Departments of Pediatrics, and Cell Biology and Anatomy, Regional Neonatal Center, Maria Fareri Children's Hospital at Westchester Medical Center-New York Medical College, Valhalla, New York 10595, Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, Oregon 97239, Department of Neuroscience, University of Connecticut, Farmington, Connecticut 06269, and Division of Endocrinology, Diabetes and Metabolism, University of Miami Miller School of Medicine, Miami, Florida 33146.
J Neurosci. 2013 Oct 30;33(44):17232-46. doi: 10.1523/JNEUROSCI.2713-13.2013.
Intraventricular hemorrhage (IVH) remains a major cause of white matter injury in preterm infants with no viable therapeutic strategy to restore myelination. Maturation of oligodendrocytes and myelination is influenced by thyroid hormone (TH) signaling, which is mediated by TH receptor α (TRα) and TRβ. In the brain, cellular levels of TH are regulated by deiodinases, with deiodinase-2 mediating TH activation and deiodinase-3 TH inactivation. Therefore, we hypothesized that IVH would decrease TH signaling via changes in the expression of deiodinases and/or TRs, and normalization of TH signaling would enhance maturation of oligodendrocytes and myelination in preterm infants with IVH. These hypotheses were tested using both autopsy materials from human preterm infants and a rabbit model of IVH. We found that deiodinase-2 levels were reduced, whereas deiodinase-3 levels were increased in brain samples of both humans and rabbits with IVH compared with controls without IVH. TRα expression was also increased in human infants with IVH. Importantly, treatment with TH accelerated the proliferation and maturation of oligodendrocytes, increased transcription of Olig2 and Sox10 genes, augmented myelination, and restored neurological function in pups with IVH. Consistent with these findings, the density of myelinating oligodendrocytes was almost doubled in TH-treated human preterm infants compared with controls. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TRα. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH.
脑室内出血（IVH）仍然是早产儿脑白质损伤的主要原因，目前尚无可行的治疗策略来恢复髓鞘形成。少突胶质细胞的成熟和髓鞘形成受甲状腺激素（TH）信号的影响，该信号由 TH 受体 α（TRα）和 TRβ介导。在大脑中，TH 的细胞水平受脱碘酶调节，其中脱碘酶-2介导 TH 的激活，脱碘酶-3介导 TH 的失活。因此，我们假设 IVH 通过脱碘酶和/或 TR 表达的变化来降低 TH 信号，而 TH 信号的正常化将增强 IVH 早产儿的少突胶质细胞成熟和髓鞘形成。这些假设使用人类早产儿的尸检材料和 IVH 的兔模型进行了测试。我们发现，与没有 IVH 的对照组相比，患有 IVH 的人类和兔的脑样本中脱碘酶-2 水平降低，而脱碘酶-3 水平升高。人类 IVH 婴儿的 TRα 表达也增加。重要的是，TH 治疗加速了少突胶质细胞的增殖和成熟，增加了 Olig2 和 Sox10 基因的转录，增强了髓鞘形成，并恢复了 IVH 幼仔的神经功能。与这些发现一致的是，与对照组相比，接受 TH 治疗的人类早产儿的髓鞘形成少突胶质细胞密度几乎增加了一倍。因此，在 IVH 婴儿中，脱碘酶-3 的升高和脱碘酶-2 的降低共同降低了 TH 信号，未结合的 TRα 的增加可能使这种情况恶化。鉴于 TH 促进 IVH 中的神经恢复，TH 治疗可能会改善 IVH 早产儿的神经发育结局。
