Abstract：
Iron deficiency (ID) has been shown to affect central nervous system (CNS) development and induce hypomyelination. Previous work from our laboratory in a gestational ID model showed that both oligodendrocyte (OLG) and astrocyte (AST) maturation was impaired. To explore the contribution of AST iron to the myelination process, we generated an in vitro ID model by silencing divalent metal transporter 1 (DMT1) in AST (siDMT1 AST) or treating AST with Fe3+ chelator deferoxamine (DFX; DFX AST). siDMT1 AST showed no changes in proliferation but remained immature. Co-cultures of oligodendrocyte precursors cells (OPC) with siDMT1 AST and OPC cultures incubated with siDMT1 AST-conditioned media (ACM) rendered a reduction in OPC maturation. These findings correlated with a decrease in the expression of AST-secreted factors IGF-1, NRG-1, and LIF, known to promote OPC differentiation. siDMT1 AST also displayed increased mitochondrial number and reduced mitochondrial size as compared to control cells. DFX AST also remained immature and DFX AST-conditioned media also hampered OPC maturation in culture, in keeping with a decrease in the expression of AST-secreted growth factors IGF-1, NRG-1, LIF, and CNTF. DFX AST mitochondrial morphology and number showed results similar to those observed in siDMT1 AST. In sum, our results show that ID, induced through two different methods, impacts AST maturation and mitochondrial functioning, which in turn hampers OPC differentiation.
摘要：
铁缺乏（ID）已被证明会影响中枢神经系统（CNS）的发育并引起脊髓过多症。我们实验室在妊娠ID模型中的先前工作表明，少突胶质细胞（OLG）和星形胶质细胞（AST）的成熟均受到损害。探讨AST铁对髓鞘形成过程的贡献，我们通过沉默AST中的二价金属转运蛋白1(DMT1)(siDMT1AST)或用Fe3+螯合剂去铁胺(DFX;DFXAST)处理AST产生了体外ID模型。siDMT1AST显示增殖没有变化，但仍不成熟。少突胶质细胞前体细胞（OPC）与siDMT1AST和与siDMT1AST条件培养基（ACM）孵育的OPC培养物的共培养物减少了OPC成熟。这些发现与AST分泌因子IGF-1、NRG-1和LIF的表达减少相关。已知促进OPC分化。与对照细胞相比,siDMT1AST还显示增加的线粒体数量和减少的线粒体大小。DFXAST也仍然不成熟，DFXAST条件培养基也阻碍了OPC在培养中的成熟，与AST分泌的生长因子IGF-1，NRG-1，LIF的表达减少保持一致，CNTF。DFXAST线粒体形态和数量显示与siDMT1AST中观察到的结果相似。总之,我们的结果表明，ID，通过两种不同的方法诱导，影响AST成熟和线粒体功能，这反过来阻碍了OPC的分化。
