Genetic Variability Overrides the Impact of Parental Cell Type and Determines iPSC Differentiation Potential

• Isogenic iPSC from fibroblasts and blood have similar differentiation propensities
• Donor-dependent variability affects molecular and differentiation propensities of iPSCs
• Impact of donor variability exceeds source-cell-specific differences in iPSC lines
• Bona fide iPSC lines from different tissues can be combined in the repositories

SummaryReports on the retention of somatic cell memory in induced pluripotent stem cells (iPSCs) have complicated the selection of the optimal cell type for the generation of iPSC biobanks. To address this issue we compared transcriptomic, epigenetic, and differentiation propensities of genetically matched human iPSCs derived from fibroblasts and blood, two tissues of the most practical relevance for biobanking. Our results show that iPSC lines derived from the same donor are highly similar to each other. However, genetic variation imparts a donor-specific expression and methylation profile in reprogrammed cells that leads to variable functional capacities of iPSC lines. Our results suggest that integration-free, bona fide iPSC lines from fibroblasts and blood can be combined in repositories to form biobanks. Due to the impact of genetic variation on iPSC differentiation, biobanks should contain cells from large numbers of donors.

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