cells persisted even after neural differentiation and resulted in teratoma formation when transplantated into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression of several genes, including those expressed from long terminal repeats of human endogenous retroviruses. These data demonstrated that many hiPSC clones are indistinguishable from hESCs, while some defective hiPSC clones need to be eliminated prior to their application for regenerative medicine. We extracted total RNA from 10 hESCs, 49 hiPSCs, 2 hECCs, 6 somatic cells and 3 cancer cell lines and hybridized them to Agilent gene expression microarrays.

2013-12-03 | E-GEOD-42445 | biostudies-arrayexpress

Comparison of gene expression profilings between SFEBq differentiation-defective clones and good clones

Project description:It remains controversial whether human induced pluripotent stem cells (hiPSCs) are distinct from human embryonic stem cells (hESCs) in their molecular signatures and differentiation properties. We examined the gene expression and DNA methylation of 49 hiPSC and 10 hESC lines and identified no molecular signatures that distinguished hiPSCs from hESCs. Comparisons of the in vitro directed neural differentiation of 40 hiPSC and four hESC lines showed that most hiPSC clones were comparable to hESCs. However, in seven hiPSC clones, significant amount of undifferentiated cells persisted even after neural differentiation and resulted in teratoma formation when transplantated into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression of several genes, including those expressed from long terminal repeats of human endogenous retroviruses. These data demonstrated that many hiPSC clones are indistinguishable from hESCs, while some defective hiPSC clones need to be eliminated prior to their application for regenerative medicine. We extracted total RNA from 10 hESCs and 40 hiPSCs, and hybridized them to Agilent gene expression microarrays.

2013-12-03 | E-GEOD-42452 | biostudies-arrayexpress

Comparison of the molecular profiles of human embryonic and isogenic induced pluripotent stem cells. [Illumina]

Project description:Many studies have compared the genetic and epigenetic profiles of human induced pluripotent stem cells (hiPSCs) to human embryonic stem cells (hESCs) and yet the picture remains unclear. To address this, we derived a population of neural precursor cells (NPCs) from the H1 (WA01) hESC line and generated isogenic iPSC lines by reprogramming. The gene expression and methylation profile of three lines were compared to the parental line and intermediate NPC population. We found no gene probe with expression that differed significantly between hESC and iPSC samples under undifferentiated or differentiated conditions. Analysis of the global methylation pattern also showed no significant difference between the two PSC populations. Both undifferentiated populations were distinctly different from the intermediate NPC population in both gene expression and methylation profiles. One point to note is that H1 is a male line and so extrapolation to female lines should be cautioned. However, these data confirm our previous findings that there are no significant differences between hESCs and hiPSCs at the gene expression or methylation level. 12 samples: 1 human NPC, 5 human ESC (UNDIFF), 6 human iPSC (UNDIFF)

2014-01-01 | E-GEOD-51747 | biostudies-arrayexpress

Exon array analysis for SFEBq differentiation-defective clones and good clones

Project description:It remains controversial whether human induced pluripotent stem cells (hiPSCs) are distinct from human embryonic stem cells (hESCs) in their molecular signatures and differentiation properties. We examined the gene expression and DNA methylation of 49 hiPSC and 10 hESC lines and identified no molecular signatures that distinguished hiPSCs from hESCs. Comparisons of the in vitro directed neural differentiation of 40 hiPSC and four hESC lines showed that most hiPSC clones were comparable to hESCs. However, in seven hiPSC clones, significant amount of undifferentiated cells persisted even after neural differentiation and resulted in teratoma formation when transplantated into mouse brains. These differentiation-defective hiPSC clones were marked by higher expression of several genes, including those expressed from long terminal repeats of human endogenous retroviruses. These data demonstrated that many hiPSC clones are indistinguishable from hESCs, while some defective hiPSC clones need to be eliminated prior to their application for regenerative medicine. We extracted total RNA from 3 differentiation-defective clones, 3 good clones and 2 somatic cells, and hybridized them to Affymetrix exon arrays.

2013-12-03 | E-GEOD-42449 | biostudies-arrayexpress

Genomic analysis of hESC pedigrees enables identification of de novo genetic alterations and determination of the timing and origin of mutational events

Project description:Given the association between mutational load and cancer, the observation that genetic aberrations are frequently found in human pluripotent stem cells (hPSCs) is of concern. Prior studies in hiPSCs have shown that deletions and regions of loss-of-heterozygosity (LOH) tend to arise during reprogramming and early culture, while duplications more frequently occur during long-term culture. For the corresponding experiments in hESCs, we studied two sets of hESC lines: one including the corresponding parental DNA; and the other generated from single blastomeres from four sibling embryos. Here, we show for the first time that genetic aberrations observed in hESCs can originate during preimplantation embryo development and/or early derivation. These early aberrations are mainly deletions and LOH, while aberrations arising during long-term culture of hESCs are more frequently duplications. Our results highlight the importance of close monitoring of genomic integrity and the development of improved methods for derivation and culture of hPSCs. Total DNA extracted at from human embryonic stem cells originated independently

2014-04-21 | E-GEOD-49452 | biostudies-arrayexpress

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