Department of Pediatrics, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97239, USA.
Neurobiol Dis. 2018 Oct;118:22-39. doi: 10.1016/j.nbd.2018.06.015. Epub 2018 Jun 22.
Intraventricular hemorrhage (IVH) in preterm infants results in reduced proliferation and maturation of oligodendrocyte progenitor cells (OPCs), and survivors exhibit reduced myelination and neurological deficits. Wnt signaling regulates OPC maturation and myelination in a context dependent manner. Herein, we hypothesized that the occurrence of IVH would downregulate Wnt signaling, and that activating Wnt signaling by GSK-3β inhibition or Wnt3A recombinant human protein (rh-Wnt3A) treatment might promote maturation of OPCs, myelination of the white matter, and neurological recovery in premature rabbits with IVH. These hypotheses were tested in autopsy samples from preterm infants and in a rabbit model of IVH. Induction of IVH reduced expressions of activated β-catenin, TCF-4, and Axin2 transcription factors in preterm newborns. Both AR-A014418 (ARA) and Wnt-3A treatment activated Wnt signaling. GSK-3β inhibition by intramuscular ARA treatment accelerated maturation of OPCs, myelination, and neurological recovery in preterm rabbits with IVH compared to vehicle controls. In contrast, intracerebroventricular rh-Wnt3A treatment failed to enhance myelination and neurological function in rabbits with IVH. ARA treatment reduced microglia infiltration and IL1β expression in rabbits with IVH relative to controls, whereas Wnt3A treatment elevated TNFα, IL1β, and IL6 expression without affecting microglia density. GSK-3β inhibition downregulated, while rh-Wnt3A treatment upregulated Notch signaling; and none of the two treatments affected the Sonic-Hedgehog pathway. The administration of ARA or rh-Wnt3A did not affect gliosis. The data suggest that GSK-3β inhibition promoted myelination by suppressing inflammation and Notch signaling; and Wnt3A treatment failed to enhance myelination because of its pro-inflammatory activity and synergy with Notch signaling. GSK-3β inhibitors might improve the neurological outcome of preterm infants with IVH.
脑室出血（IVH）可导致早产儿少突胶质前体细胞（OPC）增殖和成熟减少，幸存者表现出髓鞘形成减少和神经功能缺损。Wnt 信号在依赖于背景的情况下调节 OPC 的成熟和髓鞘形成。在此，我们假设 IVH 的发生会下调 Wnt 信号，而通过 GSK-3β 抑制或 Wnt3A 重组人蛋白（rh-Wnt3A）治疗激活 Wnt 信号可能会促进 OPC 的成熟、白质的髓鞘形成和 IVH 早产儿的神经恢复。这些假设在早产儿尸检样本和 IVH 兔模型中进行了测试。IVH 的诱导降低了早产儿中激活的β-catenin、TCF-4 和 Axin2 转录因子的表达。AR-A014418（ARA）和 Wnt-3A 治疗均激活了 Wnt 信号。与载体对照组相比，肌肉内 ARA 治疗通过抑制 GSK-3β 加速了 IVH 早产儿 OPC 的成熟、髓鞘形成和神经恢复。相比之下，rh-Wnt3A 治疗未能增强 IVH 兔的髓鞘形成和神经功能。与对照组相比，ARA 治疗降低了 IVH 兔的小胶质细胞浸润和 IL1β 表达，而 Wnt3A 治疗增加了 TNFα、IL1β 和 IL6 的表达，而不影响小胶质细胞密度。GSK-3β 抑制下调，而 rh-Wnt3A 治疗上调 Notch 信号；两种治疗均不影响 Sonic-Hedgehog 途径。ARA 或 rh-Wnt3A 的给药均不影响神经胶质增生。数据表明，GSK-3β 抑制通过抑制炎症和 Notch 信号来促进髓鞘形成；而 Wnt3A 治疗未能增强髓鞘形成，因为其具有促炎活性并且与 Notch 信号协同作用。GSK-3β 抑制剂可能改善 IVH 早产儿的神经预后。
