Genes Inducing iPS Phenotype Play a Role in Hepatocyte Survival and Proliferation InVitro and Liver Regeneration InVivo

Reprogramming factors have been used to induce pluripotent stem cells as an alternative to somatic cell nuclear transfer technology in studies targeting disease models and regenerative medicine. The neuronal repressor RE-1 silencing transcription factor (REST) maintains self-renewal and pluripotency in mouse embryonic stem cells by maintaining the expression of Oct3/4, Nanog, and cMyc. We report that primary hepatocytes express REST and most of the reprogramming factors in culture. Their expression is up-regulated by hepatocyte growth factor (HGF) and epidermal growth factor (EGF). REST inhibition results in down-regulation of reprogramming factor expression, increased apoptosis, decreased proliferation, and cell death. The reprogramming factors are also up-regulated after 70% partial hepatectomy in vivo. Conclusion: These findings show that genes inducing the iPS phenotype, even though expressed at lower levels than embryonic stem cells, nonetheless are associated with control of apoptosis and cell proliferation in hepatocytes in culture and may play a role in such processes during liver regeneration. (HEPATOLOGY 2011;54:1360-1370)