Proteome, Transcriptome, and Function of Extracellular Vesicles Secreted by Fetal Neural Stem Cells in a Developmental Model of Alcohol Exposure

Abstract

Prenatal alcohol/ethanol exposure (PAE) can result in Fetal Alcohol Spectrum Disorders (FASD), the leading cause of intellectual disability and growth deficits, and have immediate and lifelong adverse effects on an individual’s development and health. When it comes to fetal neural stem cells (NSCs), the teratogenic effects of PAE that lead to FASD may be caused by the reprogramming of NSCs to result in abnormal cell proliferation, growth, differentiation, migration, and maturation. As a mechanism for intercellular communication, extracellular vesicles (EVs) have the potential to contribute to ethanol’s dysregulation of NSCs and be a key player within ethanol teratogenesis. For this reason, I examined the protein and RNA cargo and function of EVs derived from fetal NSCs under chronic alcohol exposure. To my knowledge, this is the first study to observe that the proteome and transcriptome of EVs differ from their parents-of-origin NSCs in a dose- and sex-dependent manner, caused by a transfer of unique networks of related proteins and related RNA transcripts. Exposure of untreated EVs to naïve NSCs resulted in decreased oxidative metabolism and S-phase, with EVs derived from ethanol-treated NSCs exhibiting diminished effects. The data suggest a presence of a selective sorting mechanism that controls protein and RNA sequestration from cells into EVs, that is vulnerable to ethanol, altering the cargo content of EVs and potentially reprogramming the functionality of EVs in the neurogenic environment to contribute to the pathology of PAE and FASD.