Neuroependymal Denudation is in Progress in Full‐term Human Foetal Spina Bifida Aperta

Abstract

In human spina bifida aperta (SBA), cerebral pathogenesis [hydrocephalus, Sylvius aqueduct (SA) stenosis and heterotopias] is poorly understood. In animal models, loss of ventricular lining (ependymal denudation) causes SA stenosis and hydrocephalus. We aimed to investigate whether ependymal denudation also takes place in human foetal SBA. Considering that ependymal denudation would be related to alterations in junction proteins, sections through SA of five SBA and six control foetuses (gestational ages ranged between 37 and 40 weeks) were immunostained for markers of ependyma (caveolin 1, βIV-tubulin, S100), junction proteins (N-cadherin, connexin-43, neural cell adhesion molecule (NCAM), blood vessels (Glut-1) and astrocytes [glial fibrillary acidic protein (GFAP)]. In control foetuses, ependymal denudation was absent. In SBA foetuses different stages of ependymal denudation were observed: (i) intact ependyma/neuroepithelium; (ii) imminent ependymal denudation (with abnormal subcellular location of junction proteins); (iii) ependymal denudation (with protrusion of neuropile into SA, formation of rosettes and macrophage invasion); (iv) astroglial reaction. It is suggested that abnormalities in the formation of gap and adherent junctions result in defective ependymal coupling, desynchronized ciliary beating and ependymal denudation, leading to hydrocephalus. The presence of various stages of ependymal denudation within the same full-term SBA foetuses suggests continuation of the process after birth.

Nuclear Factor κB Activation Impairs Ependymal Ciliogenesis and Links Neuroinflammation to Hydrocephalus Formation

“…A loss of ependymal integrity is observed frequently in human developmental hydrocephalus (Domínguez-Pinos et al, 2005;Sival et al, 2011). This process is usually accompanied by activation of ventricular macrophages (Ulfig et al, 2004;Domínguez-Pinos et al, 2005), an issue that is phenocopied in our model system.…”

Neural Stem Cells and Fetal-Onset Hydrocephalus

“…4a, b) [39,40]. In hydrocephalic human fetuses, prior to becoming disrupted NSC and ependymal cells display an abnormal subcellular location of N-cadherin, connexin 43, and caveolin 1 ( Fig.…”

“…Overall, a series of findings indicates that disruption of the VZ arises from a final common pathway involving alterations in vesicle trafficking, abnormal cell junctions, and loss of VZ integrity [19]. In brief, before becoming denuded, areas of the VZ display disorganized VZ/ependyma cells with an abnormal subcellular location of N-cadherin and connexin 43 [15,18,20,21]. Interestingly, specific domains of the ventricular walls that are permanently endowed with tight junctions, such as the subcommissural organ, choroid plexus and hypothalamic tanycytes never disrupt [22].…”

Fetoscopic versus Open Repair for Spina Bifida Aperta: A Systematic Review of Outcomes

“…Firstly, there is the failed closure of the neural tube by the 6th week of gestation. Subsequently, from the 16th week onwards, there is secondary damage to the exposed spinal cord and nerves due to direct trauma and neurotoxic agents in the amniotic fluid, as well as to the brain, evidenced by the development of ventriculomegaly and Chiari II malformation (CM) [6,7,8,9]. The latter is due to cerebral spinal fluid leakage at the level of the defect, leading to a ‘suction gradient' [10].…”