Hepatic reprogramming occurs in a time-independent manner via an initial asymmetric division and continued mitotic...

Recent advancements in cellular reprogramming make it possible to alter cell fate, yet its mechanisms remain largely unclear. While previous studies have explored the link between cell division and reprogramming, it is still unknown why some cells reprogram under identical conditions, while others do not. In this study, we used the direct reprogramming of fibroblasts into induced hepatocyte-like cells (iHepCs) as a model to address this issue. Time-lapse imaging was performed throughout the entire reprogramming process, from the introduction of reprogramming factors to the completion of iHepC conversion. Spatiotemporal single-cell tracking revealed that the direct hepatic reprogramming follows a hybrid model, combining elite and stochastic models. Elite-like cells emerge from the earliest cell divisions, undergo random selection, and successfully reprogram a subset of their descendants. Moreover, cells that ultimately become iHepCs exhibited active division both before and after reprogramming. These results suggest that targeting active cell division may enhance reprogramming efficiency.