Activation of canonical Wnt signaling is required for efficient direct reprogramming into human hepatic progenitor cells.

Direct reprogramming is a technique for elucidating the mechanisms that control cell-fate decisions and holds promise as a therapeutic strategy. We previously showed that a specific combination of three transcription factors (FOXA3, HNF1A, and HNF6) can induce direct reprogramming of human umbilical vein endothelial cells (HUVECs) into human induced hepatic progenitor cells (hiHepPCs). However, low reprogramming efficiency limits their application in research and therapy. Here, we show that activation of the canonical Wnt signaling pathway increases the reprogramming efficiency of HUVECs to hiHepPCs by rapidly inducing chromatin remodeling and gene expression changes in the transduced HUVECs. Moreover, endogenous Wnt activation, mainly mediated by WNT2B, is required for the initiation of direct reprogramming from HUVECs to hiHepPCs. Wnt activation that allows rapid induction of hiHepPCs enables efficient production of a large amount of hiHepPCs, which is an advantage in research and clinical applications using hiHepPCs and their descendants.