title: Obestatin enhances in vitro generation of pancreatic islets through regulation of developmental pathways.
abstract: Availability of large amounts of in vitro generated β-cells may support replacement therapy in diabetes. However, methods to obtain β-cells from stem/progenitor cells are limited by inefficient endocrine differentiation. We have recently shown that the ghrelin gene product obestatin displays beneficial effects on pancreatic β-cell survival and function. Obestatin prevents β-cell apoptosis, preserves β-cell mass and stimulates insulin secretion in vitro and in vivo, in both normal and diabetic conditions. In the present study, we investigated whether obestatin may promote in vitro β-cell generation from mouse pancreatic islet-derived precursor cells. Treatment of cultured islets of Langerhans with obestatin (i) enriched cells expressing the mesenchymal/neuronal marker nestin, which is associated with pancreatic precursors; (ii) increased cell survival and reduced apoptosis during precursor selection; (iii) promoted the generation of islet-like cell clusters (ICCs) with increased insulin gene expression and C-peptide secretion. Furthermore, obestatin modulated the expression of fibroblast growth factor receptors (FGFRs), Notch receptors and neurogenin 3 (Ngn3) during islet-derived precursor cell selection and endocrine differentiation. These results indicate that obestatin improves the generation of functional β-cells/ICCs in vitro, suggesting implications for cell-based replacement therapy in diabetes. Moreover, obestatin may play a role in regulating pathways involved in pancreas development and regeneration.
authors.affiliation: Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baragli
authors.forename: Lessandra
authors.initials: L
authors.lastname: Baragli
authors.forename: Cristina
authors.initials: C
authors.lastname: Grande
authors.forename: Iacopo
authors.initials: I
authors.lastname: Gesmundo
authors.forename: Fabio
authors.initials: F
authors.lastname: Settanni
authors.forename: Marina
authors.initials: M
authors.lastname: Taliano
authors.forename: Davide
authors.initials: D
authors.lastname: Gallo
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gargantini
authors.forename: Ezio
authors.initials: E
authors.lastname: Ghigo
authors.forename: Riccarda
authors.initials: R
authors.lastname: Granata
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002096:C-Peptide / Q000096:biosynthesis / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects*; D007328:Insulin / Q000096:biosynthesis / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin / Q000235:genetics / Q000378:metabolism; D036361:Peptide Hormones / Q000378:metabolism / Q000494:pharmacology*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D002096:C-Peptide; D007328:Insulin; D009419:Nerve Tissue Proteins; D064231:Nestin; D036361:Peptide Hormones; D017468:Receptors, Fibroblast Growth Factor; D051880:Receptors, Notch; C577485:Nes protein, mouse; C407737:Neurog3 protein, mouse; C512328:obestatin, mouse