Kowitzke Bea, Cohrs Gesa, Leuschner Ivo, Koch Arend, Synowitz Michael, Mehdorn Hubertus Maximilian, Held-Feindt Janka, Knerlich-Lukoschus Friederike
Department of Neurosurgery (BK, GC, MS, HMM, JH-F, FK-L)Department of Pathology (IL), University Hospital of Schleswig-Holstein Campus Kiel, Kiel, Germany;Department of Neuropathology (AK), Charité - Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
J Neuropathol Exp Neurol. 2016 Sep;75(9):827-42. doi: 10.1093/jnen/nlw057. Epub 2016 Jun 28.
Myelomeningoceles (mmc) are clinically challenging CNS malformations. Although improvement in their management has been achieved with respect to antenatal diagnosis, prevention, and fetal surgery, the cellular mechanisms of damage in the neural placode are poorly understood. We aimed to identify cellular and molecular factors in lesion amplifying cascades in mmc placodes. Seventeen mmc specimens obtained during reconstructive surgery that harbored sufficient neuroepithelial tissue were investigated. Normal adult and stillborn spinal cord tissue served as controls. Placodes exhibited similar cellular profiles with consistent neuronal marker expression, elevated GFAP-/vimentin immunoreactivity in all, and CD3/CD11b/CD68-immunolabeling in some cases. Increased expression of pro-inflammatory (tumor necrosis factor, interleukin-1β [Il-1β]/IL-1 receptor type 1 [IL-R1]) and neuroprotective erythropoietin/erythropoietin receptor (Epo/EpoR) cytokines was detected by immunohistochemistry, double-fluorescence labeling, and real-time RT-PCR. In all cases, there was a multi-cellular induction of IL-1β and IL1-R1. EpoR and Epo immunoreactivity was elevated in some cases with neuronal expression patterns. Epo was further co-expressed with HIF-1/-2α, which paralleled Epo induction in the corresponding placodes. These observations confirm the induction of cellular and molecular alterations in human mmc placodes that resemble the secondary lesion cascades induced by spinal cord injury. The pro-inflammatory and neuroprotective cytokine expression in mmc placodes may represent new targets for the treatment of open neural tube defects.
脊髓脊膜膨出（MMC）是临床上具有挑战性的中枢神经系统畸形。尽管在产前诊断、预防和胎儿手术方面其治疗已有所改善，但神经基板损伤的细胞机制仍知之甚少。我们旨在确定MMC基板中病变放大级联反应中的细胞和分子因素。对在重建手术中获得的17个含有足够神经上皮组织的MMC标本进行了研究。正常成人和死产脊髓组织作为对照。基板表现出相似的细胞特征，神经元标志物表达一致，所有标本中GFAP/波形蛋白免疫反应性均升高，部分病例有CD3/CD11b/CD68免疫标记。通过免疫组织化学、双荧光标记和实时逆转录聚合酶链反应检测到促炎细胞因子（肿瘤坏死因子、白细胞介素-1β[IL-1β]/白细胞介素-1受体1型[IL-R1]）和神经保护细胞因子促红细胞生成素/促红细胞生成素受体（Epo/EpoR）表达增加。在所有病例中，均有多细胞诱导的IL-1β和IL1-R1。在一些具有神经元表达模式的病例中，EpoR和Epo免疫反应性升高。Epo进一步与缺氧诱导因子-1/-2α共表达，这与相应基板中Epo的诱导情况平行。这些观察结果证实了人类MMC基板中细胞和分子改变的诱导，类似于脊髓损伤诱导的继发性病变级联反应。MMC基板中促炎和神经保护细胞因子的表达可能代表开放性神经管缺陷治疗的新靶点。
