In order to address some of these questions, we attempted to convert definitive endodermal cells into iN cells (Marro et al., 2011). Intriguingly, the exact same three reprogramming factors were sufficient to induce iN cells from primary liver cultures as from fibroblasts. Taking advantage of a well-characterized Albumin-Cre allele, we unequivocally confirmed that Albumin-expressing hepatocytes were the origin of iN cells, thereby demonstrating that transcription factor-mediated lineage reprogramming is possible across major lineage boundaries. We were also able to assess the transcriptional network dynamics during reprogramming and to compare the expression profile of fibroblast- and hepatocyte-derived iN cells. These results indicated that the timing of the two reprogramming processes is different and hepatocytes appear to be more resistant to the lineage switch. Moreover, we also explored how thoroughly iN cells are reprogrammed. We found that the donor cell type-specific expression signatures were robustly silenced in both fibroblast- and hepatocyte-derived iN cells. This led us to the remarkable conclusion that the exact same three transcription factors can not only induce a neuronal program but can also downregulate two unrelated donor transcriptional
