DEGs was expressed at relatively low levels in our hESCs and hiPSCs and showed no overlap with previously reported gene expression signatures. However, we cannot exclude that the lack of an obvious phenotype with the abovementioned assays could be due to insufficient expression of the analyzed genes in undifferentiated hiPSCs or compensation by posttranscriptional mechanisms, as appears to be the case with LDHA (Fig. 3G). Alternatively, our metabolic and in vitro-differentiation assays may not have been sensitive enough to detect functional differences. Another possibility is that hiPSCs are distinguished from hESCs by epigenetic or genetic differences that do not manifest in the pluripotent state. However, our finding that fibroblast-like cells derived from all examined hESC and hiPSC lines show no discernable transcriptional differences argues against this explanation (Supplementary Fig. 3A,B). The fact that isogenic hESC and hiPSC lines exhibit equivalent differentiation potentials using either a directed or spontaneous differentiation paradigm further supports this interpretation (Fig. 4D-G). Critically, hiPSCs were derived from in vitro- differentiated fibroblasts in this study and, we can therefore not rule out that hiPSCs produced from primary cells accrue additional aberrations that cannot be recapitulated with our in vitro differentiation approach.
