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Oxytocin Enhances Proliferation and Alters Differentiation of Neural Progenitor Cells in Vitro
Abstract Number: BP-01
Abstract Type: Original Research
Introduction: Synthetic oxytocin (sOT) is widely used for the obstetric management of labor. Though the uterotonic and hemodynamic effects of sOT are well studied, not much is known about the direct effects of oxytocin on the fetus despite evidence that oxytocin crosses the placenta. Epidemiological evidence links sOT therapy with neurodevelopmental disorders, though the underlying mechanisms remain unexplored. Because these disorders are accompanied by changes in brain architecture, we speculated that sOT would alter the proliferation and differentiation of neural progenitor cells (NPCs), a key driver of early neurodevelopment.
Methods: NPCs were harvested from the telencephalons of Sprague Dawley rat embryos on gestational day 14 and propagated in culture. To confirm expression of OXTR, NPCs were seeded overnight on Poly-D-Lysine/Laminin coverslips, fixed, and processed for immunocytochemistry with specific primary and species-matched Alexa-Fluor® secondary antibodies. OXTR expression was also confirmed with immunoblotting. Because OXTR is a G-protein coupled receptor, we used a Gq second messenger functional assay to confirm the functional activity of these receptors (IP-One Elisa, Cisbio Assays, Bedford, MA). Finally, we investigated the effect of 24h of sOT treatment (100nM, 10μM) on NPC viability (propidium iodide), proliferation at 24h (ethynyl deoxyuridine and Ki67), and differentiation at day 10 (cell-specific markers). Imaging was done with GE In Cell Analyzer 2000, an automated high throughput epifluorescence microscope system, and analyzed with instrument-specific software. Data expressed as Mean ± S.D, and analyzed with one-way ANOVA.
Results: Both immunocytochemistry and immunoblotting revealed the presence of OXTR in NPCs. Stimulation of NPCs with 10μM sOT caused a significant increase in detectable inositol phosphate-1, a downstream product of the IP3 pathway, suggesting that the OXTR is functional. sOT increased NPC proliferation by 35% at both doses (P < 0.005***; Fig. 1), while treatment with 10μM sOT significantly increased neuronal but decreased oligodendrocytic differentiation of NPCs (P < 0.005***). Neither cell viability nor astrocytic fate was affected by sOT treatment.
Conclusion: Prolonged treatment with oxytocin profoundly affects NPC biology in vitro suggesting that it has the potential to alter neurodevelopment. Focused in vivo and behavioral studies are needed to ascertain the developmental impact of such perturbance.