Glucagon-like peptide-1 differentiation of primate embryonic stem cells into insulin-producing cells.
The present study was performed to determine whether glucagon-like peptide-1 (GLP-1) stimulates differentiation of nestin-selected embryonic stem cells into insulin-producing cells. Our experimental strategy began with the production of a highly enriched population of nestin-positive cells from embryoid bodies. These cells differentiated into insulin-producing cells after addition of GLP-1. Islet-like cell clusters (ICCs) formed in inducing culture. These nestin-positive cell-derived ICCs expressed numerous beta-cell lineage genes, including insulin; Glut-2; pancreatic duodenal homebox-1 protein (PDX-1); islet amyloid polypeptide (IAPP); neurogenin 3 (ngn3); and alpha, gamma, and delta cell gene markers. Cells of ICCs showed increased insulin protein expression, glucose-dependent insulin release, and coexpression of insulin and C-peptide. In addition, ICCs were characterized by coexpression of nestin/insulin and nestin/PDX-1. The levels of pancreas-related gene and protein expression and insulin secretion in the GLP-1 group were stronger than those in the normal controls. GLP-1 has been shown to be involved in stimulating the signaling pathways downstream of the transcription factor PDX-1, by increasing its protein and messenger RNA levels. In vivo, ICCs displayed the ability to reverse hyperglycemia in diabetic severe combined immunodeficiency (SCID) mice. We concluded that GLP-1 induced differentiation of nestin-positive progenitor embryonic stem cells into insulin-producing cells, which was achieved by upregulation of PDX-1 expression. This method may have future applications in stem cell therapy of diabetes.
Yue
Fengming
F
Department of Anatomy and Organ Technology, Institute of Organ Transplants, Reconstructive Medicine and Tissue Engineering, Shinshu University Graduate School of Medicine, Nagano, Japan. yuefm@sch.md.shinshu-u.ac.jp
Cui
Li
L
Johkura
Kohei
K
Ogiwara
Naoko
N
Sasaki
Katsunori
K
D000818:Animals; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000378:metabolism; D008252:Macaca fascicularis; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D013234:Stem Cells / Q000166:cytology*; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics
D018398:Homeodomain Proteins; D007328:Insulin; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D052216:Glucagon-Like Peptide 1