Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia

Abstract

Dysfunction of neural stem cells (NSCs) has been linked to fetal neuropathy, one of the most devastating complications of gestational diabetes. Several studies have demonstrated that melatonin (Mel) exerted neuroprotective actions in various stresses. However, the role of autophagy and the involvement of Mel in NSCs in hyperglycemia (HG) have not yet been fully established. Here, we found that HG increased autophagy and autophagic flux of NSCs as evidenced by increasing LC3B II/I ratio, Beclin-1 expression, and autophagosomes. Moreover, Mel enhanced NSCs proliferation and self-renewal in HG with decreasing autophagy and activated mTOR signaling. Consistently, inhibition of autophagy by 3-Methyladenine (3-Ma) could assist Mel effects above, and induction of autophagy by Rapamycin (Rapa) could diminish Mel effects. Remarkably, HG induced premature differentiation of NSCs into neurons (Map2 positive cells) and astrocytes (GFAP positive cells). Furthermore, Mel diminished HG-induced premature differentiation and assisted NSCs in HG differentiation as that in normal condition. Coincidentally, inhibiting of NSCs autophagy by 3-Ma assisted Mel to modulate differentiation. However, increasing NSCs autophagy by Rapa disturbed the Mel effects and retarded NSCs differentiation. These findings suggested that Mel supplementation could contribute to mimicking normal NSCs proliferation and differentiation in fetal central nervous system by inhibiting autophagy in the context of gestational diabetes. STEM CELLS 2019;37:504-515 SIGNIFICANCE STATEMENTNeural stem cells play important roles in fetal neurodevelopment. The incidences of gestational diabetes are rising in the world and prevention of fetal neuropathy in gestational diabetes mellitus (GDM) needs to be deeply explored. In addition, autophagy of NSCs in HG is still unclear. Here, it is reported that HG inhibits proliferation and induces premature differentiation of NSCs by promoting autophagy and autophagic flux. The naturally occurring hormone melatonin (Mel) antagonized HG-mediated effects and maintained normal proliferation and differentiation in NSCs by modulating autophagy, which protected NSCs mainly by downregulating Beclin-1 and up modulating mTORC1 signaling. This work indicates that Mel could be used as a potential drug to aid in fetal central nervous system (CNS) development in GDM patients.

Protective Effects of Melatonin on Neurogenesis Impairment in Neurological Disorders and Its Relevant Molecular Mechanisms

“…DM also causes fetal neurodevelopmental impairment. When female mice were subjected to STZ before pregnancy for 3 consecutive days and then fertilized with healthy male mice, the E11.5 and E17.5 mouse embryos showed decreased proliferation and increased premature differentiation of NSCs in the brain [ 110 ]. Nevertheless, melatonin could attenuate the STZ-induced neurodevelopmental deficits by inhibiting autophagy and preventing apoptosis in the embryonic brain [ 110 , 111 ].…”

“…When female mice were subjected to STZ before pregnancy for 3 consecutive days and then fertilized with healthy male mice, the E11.5 and E17.5 mouse embryos showed decreased proliferation and increased premature differentiation of NSCs in the brain [ 110 ]. Nevertheless, melatonin could attenuate the STZ-induced neurodevelopmental deficits by inhibiting autophagy and preventing apoptosis in the embryonic brain [ 110 , 111 ]. In the in vitro experiments, it was also reported that melatonin could protect the embryonic NSCs from cell death and impairments in proliferation and differentiation in the hyperglycemia condition [ 110 , 111 ] ( Table 12 and Table 13 ).…”

“…Nevertheless, melatonin could attenuate the STZ-induced neurodevelopmental deficits by inhibiting autophagy and preventing apoptosis in the embryonic brain [ 110 , 111 ]. In the in vitro experiments, it was also reported that melatonin could protect the embryonic NSCs from cell death and impairments in proliferation and differentiation in the hyperglycemia condition [ 110 , 111 ] ( Table 12 and Table 13 ).…”

MBNL1 reverses the proliferation defect of skeletal muscle satellite cells in myotonic dystrophy type 1 by inhibiting autophagy via the mTOR pathway

“…However, macrophagy (henceforth named autophagy), a protein-degradation system closely related to cell proliferation 21 , is also involved in repairing damaged skeletal muscle 22 and reversing muscle atrophy 23 , 24 . Previous studies have reported that melatonin can promote proliferation of neural stem cells by repressing elevated autophagy under hyperglycemic conditions 25 . Suppressing autophagy can also enhance the proliferation of germ cells 26 .…”

N‐acetylcysteine alleviated paraquat‐induced mitochondrial fragmentation and autophagy in primary murine neural progenitor cells

“…However, dying neurons display grossly enhanced autophagic features, indicating that autophagy may mediate cell death (Xie et al, 2016). Moreover, some studies suggest that autophagy is involved in NSC function maintenance (Li, Zhang, et al, 2019;Wang, Wang, Cai, & Xu, 2018). Our previous study documented that PQ may induce autophagic cell death in neural progenitor cells (NPCs) (Zhao et al, 2018;Zhao, Yan, & Wang, 2016).…”