Sevoflurane inhibits embryonic stem cell self-renewal and subsequent neural differentiation by modulating the let-7a-Lin28 signaling pathway

Abstract

The commonly used inhalational anesthetic, sevoflurane, can cause toxicity to the central nervous system of the developing fetus. Lin28 has been reported to regulate let-7a, thereby modulating embryo development, neurodegeneration, and even neuron-related tumorigenesis. We demonstrate that pregnant mice receiving sevoflurane treatment during the early stage of pregnancy give birth to fewer offspring presenting a lower birth weight. We have also treated mouse embryonic stem cells (mESCs) with sevoflurane for 6 h and determined that mESCs self-renewal is repressed, and that differentiation is initiated earlier than in controls. We have induced neural differentiation in the treated mESCs and determined that their neurogenesis is weakened. Furthermore, sevoflurane upregulates the level of let-7a, which might repress mESC self-renewal by directly targeting the Lin28 3'-untranslated region. Lin28 overexpression attenuates the influence of sevoflurane or of let-7a on the self-renewal of mESCs and their subsequent neural differentiation. The let-7a inhibitor also abolishes the influence of sevoflurane. Thus, the let-7a-Lin28 pathway is involved in the sevoflurane-induced inhibition of ESC self-renewal and subsequent neurogenesis. Our study demonstrates the molecular mechanism underlying the side effects of sevoflurane during early development, laying the foundation for studies on the safe and reasonable usage of other inhalational anesthetics.

Maternal sevoflurane exposure affects differentiation of hippocampal neural stem cells by regulating miR-410-3p and ATN1

“…Although some study results have shown certain anesthesia drugs may affect NSC differentiation, the ndings are con icting and controversial during different periods of brain development. For example, in a previous study, 4.1% sevo urane for 6 h repressed neural differentiation by in uencing self-renewal of mouse embryonic stem cells (mESCs) (Yi, Cai, Zhang, Wang, & Li, 2016). In another study, 7-day-old rats exposed to ketamine showed signi cantly reduced number of nestin/BrdU double-stained positive cells and GFAP/BrdU double-stained positive cells and increased number of β-tubulin III/BrdU double-stained positive cells (Huang et al, 2015).…”

“…In the present study, 3% sevo urane (1.5 minimum alveolar concentration, MAC) was chosen on pregnant rats, a commonly used concentration in clinical non-obstetric surgeries. 4.1% sevo urane was commonly used in NSCs to explore the neurotoxicity of SEV in vitro in previous studies (Yi et al, 2016) (S. Liu et al, 2018. There are other studies (Y.…”

Maternal sevoflurane exposure affects differentiation of hippocampal neural stem cells by regulating microRNA-410-3p and ATN1

“…In the present study, 3% sevo urane (1.5 minimum alveolar concentration, MAC) was chosen on pregnant rats, a commonly used concentration in clinical non-obstetric surgeries. 4.1% sevo urane was commonly used in NSCs to explore the neurotoxicity of SEV in vitro in previous studies (Yi et al, 2016) (S. Liu et al, 2018. There are other studies (Y. Zhang et al, 2019) (J. Zhang, Dong, Zhou, Zhang, & Xie, 2015) using 3% SEV in vivo and 4.1% SEV in vitro to investigate the mechanism of SEV.…”

LncRNA Riken‐201 and Riken‐203 modulates neural development by regulating the Sox6 through sequestering miRNAs

“…3 In mouse embryonic retinas, miR-96 expression level is minimal and up-regulates following birth, peaking in adult retinas. 60,61 The mechanisms by which these effects are created have yet to be identified, impeding further research in anaesthesia neurotoxicity in the developing brain. 60,61 The mechanisms by which these effects are created have yet to be identified, impeding further research in anaesthesia neurotoxicity in the developing brain.…”