Abstract
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.