Although ideal, generic iPSC may be functionally and molecularly indistinguishable from fESC, we have shown in practice that even rigorously selected iPSC can retain epigenetic marks characteristic of the donor cell that influence differentiation propensity. Epigenetic differences are unlikely to be essential features of iPSC, but rather reflect stochastic variations associated with the technical challenges of achieving complete reprogramming. Given that we lack reporter genes for selecting human iPSC, and cannot qualify their pluripotency by assaying embryo chimerism, the behavior of human cells will likely be influenced by epigenetic memory. Human ESC can also manifest variable differentiation potential47. These data highlight our limited understanding of the epigenetic heterogeneity of pluripotent stem cells, and the need for improved methods to ensure reprogramming of somatic cells to a fully naïve, “ground state” of pluripotency48.
