The present invention pertains to a method for creating reprogramed cells from somatic cells without gene introduction. The method includes a step (a) for culturing somatic cells in a medium containing a histone deacetylase inhibitor, and a step (b) for culturing the cells cultured in step (a) in a medium containing an OCT3/4 transcription stimulating factor to create reprogrammed cells.

Human pluripotent stem cells (hPSCs) are a concrete source of hepatic cells for regenerative medicine applications and are largely contributing to the study of liver diseases, toxicity, and drug efficacy. However, hP SC-derived hepatocyte-like cells possess morphological and functional features typical of foetal hepatocytes rather than post-natal or adult hepatocytes. By self-assembling hepatic progenitors into spheroids and by refining the maturation step of their differentiation protocol, the inventors aim at generating hPSC-derived hepatocyte-like cells with an improved maturation degree, showing morphological and functional features of adult hepatocytes. More particularly, they adjusted the morphogen cocktail used for the maturation step by the regular administration of vitamin Kl, a daily regulation of glucocorticoid supply, and a progressive decrease of Oncostatin M (OSM) supply in the last days. They demonstrated that the hepatocytes produced with their protocol have reached the highly functional ability of primary human hepatocytes, an improved maturation stage compared to previously reported data on hPSC-derived hepatocytes. Thus the invention relates to a new method for improving the differentiation of hepatoblasts into hepatocytes.