Perivascular-resident macrophage-like melanocytes in the inner ear are essential for the integrity of the intrastrial fluid–blood barrier

TLDR

The cochlear microenvironment is preserved by a fluid–blood barrier formed by endothelial tight junctions and a basement membrane, yet the mechanisms governing its permeability remain largely unknown. This study aims to demonstrate that perivascular‑resident macrophage‑like melanocytes (PVM/Ms) are essential for maintaining the integrity of this barrier and normal hearing function. Using in vitro cultures and a genetically induced PVM/M‑depleted mouse model, the authors show that loss of PVM/Ms increases barrier permeability by downregulating pigment epithelial‑derived factor, which in turn reduces tight‑junction protein expression. PVM/M‑depleted animals exhibit a marked drop in endocochlear potential and hearing loss, confirming that PVM/Ms regulate barrier permeability to support normal auditory thresholds.

Abstract

The microenvironment of the cochlea is maintained by the barrier between the systemic circulation and the fluids inside the stria vascularis. However, the mechanisms that control the permeability of the intrastrial fluid–blood barrier remain largely unknown. The barrier comprises endothelial cells connected to each other by tight junctions and an underlying basement membrane. In a recent study, we found that the intrastrial fluid–blood barrier also includes a large number of perivascular cells with both macrophage and melanocyte characteristics. The perivascular-resident macrophage-like melanocytes (PVM/Ms) are in close contact with vessels through cytoplasmic processes. Here we demonstrate that PVM/Ms have an important role in maintaining the integrity of the intrastrial fluid–blood barrier and hearing function. Using a cell culture-based in vitro model and a genetically induced PVM/M-depleted animal model, we show that absence of PVM/Ms increases the permeability of the intrastrial fluid–blood barrier to both low- and high-molecular-weight tracers. The increased permeability is caused by decreased expression of pigment epithelial-derived factor, which regulates expression of several tight junction-associated proteins instrumental to barrier integrity. When tested for endocochlear potential and auditory brainstem response, PVM/M-depleted animals show substantial drop in endocochlear potential with accompanying hearing loss. Our results demonstrate a critical role for PVM/Ms in regulating the permeability of the intrastrial fluid–blood barrier for establishing a normal endocochlear potential hearing threshold.