HES6 reverses nuclear reprogramming of insulin-producing cells following cell fusion

To examine the mechanism by which growth-stimulated pancreatic β-cells dedifferentiate, somatic cell fusions were performed between MIN6, a highly differentiated mouse insulinoma, and βlox5, a cell line derived from human β-cells which progressively dedifferentiated in culture. MIN6/βlox5 somatic cells hybrids underwent silencing of insulin expression and a marked decline in PDX1, NeuroD, and MafA, indicating that βlox5 expresses a dominant transacting factor(s) that represses β-cell differentiation. Expression of Hes1, which inhibits endocrine differentiation was higher in hybrid cells than in parental MIN6 cells. Hes6, a repressor of Hes1, was highly expressed in primary β-cells as well as MIN6, but was repressed in hybrids. Hes6 overexpression using a retroviral vector led to a decrease in Hes1 levels, an increase in β-cell transcription factors and partial restoration of insulin expression. We conclude that the balance of Notch activators and inhibitors may play an important role in maintaining the β-cell differentiated state.