Abstract
Alcohol (ethanol, EtOH) consumption during pregnancy can result in fetal alcohol spectrum disorders (FASDs), which are characterized by prenatal and postnatal growth restriction and craniofacial dysmorphology. Recently, cell-derived extracellular vesicles, including exosomes and microvesicles containing several species of RNAs (exRNAs), have emerged as a mechanism of cell-to-cell communication. However, EtOH’s effects on the biogenesis and function of non-coding exRNAs during fetal development have not been explored. Therefore, we studied the effects of maternal EtOH exposure on the composition of exosomal RNAs in the amniotic fluid (AF) using rat fetal alcohol exposure (FAE) model. Through RNA-Seq analysis we identified and verified AF exosomal miRNAs with differential expression levels specifically associated with maternal EtOH exposure. Uptake of purified FAE AF exosomes by rBMSCs resulted in significant alteration of molecular markers associated with osteogenic differentiation of rBMSCs. We also determined putative functional roles for AF exosomal miRNAs (miR-199a-3p, miR-214-3p and let-7g) that are dysregulated by FAE in osteogenic differentiation of rBMSCs. Our results demonstrate that FAE alters AF exosomal miRNAs and that exosomal transfer of dysregulated miRNAs has significant molecular effects on stem cell regulation and differentiation. Our results further suggest the usefulness of assessing molecular alterations in AF exRNAs to study the mechanisms of FAE teratogenesis that should be further investigated by using an in vivo model.
Highlights
IntroductionAlcohol (ethanol, EtOH) consumption is recognized as the leading preventable cause of birth defects and intellectual diability [1]
Alcohol consumption is recognized as the leading preventable cause of birth defects and intellectual diability [1]
Effects of Amniotic fluid (AF) exosomes from fetal alcohol exposure (FAE) on osteogenic potency of rat bone marrow stem cells We have recently reported EtOH’s significant effects on genetic and epigenetic signatures in human ESCs, human embryonic stem cells (hESCs)-derived neural stem cells and adult stem cells [6, 8, 35], and others showed that EtOH altered the differentiation potential of AF-derived stem cells [9]
Summary
Alcohol (ethanol, EtOH) consumption is recognized as the leading preventable cause of birth defects and intellectual diability [1]. While the developmental defects from alcohol abuse during gestation have been described, the specific mechanisms by which alcohol mediates these injuries have yet to be determined [3, 4]. This is an important question to address if we are to identify affected children at an early age and intervene to prevent or mitigate the damage. We recently described the molecular signatures of EtOH’s effects on pluripotency and differentiation of human embryonic stem cells (hESCs), hESC-derived neuronal stem cells, as well as adult dental pulp mesenchymal stem cells (MSCs) [6,7,8]. Studies showed that EtOH exposure alters the differentiation potential of amniotic fluid-derived stem cells [9] and reduces neuronal stem cell numbers in developing and adult brains [10, 11]
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