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

• Published in: Biochemical and biophysical research communications 2007-04, Vol.355 (2), p.331-337
• Main Authors: Ball, Andrew J., Abrahamsson, Annelie E., Tyrberg, Björn, Itkin-Ansari, Pamela, Levine, Fred
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ANIMAL GROWTH; Animals; Basic Helix-Loop-Helix Transcription Factors - physiology; BIOLOGICAL RECOVERY; CELL DIFFERENTIATION; Cell Fusion; Cell Line; Cell Nucleus - metabolism; Differentiation; Homeodomain Proteins - metabolism; Humans; Hybrid Cells; HYBRIDIZATION; INSULIN; Insulin - biosynthesis; Islet; Islets of Langerhans - metabolism; MICE; PANCREAS; Polymerase Chain Reaction; Repressor Proteins - physiology; Somatic cell hybrids; SOMATIC CELLS; Trans-Activators - metabolism; TRANSCRIPTION FACTORS; β-Cell
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2007.01.153

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.