The Mystery of the Interstitial Cells in the Urinary Bladder

Abstract

Intrinsic mechanisms to restrain smooth muscle excitability are present in the bladder, and premature contractions during filling indicate a pathological phenotype. Some investigators have proposed that c-Kit interstitial cells (ICs) are pacemakers and intermediaries in efferent and afferent neural activity, but recent findings suggest these cells have been misidentified and their functions have been misinterpreted. Cells reported to be c-Kit cells colabel with vimentin antibodies, but vimentin is not a specific marker for c-Kit cells. A recent report shows that c-Kit cells in several species coexpress mast cell tryptase, suggesting that they are likely to be mast cells. In fact, most bladder ICs labeled with vimentin antibodies coexpress platelet-derived growth factor receptor α (PDGFRα). Rather than an excitatory phenotype, PDGFRα cells convey inhibitory regulation in the detrusor, and inhibitory mechanisms are activated by purines and stretch. PDGFRα cells restrain premature development of contractions during bladder filling, and overactive behavior develops when the inhibitory pathways in these cells are blocked. PDGFRα cells are also a prominent cell type in the submucosa and lamina propria, but little is known about their function in these locations. Effective pharmacological manipulation of bladder ICs depends on proper identification and further study of the pathways in these cells that affect bladder functions.

An ex vivo bladder model with detrusor smooth muscle removed to analyse biologically active mediators released from the suburothelium

“…The subU/LP also appeared to be intact as demonstrated by Masson's trichrome staining, haematoxylin and eosin staining, and differential interference contrast imaging. Fluorescence microscopy of denuded bladders from PDGFRα EGFP mice demonstrated the presence of eGFP-tagged PDGFRα + cells, a novel population of interstitial cells that occur in high density in the SubU/LP in the bladder (Koh et al 2012;Koh et al 2018). Fluorescent dye permeability assays during filling of the denuded bladder preparation demonstrated efflux of fluorescent dyes, as documented previously (Carattino et al 2013;Greenwood-Van Meerveld et al 2015).…”

“…2A-C), (ii) aquaporin 3 (AQP3)-like immunoreactivity was expressed predominantly in basal and some intermediate cells of urothelium ( Fig. 2D) as previously described (Spector et al 2002;Kim et al 2012), and (iii) suburothelial PDGFRα + cells were preserved in the wall of a denuded bladder of a PDGFRα EGFP mouse (Koh et al 2012;Koh et al 2018) ( Fig. 2E and F).…”

“…; Koh et al . ). Fluorescent dye permeability assays during filling of the denuded bladder preparation demonstrated efflux of fluorescent dyes, as documented previously (Carattino et al .…”

“…These findings once again validate the usefulness of the novel detrusor-denuded bladder preparation for studies of local mechanisms of urothelial control of bladder function and connectivity of the urothelium with sensory afferent neurons and detrusor contractile activity during filling. Mediators released in the SubU/LP might affect a variety of cell types in the bladder wall, including SMC, interstitial cells (Koh et al 2012;Koh et al 2018) and afferent nerves in both urothelium and detrusor muscle (Spencer et al 2018). In fact, recent studies highlight the role of detrusor muscle TCs in stimulating afferent neurons within the muscle to trigger micturition .…”

Targetable purinergic receptors P2Y12 and A2b antagonistically regulate bladder function

“…Purinergic dysfunction is a common phenomenon in human bladder diseases; elevated ATP release, impaired ATP hydrolysis, and dysregulated P2X expression have all been reported in patients with OAB, interstitial cystitis, and outlet obstruction (16)(17)(18)(43)(44)(45)(46)(47)(48)(49)(50). The role of P2Y 12 and A2b receptors in human bladder function is not well known.…”