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Science Made Simple Interstitial cells in the urinary tract, where are they and what do they do? Christopher H. Fry School of Physiology and Pharmacology, University of Bristol, Bristol, UK

An interstitial cell (IC) is a non-specific description of any number of cells, situated between other cells that are generally better-characterised. Throughout the urinary tract ICs are found between smooth muscle bundles, below the true epithelial layer that faces the lumen of the tract, or between glandular and stromal cells. Because of their widespread distribution they are likely to express a variety of phenotypes, from say a fibroblast-like cell to one with characteristics more reminiscent of a muscle cell, a myofibroblast. Moreover, the phenotype may change with urinary tract pathologies, for example to a fibroblast-like cell in neuropathically overactive bladders [1]. Because of this phenotypic variety ubiquitous distinctive markers are also difficult to identify; whilst most label for the intermediate filament vimentin, some will, but many will not, for the c-kit receptor – an epitope also absent on muscle cells and fibroblasts. ICs in the gastrointestinal tract, ICs of Cajal (ICC), form a functional network, are key to the generation of slow-wave activity and mediate the neural drive to smooth muscle [2]. ICs from the urinary tract generate similar repetitive electrical responses and intracellular Ca2+ transients to ICCs. For this reason it has been tempting to ascribe similar pacemaking function to urinary tract ICs, but the evidence thus far for this function is lacking. ICs in muscle layers of the urinary tract are found between muscle bundles and generate spontaneous responses but are not in synchrony with those in muscle

cells themselves [3]. It has therefore been proposed that intramuscular ICs can co-ordinate responses between otherwise isolated muscle bundles to generate more global responses. A greater concentration of ICs may be found in the suburothelium layer, wherein also lies a dense network of blood vessels and afferent nerves (Fig. 1). Here, ICs form a cellular network and make intimate associations with nerves. One function ascribed to suburothelial ICs is that they also mediate information transfer, like ICCs, but this time from epithelial (urothelial) cells to nerves. Urothelium when subjected to physical or chemical stresses, as may occur during bladder filling, releases mediators such as ATP and acetylcholine. Suburothelial ICs respond to these agents and because they are functionally connected can integrate these signals over a wider area of the urinary tract wall. Overactive bladder syndromes are associated with both an increase of mediator release and also IC number, so that up-regulation of this sensory process can contribute to the pathological condition [4]. Because ICs respond to exogenous agents and also develop spontaneous electrical and intracellular Ca2+ transients they may be classed as excitable cells. It is therefore important to characterise the membrane receptors, ion channels and intracellular routes that generate these excitable cell responses. ICs from various regions of the urinary tract and within different layers of the wall (i.e. suburothelial and muscular) Fig. 1 Cross section of the bladder wall of a

urothelium

young sheep. Left: haematoxylin and eosin stained section. The detrusor muscle, suburothelium and urothelium layers are

suburothelium

labelled. Right: a magnified image of the urothelium/suburothelium showing a superficial urothelium and a network of ICs in the underlying suburothelium.

detrusor

1 mm

BJU Int 2014; 114: 434–435 wileyonlinelibrary.com

50 µm

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utilise different such pathways. This may be of translational value as the functional performance of various regions of the urinary tract may be separately regulated as desired, i.e. the sensory function of the bladder wall may be regulated without affecting detrusor function. In this issue of BJU International, Lang et al. [5] have characterised ion channels in ICs from the prostate gland and propose that a unique combination of Ca2+ channels to drive activity in these cells may allow therapies to be developed that target more specifically this tissue. Research in the biology of urinary tract ICs is in its infancy but offers great potential to understand how different tissues within the wall of the tract functionally interact both in normal and pathological conditions.

Conflict of Interest C.H.F. is on an advisory board for Eli Lilly and receives a research grant from Allergan.

References 1

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detrusor overactivity and bladder pain syndrome. J Cell Mol Med 2011; 15: 2586–93 Sanders KM, Hwang SJ, Ward SM. Neuroeffector apparatus in gastrointestinal smooth muscle organs. J Physiol 2010; 588: 4621–39 Hashitani H, Yanai Y, Suzuki H. Role of interstitial cells and gap junctions in the transmission of spontaneous Ca2+ signals in detrusor smooth muscles of the guinea-pig urinary bladder. J Physiol 2004; 559: 567–81 Birder LA, Ruggieri M, Takeda M et al. How does the urothelium affect bladder function in health and disease? ICI-RS 2011. Neurourol Urodyn 2012; 31: 293–9 Lang RJ, Tonta MA, Takano H, Hashitani H. Voltage-operated Ca2+ currents and Ca2+-activated Cl- channels in single interstitial cells of the guinea-pig prostate. BJU Int 2014; 114: 436–46

Correspondence: Christopher H. Fry, School of Physiology and Pharmacology, University of Bristol, University Walk, Bristol BS8 1TD, UK. e-mail: [email protected] Abbreviation: IC(C), interstitial cell (of Cajal).

Gevaert T, De Vos R, Everaerts W et al. Characterization of upper lamina propria interstitial cells in bladders from patients with neurogenic

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Interstitial cells in the urinary tract, where are they and what do they do?

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