Noninvasive assessment of fetal central nervous system insult: Potential application to prenatal diagnosis

Abstract

Objective: We have developed novel methods for isolating fetal central nervous system (CNS)-derived extracellular vesicles (FCEs) from maternal plasma as a noninvasive platform for testing aspects of fetal neurodevelopment in early pregnancy.We investigate the hypothesis that levels of defined sets of functional proteins in FCEs can be used to detect abnormalities in fetal neuronal and glial proliferation, differentiation, and survival.Method: Maternal plasma was obtained between 10 and 19 weeks from women with current heavy EtOH exposure and matched controls. FCE levels of synaptophysin, synaptotagmin, synaptopodin, and neurogranin were quantified normalized to the exosome marker CD81. Quantitative RT-PCR was performed with specific primers for miR-9.Results: FCE cargo protein levels of synaptophysin, synaptotagmin, synaptopodin, and neurogranin were all significantly reduced in pregnancies exposed to current heavy EtOH use (P < .001 for all). Both synaptophysin and neurogranin appeared to be particularly discriminatory with no overlap between exposed and control subjects.Up to tenfold inhibition (90%) in MicroRNA-9 was observed in FCEs from EtOH exposed fetuses compared with controls. Conclusion:Our results suggest that FCEs purified from maternal plasma may be a powerful tool to assess abnormal proliferation and differentiation of CNS stem cells as early as the late first trimester.

Role of Exosomes in Central Nervous System Diseases

“…Exosomes can be used as both therapeutic means and ideal biological indicators in central nervous system diseases, and of course, this ability can apply to other diseases as well. The non-invasive nature of exosome analysis means that it can be safely used for prenatal evaluation of fetal central nervous system injury (Goetzl et al, 2019), and diagnostic testing of elderly patients (Cicognola et al, 2019).…”

The Role of Extracellular Vesicles in the Developing Brain: Current Perspective and Promising Source of Biomarkers and Therapy for Perinatal Brain Injury

“…In addition to the above established and putative roles of EVs within the brain, accumulating evidence suggests that the number and composition of EVs can reflect both healthy and pathological states within the CNS (Fiandaca et al, 2015;Yan et al, 2017;Goetzl et al, 2019;Ohmichi et al, 2019). Although investigations are yet in their infancy, evidence suggests that EVs are found throughout the developing CNS (Morton and Feliciano, 2016) and are likely responsible, at least in part, for normal and pathophysiological brain development in the embryonic and early fetal periods.…”

“…A recently revealed key characteristic of small EVs derived from the fetal CNS is that they are able to cross the fetal BBB and the placental barrier into the maternal circulation making them an attractive source of biomarkers (Sheller-Miller et al, 2016;Goetzl et al, 2019). Adsorptive-mediated transcytosis, translocation and passage from the CSF via arachnoid granulations are all proposed mechanisms of small EV transfer from the CNS into the periphery (Thompson et al, 2016;Matsumoto et al, 2017).…”

Role of Extracellular Vesicles in Placental Inflammation and Local Immune Balance

“…They found that reduced expression of EV-transmitting miR-300 and miR-299-5p in amniotic fluid of congenital hydronephrosis could predict renal fibrosis. Interestingly, studies by Goetzl et al showed that EVs derived from fetal central nervous system could be purified from maternal plasma, which was related to the abnormal proliferation and differentiation of neural stem cells [ 100 ]. Therefore, EVs may be a potential way for early prenatal diagnosis of fetal neurological diseases.…”