Abstract

Up-regulation of MafA renders embryonic progenitor-derived insulin-producing cells towards maturation and functional improvement both in vitro and in vivo

GuoDong Li, Snr Principal Research Scientist , Singapore General Hospital (SGH)

Our previous work has generated insulin-producing cells (IPCs) from mouse ES cells and embryos-derived progenitor cells, but they revealed features of immaturity and failed to function completely alike adult ß-cells. This study aimed to investigate if up-regulation of MafA, a master transcription factor in regulating ß-cell development and glucose responsiveness, could improve these cells. MafA levels in IPCs could be significantly elevated near to that in isolated adult islets by a lentivirus-based system. Consequently, insulin production was augmented and the expression of many genes essential for ß-cell development and function was significantly enhanced. These cells also exhibited higher activity of signaling events required for glucose-stimulated insulin secretion including metabolism, membrane potential depolarization and intracellular Ca2+ rise. MafA up-regulation markedly improved glucose-stimulated insulin secretion by reducing basal insulin release and shifting the dose-response curve of insulin secretion upon glucose stimulation closer to physiological pattern. When transplanted into streptozotocin-induced diabetic mice, MafA-upregulated IPCs were able to correct hyperglycemia for a longer term and reduce the hypoglycemic incidences. Moreover, MafA up-regulation slowed down cell growth with elevated expression of p27. These findings indicate that MafA can promote maturation of embryonic stem cell-derived IPCs, enabling them to achieve better correction of hyperglycemia for diabetes.