Third, we show that iPSC differentiation propensities are significantly biased by donor-dependent variability and not by cell type of origin. Earlier studies have focused on the relationship between genetic variability and molecular signatures of iPSC lines (Kajiwara et al., 2012, Rouhani et al., 2014, Shao et al., 2013). However, only limited information was available on the contribution of donor background to the functional differences of iPSC lines arising from the source-cell-specific differences. This was thoroughly addressed in the present study by combining global transcriptional and epigenetic analyses with spontaneous and targeted differentiation of isogenic iPSC lines. Although we selected iPSC lines from healthy donors showing the highest intra-individual variation in transcriptional and epigenetic analyses, we could not detect major differences in the differentiation potential of isogenic iPSC lines originating from fibroblasts and blood. However, we detected donor-dependent transcriptional differences in spontaneously differentiated EBs and significant variation in erythroid differentiation potential between iPSC lines derived from two healthy donors, regardless of the cell type of origin. Using GSEA we were able to associate the low erythroid-forming potential of the healthy donor
