Adherens, tight, and gap junctions in ependymal cells: A systematic review of their contribution to CSF-brain barrier

Abstract

Introduction: The movement of fluids and solutes across the ependymal barrier, and their changes in physiologic and disease states are poorly understood. This gap in knowledge contributes strongly to treatment failures and complications in various neurological disorders.

Methods: We systematically searched and reviewed original research articles treating ependymal intercellular junctions on PubMed. Reviews, opinion papers, and abstracts were excluded. Research conducted on tissue samples, cell lines, CSF, and animal models was considered.

Results: A total of 45 novel articles treating tight, adherens and gap junctions of the ependyma were included in our review, spanning from 1960 to 2022. The findings of this review point toward a central and not yet fully characterized role of the ependymal lining ultrastructure in fluid flow interactions in the brain. In particular, tight junctions circumferentially line the apical equator of ependymal cells, changing between embryonal and adult life in several rodent models, shaping fluid and solute transit in this location. Further, adherens and gap junctions appear to have a pivotal role in several forms of congenital hydrocephalus.

Conclusions: These findings may provide an opportunity for medical management of CSF disorders, potentially allowing for tuning of CSF secretion and absorption. Beyond hydrocephalus, stroke, trauma, this information has relevance for metabolite clearance and drug delivery, with potential to affect many patients with a variety of neurological disorders. This critical look at intercellular junctions in ependyma and the surrounding interstitial spaces is meant to inspire future research on a central and rather unknown component of the CSF-brain interface.

Keywords: adherens junctions; ependyma; gap junctions; hydrocephalus; tight junctions.

Figure 1

Flow diagram of the systematic research and selection process used to identify the final papers in this review.

Figure 2

Overview of membrane, trafficking, junctional, cytoplasmic structural proteins involved in intercellular junctions and pathological processes of the ependyma. Failure of one of these components can induce ependymal denudation and hydrocephalus in murine models. A dedicated legend is provided with the figure.

Figure 3

Progression of ependymal failure and development of hydrocephalus. (1) normal ependyma with intact junctions, solute/CSF interchange is maintained. (2) junctional damage with increased transependymal flow toward the ventricles represented by yellow arrows and water particles penetrating into the ependymal layer. This could be caused by an osmotic gradient secondary to high CSF protein concentration. A form of communicating hydrocephalus may develop at this stage. (3) failure and collapse of the ependymal layer, with denudation of the ventricular wall and aqueductal/subarachnoid occlusion. This mechanism could lead to obstructive hydrocephalus. Green arrows represent ependymocytes detaching from the ependymal basement membrane and causing ventricular denudation. Trans-ependymal flow of water and solutes is at this point uncontrolled, leading to additional ventricular enlargement, further ependymal distension and damage.