GSE176206
Partial reprogramming restores youthful gene expression through transient suppression of cell identity
Transient induction of pluripotent reprogramming factors has been reported to reverse some features of aging in mammalian cells and tissues. However, the impact of transient reprogramming on somatic cell identity programs and the necessity of individual pluripotency factors remain unknown. Here, we mapped trajectories of transient reprogramming in young and aged cells from multiple murine cell types using single cell transcriptomics to address these questions. We found that transient reprogramming restored youthful gene expression in adipogenic cells and mesenchymal stem cells but also temporarily suppressed somatic cell identity programs. We further screened Yamanaka Factor subsets and found that many combinations had an impact on aging gene expression and suppressed somatic identity, but that these effects were not tightly entangled. We also found that a transient reprogramming approach inspired by amphibian regeneration restored youthful gene expression in aged myogenic cells. Our results suggest that transient pluripotent reprogramming poses a neoplastic risk, but that restoration of youthful gene expression can be achieved with alternative strategies. Overall design: Mouse adipogenic cells and mesenchymal stem cells (MSCs) were treated with inducible OSKM reprogramming factors delivered by lentivirus for 3 days followed by a 3 day chase and subsequently profiled by single cell RNA-seq. MSCs were treated with barcoded lentiviral vectors carrying each of the OSKM factors separately. Cells from young (2-4 months old) and aged (20-30 months old) animals were used for all experiments. Myogenic cells from aged animals were treated with transient Msx1 expression on an inducible lentivirus for 3 days followed by a 3-4 day chase period. Pooled screens were performed with barcoded S, O, K, M viruses in MSCs.