Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia
Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia
复制标题
褪黑激素通过高血糖中的自噬增强神经干细胞的增殖并调节分化
DOI：
10.1002/stem.2968
复制
发表时间：
2019-04-01
期刊：
影响因子：
5.2
通讯作者：
Ni, Shilei
中科院分区：
文献类型：
--
作者：
Li, Haoyuan;Zhang, Yanmin;Ni, Shilei
神经干细胞（NSC）的功能障碍与胎儿神经病变有关，这是妊娠糖尿病最具破坏性的并发症之一。许多研究表明，褪黑激素（Mel）在各种应激中具有神经保护作用。然而，自噬的作用和Mel参与神经干细胞在高血糖症（HG）尚未完全建立。在这里，我们发现HG增加了NSC的自噬和自噬通量，如通过增加LC 3B II/I比率、Beclin-1表达和自噬体所证明的。此外，Mel增强了HG中NSCs的增殖和自我更新，降低了自噬并激活了mTOR信号转导。3-甲基腺嘌呤（3-Ma）抑制自噬可增强Mel的上述作用，雷帕霉素（Rapa）诱导自噬可减弱Mel的上述作用。值得注意的是，HG诱导NSC过早分化为神经元（Map 2阳性细胞）和星形胶质细胞（GFAP阳性细胞）。此外，与正常情况下一样，Mel可抑制HG诱导的神经干细胞的过早分化，并促进HG诱导的神经干细胞分化。巧合的是，3-Ma抑制NSCs自噬有助于Mel调节分化。然而，增加神经干细胞自噬的拉帕干扰Mel效应和延迟神经干细胞分化。这些发现表明，Mel补充可以通过抑制妊娠糖尿病背景下的自噬来促进模拟胎儿中枢神经系统中正常NSCs的增殖和分化。干细胞2019;37：504-515
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 Cells2019;37:504-515