title: Pro-oxidant/antioxidant balance controls pancreatic β-cell differentiation through the ERK1/2 pathway.
abstract: During embryogenesis, the intrauterine milieu affects cell proliferation, differentiation, and function by modifying gene expression in susceptible cells, such as the pancreatic β-cells. In this limited energy environment, mitochondrial dysfunction can lead to overproduction of reactive oxygen species (ROS) and to a decline in β-cell function. In opposition to this toxicity, ROS are also required for insulin secretion. Here we investigated the role of ROS in β-cell development. Surprisingly, decreasing ROS production in vivo reduced β-cell differentiation. Moreover, in cultures of pancreatic explants, progenitors were highly sensitive to ROS stimulation and responded by generating β-cells. ROS enhanced β-cell differentiation through modulation of ERK1/2 signaling. Gene transfer and pharmacological manipulations, which diminish cellular ROS levels, also interfered with normal β-cell differentiation. This study highlights the role of the redox balance on β-cell development and provides information that will be useful for improving β-cell production from embryonic stem cells, a step in cell therapy for diabetes.
authors.affiliation: 1] INSERM, U1016, Institut Cochin, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Hoarau
authors.affiliation: 1] INSERM, U1016, Institut Cochin, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: V
authors.initials: V
authors.lastname: Chandra
authors.affiliation: INSERM U676, Hopital Robert Debre, Paris, France.
authors.forename: P
authors.initials: P
authors.lastname: Rustin
authors.affiliation: 1] INSERM, U1016, Institut Cochin, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: R
authors.initials: R
authors.lastname: Scharfmann
authors.affiliation: 1] INSERM, U1016, Institut Cochin, Paris, France [2] Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.
authors.forename: B
authors.initials: B
authors.lastname: Duvillie
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002374:Catalase / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D004622:Embryo, Mammalian / Q000166:cytology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006861:Hydrogen Peroxide / Q000633:toxicity; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D017208:Rats, Wistar
chemical_list: D000111:Acetylcysteine; D000975:Antioxidants; D051792:Basic Helix-Loop-Helix Proteins; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D002374:Catalase; D006861:Hydrogen Peroxide; D009419:Nerve Tissue Proteins; D016877:Oxidants; C498696:Neurog3 protein, rat