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Review
. 2016 Aug:338:52-63.
doi: 10.1016/j.heares.2016.01.010. Epub 2016 Jan 20.

Pathophysiology of the cochlear intrastrial fluid-blood barrier (review)

Xiaorui Shi  1
Affiliations
Review

Pathophysiology of the cochlear intrastrial fluid-blood barrier (review)

Xiaorui Shi. Hear Res. 2016 Aug.

Abstract

The blood-labyrinth barrier (BLB) in the stria vascularis is a highly specialized capillary network that controls exchanges between blood and the intrastitial space in the cochlea. The barrier shields the inner ear from blood-born toxic substances and selectively passes ions, fluids, and nutrients to the cochlea, playing an essential role in the maintenance of cochlear homeostasis. Anatomically, the BLB is comprised of endothelial cells (ECs) in the strial microvasculature, elaborated tight and adherens junctions, pericytes (PCs), basement membrane (BM), and perivascular resident macrophage-like melanocytes (PVM/Ms), which together form a complex "cochlear-vascular unit" in the stria vascularis. Physical interactions between the ECs, PCs, and PVM/Ms, as well as signaling between the cells, is critical for controlling vascular permeability and providing a proper environment for hearing function. Breakdown of normal interactions between components of the BLB is seen in a wide range of pathological conditions, including genetic defects and conditions engendered by inflammation, loud sound trauma, and ageing. In this review, we will discuss prevailing views of the structure and function of the strial cochlear-vascular unit (also referred to as the "intrastrial fluid-blood barrier"). We will also discuss the disrupted homeostasis seen in a variety of hearing disorders. Therapeutic targeting of the strial barrier may offer opportunities for improvement of hearing health and amelioration of auditory disorders. This article is part of a Special Issue entitled <Annual Reviews 2016>.

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Figures

Figure 1
Figure 1
(A) The illustration of a cochlear micro-vessel in cross-section shows the major components of the intrastrial fluid-blood barrier. The vessel lumen comprises ECs connected by TJs. ECs are ensheathed by a dense basement membrane shared with PCs. PVM/M end-feet cover a large portion of the capillary surface. (B) & (C) The reconstructed confocal image of the intrastrial fluid-blood barrier highlights the morphological complexity of interactions between ECs, PCs, and PVM/Ms. The PVM/Ms are immunolabeled for F4/80, PCs for desmin, and ECs with fluorescent Dil.
Figure 2
Figure 2
(A) The super-resolution image shows the high density of strial PCs (labeled with NG2, gray) in the mouse SV (~1220-1300 PCs per SV). (B) The confocal projection shows the PC soma (stained with DAF-2DA, short arrow, green) and primary processes (labeled with desmin, long arrow, red). Two PCs are shown, each having a characteristic of a “bump on a log” shape, situated on the outer wall of a strial vessel (PC: pericyte, PVM/M: perivascular resident macrophage, V/SV: vessels of the stria vascularis, V/SL: vessels of the spiral ligament). (C) TEM tomography shows the cochlear PCs are embedded in the basement membrane (BM) and are closely associated with ECs. TEM tomography enables detection of the interactions between PCs, ECs, and the BM at high resolution (BM: basement membrane, EC: endothelial cell).
Figure 3
Figure 3
PVM/Ms in the stria vascularis interface with capillaries. (A) PVM/Ms in the 3-D reconstruction are immunohistochemically labeled with antibody for F4/80 (white), the cytoskeleton labeled with Alexa Fluor® 568 phalloidin (red). The ramified processes of PVM/Ms are sandwiched between marginal and basal cell layers of the stria vascularis. (B) The 3-D reconstruction shows PVMs are situated in or under subepithelial marginal cells and have no basal cell contacts (C). (D) The ramified processes of PVM/Ms interface with the endothelial tube. Capillaries have been labeled with an antibody for IgG.
Figure 4
Figure 4
Noise exposure activates PVM/Ms. (A) & (B) Confocal images show the morphology of PVM/Ms on strial capillaries labeled with GS-IB4 (red) in a control animal. (C) & (D) Activated PVM/Ms in noise-exposed animals show reduced branching and withdrawal of ramifications, and display less physical contact with capillaries. (E–G) Double-labeling of whole-mounted stria vascularis shows activated PVM/Ms are positive for GS-IB4. (H–J) show PVM/M activation in C57/6J mice at age 6m (I), with progressively more activation by age 15-21m.
Figure 5
Figure 5
The schematic illustrates several variations of the in vitro blood-labyrinth barrier model. (a) Model I shows a schematic of cells co-cultivated on a Transwell layer. Images of an EC monolayer labeled with antibody for ZO-1 are shown in both a mono-culture and co-culture setup. (b) Model II shows an EC monolayer labeled with antibody for ZO-1 and treated with different conditioning growth media. (c) Model III is a CytoVu/SiMPore thin membrane co-culture system. (d) The accompanying confocal fluorescence images show direct visualization of BSI-B4-labeled ECs on the thin membrane (left) and a population of PE-PDGFRβ–labeled PCs to one side of the thin membrane and FITC-BSI-B4–labeled ECs on the other (right).
Figure 6
Figure 6
Mono-culture of ECs and co-culture of ECs + PCs, ECs + PVM/ Ms, and ECs + PCs + PVM/Ms at various times in a three-dimensional (3-D) matrix gel. (A–H) Representative confocal images of a mono-culture of ECs and co-culture of ECs +PCs, ECs + PVM/Ms, and ECs + PCs + PVM/Ms at 11 h and 56 h in a matrix gel. No angiogenesis or EC tube regression is seen at 11 h in culture (A–D). Significant angiogenesis and EC tube formation is seen at 56 h (E–H). (E) Sparse branched networks and sprouting angiogenesis are seen in the EC alone group at 56 h (arrow). PCs promote sprouting angiogenesis of the tube structures (arrow). (G) PVM/Ms significantly delay regression of EC-formed capillary-like tubes. (H) Both PCs and PVM/Ms are required for capillary stability and angiogenesis. The PCs and PVM/Ms cooperate to promote sprouting angiogenesis.
Figure 7
Figure 7
(A) The surgical view shows an opened bulla and location of a vessel-window on the basal turn of a murine cochlea (black rectangle in panel A). Cochlear blood vessels are visualized with intravenously administered FITC-dextran. (B) & (C) compare in vivo images of strial blood vessels though a thin vessel-window and open vessel-window. (D) An open vessel-window preparation was used to visualize PCs and determine PC contractility using a NG2 DsRed labeled-PC transgenic cell mouse model. (E) Migrated GFP+-bone marrow cells are shown extravasated through blood vessels (red, labeled by Dil). The arrowhead alone points to a GFP+ bone marrow cell within the vessel, the arrow to a GFP+ bone marrow cell outside the vessel.
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