Modulation of Specific Beta Cell Gene (Re)Expression during In Vitro Expansion of Human Pancreatic Islet Cells

Abstract

The need for transplantable beta cells with a stable phenotype has given rise to several strategies including the expansion of existing pancreatic islets and/or growth of new ones. In vitro studies of beta cell proliferation on extracellular matrices plus growth factors have highlighted a possible cell expansion technique; however, the technique was accompanied with loss of insulin secretion. Herein we showed that human islet cell proliferation was marked by a decreased expression of specific differentiation markers, particularly insulin, insulin promoting factor-1 (IPF-1), and glucokinase. After a 6-day expansion period, we tried to reexpress the beta cell differentiation markers with compounds known for their differentiation and/or insulin-secreting properties. Sodium butyrate was a potent factor of IPF-1, insulin, and glucokinase gene reexpression; it also clearly induced secretion of gastrin, a known neogenic factor. Other compounds, namely TGF-β, calcitriol, GLP-1, and activin A, efficiently enhanced the glucose sensor machinery, particularly Glut-1 and glucokinase, thus triggering glucose responsiveness. Our results indicate that specific beta cell gene expression may be induced after expansion and dedifferentiation. This rekindles interest in human beta cell expansion. The possible stabilization of specialized genes needed by beta cells to fulfill their role as nutrient sensors and metabolic regulators may also be of interest to ensure graft maintenance and efficiency.