Pro-oxidant/antioxidant balance controls pancreatic β-cell differentiation through the ERK1/2 pathway

E Hoarau,P Rustin,R Scharfmann,V Chandra,B Duvillie

doi:10.1038/cddis.2014.441

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.

Highlights

Reactive oxygen species (ROS) have been implicated in various human diseases including cancer and Parkinson’s disease.[2]
We examined the mitogen-activated protein kinase (MAPK) ERK1/2 pathway that was recently shown to be sensitive to ROS production in several cell types.[29]
We have demonstrated that ROS have a significant impact on pancreatic progenitor cell differentiation

Summary

Introduction

ROS have been implicated in various human diseases including cancer and Parkinson’s disease.[2] low physiological levels of ROS have been reported recently to operate as signaling molecules.[3] depending on the context, ROS can modulate cell proliferation,[4] survival,[5] and differentiation.[6]. Inactivating enzymes are expressed at very low levels in pancreatic β-cells, rendering them highly sensitive to oxidative stress.[7,8] Hyperglycemia is a cause of oxidative stress-related damage in a number of cell types, including neurons, retinal cells, vascular endothelium,[9] and pancreatic β-cells. In human type II diabetes, the link between oxidative stress and β-cell dysfunction is well established.[11,12] despite these toxic effects, recent findings have shed light on the necessity of ROS for β-cell function.[13]. PDX1 is necessary for the morphogenesis and differentiation of the pancreatic buds in both rodents and humans.[17,18] Upon FGF10 signaling, the pancreatic epithelium grows.[19]

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Conclusion