Isoflurane Inhibits Embryonic Stem Cell Self-Renewal and Neural Differentiation Through miR-9/E-cadherin Signaling.

The commonly used inhalation anesthetic, isoflurane, can permeate rapidly through the placental barrier and thus cause toxicity to the central nervous system of the developing fetus. In this study, we treated pregnant mice with clinically relevant concentration of isoflurane early on in development (days 3.5-6.5), and then found that the fetus growth was inhibited by isoflurane. We further used the mouse embryonic stem cell (mES cell) to be the early development model to investigate the mechanism of the embryotoxicity of isoflurane and found that isoflurane inhibited self-renewal of mES cells. In addition, neuronal differentiation from the mES cells treated with isoflurane was also inhibited. Overexpression of E-cadherin attenuated the effects of isoflurane on self-renewal and the subsequent neuronal differentiation. We also found that miR-9 can be upregulated by isoflurane. Overexpression of miR-9 inhibited the self-renewal and subsequent neuronal differentiation. E-cadherin was directly targeted by miR-9. Overexpression of E-cadherin can abolish the function of miR-9 or isoflurane on self-renewal and subsequent neuronal differentiation. These data suggested that isoflurane inhibits self-renewal and neuronal differentiation of mES cells, possibly by regulating the miR-9-E-cadherin signaling. The result of the current study may provide a novel idea for preventing the toxicity of inhalation anesthetics in the developing fetal brain in clinical practice when pregnant women accept nonobstetric surgery under inhalation general anesthesia.