The FASEB Journal, April 2014.
Twaroski D, Bail X, Olson J, Yan Y, Liu Y, Bosnjak, Z.
Recent studies in animal models have suggested that anesthetics such as propofol, when administered early in life, can lead to neurotoxicity. These studies have raised safety concerns regarding the use of anesthetics in the pediatric population. Human embryonic stem cells (hESCs) are capable of differentiating into any cell type and represent a promising model by which to study mechanisms governing anesthetic-induced neurotoxicity in humans. In this study, we assessed the effects of propofol on hESC-derived neurons and the role of microRNAs (miRs) in the toxicity observed. hESCs were differentiated into neurons following a four-step differentiation protocol. Cell death in the hESC-derived neurons was assessed using TUNEL staining and microRNA expression was assessed using qRT-PCR. miR-21 was overexpressed using a miR-21 mimic and the expression of the miR-21 targets of interest was assessed by Western blot. Exposure to 20 µg/mL propofol for 6 hours induced significant cell death in the hESC-derived neurons and downregulated several microRNAs, including miR-21. Overexpression of miR-21 significantly attenuated the increase in cell death following propofol administration. In addition, several targets within the miR-21 pathway (eg. Sprouty 2 and pSTAT3) were significantly altered by propofol exposure, suggesting that miR-21 is contributing to the propofol-induced neurotoxicity.
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