The cochlea is the organ that continuously controls water and ion homeostasis for auditory perception. Like the retina, cochlea maintains continuous extracellular potential and ion gradients through transporting ions even in the absence of an acoustic stimulus, which was called “silent current” by Zidanic and Brownell [26]. In addition, these gradients are not generated by hair cells but in the stria vascularis, which benefits significantly for the detection of mechanical stimuli. As generation of EP and K⁺ recycling from perilymph to endolymph are inseparably connected, we will discuss physiological roles and mechanisms of the cochlear lateral wall in terms of generation of EP.

As described above, the cochlear endolymph exhibits a positive potential of +80 mV, which is called the endocochlear potential. von Bekesy in 1952 first reported the DC potential in endolymph with a +80 mV positive potential to the perilymph [27]. Davis et al. measured the cochlear microphonic and found that the energy of the cochlear microphonic is derived from the polarization potential across the interface between the endolymph and the interior of the hair cells, which is called “battery theory.” In addition, they described that the movements of hair bundles modulate the flow of electric current [28]. These batteries that drive auditory-evoked excitation in hair cell are comprised of electrochemical gradients across the apical surface of hair cell produced by EP. Since then, so many works have been done on the mechanism of generation of EP and high potassium concentration [29, 30]. Salt et al. found the intrastrial space with a positive potential and a low K⁺ concentration through measurement of the potential and K⁺ gradient in the stria vascularis using K⁺-selective electrodes. The results also indicate that EP is not generated by the marginal cells alone but also by K⁺ movement across the cell membrane of components in the stria vascularis [31]. The works by Salt et al. redefined the investigation for EP as research on cellular compartments and ion pumps that positively transport cation and anion across cellular membrane and intercellularly.

The two-cell model, also referred to as the five-compartment model [32], has been widely accepted as the mechanism for origin of EP [33]. In this hypothesis, the cochlear lateral wall comprises two epithelial compartments, the strial marginal cells and the syncytium that forms cellular complex of fibrocytes, strial basal cells, and strial intermediate cells. Type I fibrocytes, strial basal cells, and strial intermediate cells are interconnected by gap junction network, which means these cells are electrically equivalent. Type I fibrocytes in the cochlear lateral wall express both Na⁺,K⁺-ATPase and Na⁺,K⁺,2Cl⁻ cotransporter. Vascular perfusion of either ouabain, an inhibitor for Na⁺,K⁺-ATPase, or furosemide, an inhibitor for Na⁺,K⁺,2Cl⁻ cotransporter, dramatically reduces EP [34, 35], indicating that these two ion transporters are required for generation of EP. The strial intermediate cells express Kir 4.1 [36] which secretes K⁺ into the intrastrial space. Vascular perfusion of Ba²⁺, a potential blocker for the Kir family, remarkably suppresses EP [37], suggesting that the K⁺ diffusion potential is primarily formed by Kir4.1 and critical for generation of EP. Tight junctions between n the basal cells make the syncytium a diffusional barrier and serve as the boundary of the apical surface composed of intermediate cell membranes and the basolateral surface comprising the fibrocyte membranes. Mice lacking Claudin11, a major constituent of tight junctions of basal cells, exhibit disruption of EP despite normal K⁺ recycling, indicating the importance of basal cell tight junctions in the stria vascularis for generation of EP [38, 39]. The results also support two-cell model that EP is not generated by the marginal cells alone but the intrastrial space contributes generation of endocochlear potential. Expression of Na⁺,K⁺-ATPase and Na⁺,K⁺,2Cl⁻ cotransporter in the basolateral membrane of the strial marginal cells sustains a low K⁺ concentration in the extracellular fluid in the intrastrial space. Chloride ions exit from the marginal cells through ClC-Kb chloride channels, Barttin, which is supposed to be essential for K⁺ recycling in the stria vascularis [40]. KCNq1/KCNE1 K⁺ channels which are expressed in the apical surface of the marginal cells secrete K⁺ into the endolymph contributing a K⁺ diffusion potential and the dynamics of EP [41]. Whereas the basal cells in the stria vascularis express only Claudin11, the marginal cells express a variety of Claudin family including Claudin1, 2, 3, 8, 9, 10, 12, 14, and 18, suggesting importance of the barrier formation in the marginal cells [42]. Researches in the field of physiology and molecular biology have made substantial advance to complete understanding for roles and mechanisms of the cochlear lateral wall. In the next section, we will discuss potential molecular targets for regenerative medicine in the cochlear lateral wall identified in either humans and mice or both.

Several genes that are involved in ion transporting are reported to account for hereditary hearing loss. Mutations in GJB2 encoding connexin 26 are the most prevalent inherited source of congenital hearing loss in humans [43]. In most of these cases, the inheritance type is autosomal recessive; however, some cases of dominant inheritance are also reported. In Gjb2 knockout mice, degeneration of the organ of Corti is observed as early as postnatal day (P)14 and their hearing are profoundly impaired [44]. Endolymphatic K⁺ concentration and EP are much lower in Gjb2 knockout mice than wild type, suggesting that Cx26 is essential for maintenance and function of the organ of Corti, but is not required for normal development of the cochlear sensory epithelium. A Gjb6 knockout mouse model was also developed, and homozygous mice are hearing impaired and lack EP. Degeneration of the organ of Corti is observed from P18, which is similar to Gjb2 mutant mice [45].

The SLC26 family is responsible for membranous transporting of anion, including chloride, iodide, and bicarbonate. SLC26A4 mutations are associated with syndromic hearing loss, Pendred syndrome, and non-syndromic hereditary hearing loss [46]. Most of the patients display radiologically detectable structural malformations of the inner ear, the most common feature of which is an enlarged vestibular aqueduct. Enlarged endolymphatic ducts are also observed in some patients with non-syndromic hereditary hearing loss due to SLC26A4 mutations. In the mouse inner ear, Slc26a4 is expressed on apical surface of cells covered by the endolymphatic space [47]. Slc26a4 knockout mice exhibit waltzer-like vestibular dysfunction and complete deafness with a severe dilatation of the endolymphatic duct and sac [48]. Functional analyses revealed that Slc26a4 knockout mice gradually loss EP, beginning at P12, before normal onset of hearing despite normal concentration of K⁺ in the endolymph.

In the cochlea, the essential segregation of endolymph from perilymph is achieved by tight junctions of epithelial cells bordering the fluid compartments. Tight junctions are composed of at least three types of transmembrane proteins: occludin, claudins, and the junction adhesion molecule family. Claudin proteins are widely expressed in the inner ear, with 10 types of claudin proteins of differential distribution or localization [42]. Recessive mutations of human CLDN14 were identified as a source of non-syndromic hearing loss [49]. Claudin14 is detected in tight junctions of the reticular lamina in the organ of Corti in mice, and Claudin14-null mice are deaf, whereas their EP stays normal [50]. Tight junctions in the basal cells of stria vascularis are primarily composed of Claudin11, and Claudin11-deficient mice show severe hearing loss without obvious degeneration of the organ of Corti [39]. In addition, EP in Claudin11-deficient mice is suppressed, while K⁺ concentration in the endolymph is maintained at almost normal level. These findings indicate that establishment of the basal cell barrier in the stria vascularis is indispensable for hearing function through generation and maintenance of EP.

Kcne1, Kcnq1, and Kcnq4 encode for subunits of low-voltage-activated K⁺ channel, which are the major determinants of cellular depolarization in excitable cells. Stria vascularis marginal cells secrete K⁺ into the endolymph by K⁺ channel composed of Kcnq1 and Kcne1 subunits. Mutations in KCNE1 or KCNQ1 in human induce syndromic hearing loss with cardiac symptoms, including prolonged QT interval in the electrocardiogram and arrhythmias (Jervell and Lange-Nielsen syndrome) [51–53]. Kcne1 or Kcnq1 knockout mice exhibit severe hearing loss and vestibular dysfunction [54, 55]. Although morphology of the cochlear duct is likely to be normal at birth, degeneration develops later after birth including a collapse of Reissner’s membrane and a decrease in the volume of endolymphatic space. Kcnq4 is detected in the basolateral membrane of cochlear hair cells, suggesting that Kcnq4 channels are responsible for secretion of K⁺ from hair cells to the perilymph [56].

Kir4.1, or KCNJ10, is expressed in the intermediate cells of stria vascularis [57]. K⁺ concentration as well as EP and volume of the endolymphatic space is reduced in Kcnj10 knockout mice, suggesting that the Kir4.1 channel provides the molecular mechanism for generation of EP in concert with other channels for K⁺ secretion, as is indicated by the fact that Slc26a4 knockout mice lack Kir4.1 expression in the stria vascularis [58].

In human, Bartter syndrome IV is an autosomal recessive disorder characterized by congenital deafness and severe renal salt and fluid loss, which is caused by mutations in Barttin, a beta-subunit of ClC-Ka and ClC-Kb chloride channels [59]. NKCC, Na⁺,K⁺,2Cl⁻ cotransporter, and ClC, Barttin-type Cl⁻ channel are expressed in the basolateral membrane of the stria marginal cells. Barttin-knockout mice demonstrate severe hearing loss with a decrease of EP despite normal concentration of K⁺ in the endolymph [60]. These observations indicate that Cl⁻ transport in the stria vascularis is also involved in the formation of EP.

Finally, DFN3, an X chromosome-linked non-syndromic mixed deafness, is caused by mutations in the POU3F4 gene, which encodes a POU transcription factor [61, 62]. Pou3f4-deficient mice were created and found to exhibit profound deafness with a dramatic reduction in EP. Histological analyses demonstrated a hypoplasia of fibrocytes in the cochlear lateral wall. The findings suggest that fibrocytes responsible for K⁺ homeostasis in the lateral wall play a critical role in generating EP and auditory function as well. Taken together, these molecules described above could be potential targets for regenerative medicine to improve hearing in disorders of the cochlear lateral wall through regenerative therapy.

In human, some types of hearing impairment are clinically suggested to be caused by disorder or damage of the cochlear lateral wall. The most widely referenced scheme for describing age-related hearing loss is one attributed to Schuknecht, in which three major cochlear structures, afferent neuron, organ of Corti, and stria vascularis, can degenerate independently [63, 64]. In addition, an age-related loss of fibrocytes in the spiral ligament has been reported in the basal portion of the mouse cochlea [65]. Moreover, Ohlemiller et al. reported that degeneration of the strial intermediate cells plays essential roles in age-related hearing loss through providing melanin to both the marginal cells and the basal cells [66]. Taken together, the cochlear lateral wall is very likely to be affected in the pathology of presbycusis according to the data shown above.

Pathological changes in fibrocytes have been linked to noise-induced hearing loss as well as age-related hearing loss, where fibrocyte degeneration was shown to precede loss of hair cells and neurons [65]. Widespread degeneration of fibrocytes in the spiral ligament, especially among the type IV fibrocyte areas, was observed in aged mouse cochlea prior to hair cell loss or degeneration of spiral ganglion neurons, suggesting that pathological changes in the fibrocytes in the cochlear lateral wall might be responsible for hair cell degeneration in age-related hearing loss.

Sudden deafness, or sudden-onset unilateral hearing loss due to unknown etiology, is suggested to be caused, at least in part, by damage of the lateral wall. Whereas some studies focused on degeneration of the spiral ganglion or the organ of Corti in models of transient cochlear ischemia [67], recent studies have revealed that the cochlear lateral wall is also affected by cochlear ischemia or energy failure, which seems to be reasonable as vasculature and mitochondrial activity are abundantly distributed in the cochlear lateral wall. In a mouse model of acute mitochondrial dysfunction caused by application of 3-nitropropionic acid, cellular degeneration in the cochlear lateral wall primarily accounts for hearing impairment due to acute energy failure [68]. These clinical entities could be candidate diseases for regenerative medicine in the cochlear lateral wall, whereas much works should be done to elucidate the pathophysiology of each clinical condition in the future.