Abstract
BackgroundThe fetal cortical neuroepithelium is a mosaic of distinct progenitor populations that elaborate diverse cellular fates. Ethanol induces apoptosis and interferes with the survival of differentiating neurons. However, we know little about ethanol's effects on neuronal progenitors. We therefore exposed neurosphere cultures from fetal rat cerebral cortex, to varying ethanol concentrations, to examine the impact of ethanol on stem cell fate.ResultsEthanol promoted cell cycle progression, increased neurosphere number and increased diversity in neurosphere size, without inducing apoptosis. Unlike controls, dissociated cortical progenitors exposed to ethanol exhibited morphological evidence for asymmetric cell division, and cells derived from ethanol pre-treated neurospheres exhibited decreased proliferation capacity. Ethanol significantly reduced the numbers of cells expressing the stem cell markers CD117, CD133, Sca-1 and ABCG2, without decreasing nestin expression. Furthermore, ethanol-induced neurosphere proliferation was not accompanied by a commensurate increase in telomerase activity. Finally, cells derived from ethanol-pretreated neurospheres exhibited decreased differentiation in response to retinoic acid.ConclusionThe reduction in stem cell number along with a transient ethanol-driven increase in cell proliferation, suggests that ethanol promotes stem to blast cell maturation, ultimately depleting the reserve proliferation capacity of neuroepithelial cells. However, the lack of a concomitant change in telomerase activity suggests that neuroepithelial maturation is accompanied by an increased potential for genomic instability. Finally, the cellular phenotype that emerges from ethanol pre-treated, stem cell depleted neurospheres is refractory to additional differentiation stimuli, suggesting that ethanol exposure ablates or delays subsequent neuronal differentiation.
Highlights
The fetal cortical neuroepithelium is a mosaic of distinct progenitor populations that elaborate diverse cellular fates
Children exposed to alcohol during gestation can exhibit a spectrum of abnormalities that range from Alcohol Related Neurodevelopmental Disorders (ARND) to Fetal Alcohol Syndrome (FAS), based upon the severity of symptoms
Differentiation, induced by removal of Epidermal Growth Factor and culturing neurosphere-derived cells on a laminin substrate, leads to clear nuclear expression of neuronal nuclear antigen (NeuN) (Figure 1C) and suppression of nestin immunoreactivity, suggesting that neurosphere-derived cells can be committed to a neuronal lineage
Summary
The fetal cortical neuroepithelium is a mosaic of distinct progenitor populations that elaborate diverse cellular fates. Children exposed to alcohol during gestation can exhibit a spectrum of abnormalities that range from Alcohol Related Neurodevelopmental Disorders (ARND) to Fetal Alcohol Syndrome (FAS), based upon the severity of symptoms. These abnormalities can include facial anomalies, growth deficits, mental retardation, attention deficit/hyperactivity disorders, motor difficulties, learning and memory impairment and psychological disorders such as depression [1,2,3,4,5,6,7,8,9]. We hypothesized that if ethanol influenced the proliferation of neuroepithelial cells, it would alter the numbers of stem cells within the cortical neuroepithelium
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