Transdifferentiation, the process of converting from one cell type to another without going through a pluripotent state, has great promise for regenerative medicine. The identification of key transcription factors for reprogramming is currently limited by the cost of exhaustive experimental testing of plausible sets of factors, an approach that is inefficient and unscalable. Here we present a predictive system (Mogrify) that combines gene expression data with regulatory network information to predict the reprogramming factors necessary to induce cell conversion. We have applied Mogrify to 173 human cell types and 134 tissues, defining an atlas of cellular reprogramming. Mogrify correctly predicts the transcription factors used in known transdifferentiations. Furthermore, we validated two new transdifferentiations predicted by Mogrify. We provide a practical and efficient mechanism for systematically implementing novel cell conversions, facilitating the generalization of reprogramming of human cells. Predictions are made available to help rapidly further the field of cell conversion.
Recent reports on the characteristics of naive human pluripotent stem cells (hPSCs) obtained using independent methods differ. Naive hPSCs have been mainly derived by conversion from primed hPSCs or by direct derivation from human embryos rather than by somatic cell reprogramming. To provide an unbiased molecular and functional reference, we derived genetically matched naive hPSCs by direct reprogramming of fibroblasts and by primed-to-naive conversion using different naive conditions (NHSM, RSeT, 5iLAF and t2iLGöY). Our results show that hPSCs obtained in these different conditions display a spectrum of naive characteristics. Furthermore, our characterization identifies KLF4 as sufficient for conversion of primed hPSCs into naive t2iLGöY hPSCs, underscoring the role that reprogramming factors can play for the derivation of bona fide naive hPSCs.
Reprogramming human somatic cells to primed or naive induced pluripotent stem cells (iPSC) recapitulates the different stages of early human embryonic development [1][2][3][4][5][6] . The molecular mechanism underpinning the reprogramming of human somatic cells to primed or naive induced pluripotency remains largely unexplored, impeding our understanding and limiting rational improvements to reprogramming protocols. To address this, we reconstructed molecular reprogramming trajectories using single-cell transcriptomics. This revealed that reprogramming into primed and naive human pluripotency follows diverging and distinct trajectories. Moreover, genome-wide accessible chromatin analyses showed key changes in regulatory elements of core pluripotency genes, and orchestrated global changes in chromatin accessibility over time. Integrated analysis of these datasets unveiled an unexpected role of trophectoderm (TE) lineage-associated transcription factors and the existence of a subpopulation of cells that enter a TE-like state during reprogramming. Furthermore, this TE-like state could be captured, allowing the derivation of induced Trophoblast Stem Cells (iTSCs). iTSCs are molecularly and functionally similar to TSCs derived from human blastocysts or first-trimester placental trophoblasts 7 . Altogether, these results provide a high-resolution roadmap for transcription factor-mediated human 3 reprogramming, revealing an unanticipated role of the TE-lineage specific regulatory program during this process and facilitating the direct reprogramming of somatic cells into iTSCs.
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