Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Mechanisms of Disease: specialized interstitial cells of the urinary tract—an assessment of current knowledge

Nature Clinical Practice Urology volume 2, pages 546–554 (2005)Cite this article

Abstract

Scientists interested in the smooth muscles of the urinary tract, and their control, have recently been studying cells in the interstitium of tissues that express the c-kit antigen (Kit+ cells). These cells have morphologic features that are reminiscent of the well-described pacemaker cells in the gut, the interstitial cells of Cajal (ICC). The spontaneous contractile behavior of muscles in the urinary tract varies widely, and it is clear that urinary tract Kit+ interstitial cells cannot be playing an identical role to that played by the ICC in the gut. Nevertheless, there is increasing evidence that they do play a role in modulating the contractile behavior of adjacent smooth muscle, and might also be involved in mediating neural control. This review outlines the properties of ICC in the gut, and gives an account of the discovery of cells in the interstitium of the main components of the urinary tract. The physiologic properties of such cells and the functional implications of their presence are discussed, with particular reference to the bladder. In this organ, Kit+ cells are found under the lamina propria, where they might interact with the urothelium and with sensory nerves, and also between and within the smooth-muscle bundles. Confocal microscopy and calcium imaging are being used to assess the physiology of ICC and their interactions with smooth muscles. Differences in the numbers of ICC are seen in smooth muscle specimens obtained from patients with various pathologies; in particular, bladder overactivity is associated with increased numbers of these cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Whole-mount preparation of guinea-pig detrusor labeled with antibodies to c-kit.
Figure 2: Whole-mount preparation of guinea-pig bladder mucosa labeled with antibodies to c-kit.
Figure 3: Epifluoresence image of a whole-mount preparation of guinea-pig detrusor labeled with anti-smooth-muscle myosin.
Figure 4: Microelectrode recordings of spontaneous activity in a strip of mouse detrusor.
Figure 5: (A) Nerve bundles within the guinea-pig bladder wall (red) showing neuronal nitric-oxide synthase containing nitrergic nerves in green.
Figure 6: Ca2+ signalling responses of a detrusor interstitial cell to the application of carbachol (10 μM) and α,β,me-ATP (10 μM).
Figure 7: Kit+ (reddish-brown) cells in detrusor specimens from (A) normal and (B) overactive human bladders.

Similar content being viewed by others

References

  1. Cajal SR (1893) Sur les ganglions et plexus nerveux de l'intestin. C R Seances Soc Biol Fil 45: 217–223

    Google Scholar 

  2. Cajal SR (1911) Histologie du Système Nerveux de l'Homme et des Vertébrés. Paris: Maloine

    Google Scholar 

  3. Thuneberg L (1999) One hundred years of interstitial cells of Cajal. Microsc Res Tech 47: 223–238

    Article  CAS  Google Scholar 

  4. Sanders KM (1996) A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract. Gastroenterology 111: 492–515

    Article  CAS  Google Scholar 

  5. Rumessen JJ and Thuneberg L (1996) Pacemaker cells in the gastrointestinal tract: interstitial cells of Cajal. Scand J Gastroenterol 216 (Suppl): 82–94

    Article  CAS  Google Scholar 

  6. Cousins HM et al. (2003) Electrical coupling between the myenteric interstitial cells of Cajal and adjacent muscle layers in the guinea-pig gastric antrum. J Physiol 550: 829–844

    Article  CAS  Google Scholar 

  7. Ward SM and Sanders KM (2001) Interstitial cells of Cajal: primary targets of enteric motor innervation. Anat Rec 262: 125–135

    Article  CAS  Google Scholar 

  8. Horowitz B et al. (1999) Cellular and molecular basis for electrical rhythmicity in gastrointestinal muscles. Annu Rev Physiol 61: 19–43

    Article  CAS  Google Scholar 

  9. Komuro T et al. (1999) Ultrastructural characterization of the interstitial cells of Cajal. Arch Histol Cytol 62: 295–316

    Article  CAS  Google Scholar 

  10. Ward SM et al. (2003) Propagation of slow waves requires IP3 receptors and mitochondrial Ca2+ uptake in canine colonic muscles. J Physiol 549: 207–218

    Article  CAS  Google Scholar 

  11. Koh SD et al. (2003) Conductances responsible for slow wave generation and propagation in interstitial cells of Cajal. Curr Opin Pharmacol 3: 579–582

    Article  CAS  Google Scholar 

  12. Mikkelsen HB et al. (1998) Action potential generation, Kit receptor immunohistochemistry and morphology of steel-Dickie (Sl/Sld) mutant mouse small intestine. Neurogastroenterol Motil 10: 11–26

    Article  CAS  Google Scholar 

  13. Sanders KM et al. (2002) Physiology and pathophysiology of the interstitial cells of Cajal: from bench to bedside. IV. Genetic and animal models of GI motility disorders caused by loss of interstitial cells of Cajal. Am J Physiol Gastrointest Liver Physiol 282: 747–756

    Article  Google Scholar 

  14. Smet PJ et al. (1996) Distribution of nitric oxide synthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. Neuroscience 71: 337–348

    Article  CAS  Google Scholar 

  15. Sergeant GP et al. (2000) Specialised pacemaking cells in the rabbit urethra. J Physiol 526: 359–366

    Article  CAS  Google Scholar 

  16. Sergeant GP et al. (2001) Spontaneous Ca2+ activated Cl− currents in isolated urethral smooth muscle cells. J Urol 166: 1161–1166

    Article  CAS  Google Scholar 

  17. Hollywood MA et al. (2003) Activation of Ca2+-activated Cl− current by depolarizing steps in rabbit urethral interstitial cells. Am J Physiol Cell Physiol 285: 327–333

    Article  Google Scholar 

  18. Johnston L et al. (2005) Calcium oscillations in interstitial cells of the rabbit urethra. J Physiol 565: 449–461

    Article  CAS  Google Scholar 

  19. McCloskey KD and Gurney AM . (2002) Kit positive cells in the guinea pig bladder. J Urol 168: 832–836

    Article  Google Scholar 

  20. Davidson RA and McCloskey KD (2005) Morphology and localization of interstitial cells in the guinea-pig bladder: structural relationships with smooth muscle and neurons. J Urol 173: 1385–1390

    Article  Google Scholar 

  21. Hashitani H et al. (2004) 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 559: 567–581

    Article  CAS  Google Scholar 

  22. Sui GP et al. (2002) Gap junctions and connexin expression in human suburothelial interstitial cells. BJU Int 90: 118–129

    Article  CAS  Google Scholar 

  23. Gosling JA and Dixon JS (1972) Structural evidence in support of an urinary tract pacemaker. Br J Urol 44: 550–560

    Article  CAS  Google Scholar 

  24. Klemm MF et al. (1999) Identification of the cells underlying pacemaker activity in the guinea-pig upper urinary tract. J Physiol 519: 867–884

    Article  CAS  Google Scholar 

  25. Pezzone MA et al. (2003) Identification of c-kit-positive cells in the mouse ureter: the interstitial cells of Cajal of the urinary tract. Am J Physiol Renal Physiol 284: 925–929

    Article  Google Scholar 

  26. Metzger R et al. (2004) Cajal-like cells in the human upper urinary tract. J Urol 172: 769–772

    Article  Google Scholar 

  27. Solari V et al. (2003) Altered expression of interstitial cells of Cajal in congenital ureteropelvic junction obstruction. J Urol 170: 2420–2422

    Article  Google Scholar 

  28. Exintaris B et al. (2002) Spontaneous slow wave and contractile activity of the guinea pig prostate. J Urol 168: 315–322

    Article  Google Scholar 

  29. Van der Aa F et al. (2003) Interstitial cells in the human prostate: a new therapeutic target? Prostate 56: 250–255

    Article  Google Scholar 

  30. Hashitani H and Suzuki H (2004) Identification of interstitial cells of Cajal in corporal tissues of the guinea-pig penis. Br J Pharmacol 141: 199–204

    Article  CAS  Google Scholar 

  31. Burton LD et al. (2000) P2X2 receptor expression by interstitial cells of Cajal in vas deferens implicated in semen emission. Auton Neurosci 84: 147–161

    Article  CAS  Google Scholar 

  32. Drake MJ et al. (2003) Morphology, phenotype and ultrastructure of fibroblastic cells from normal and neuropathic human detrusor: absence of myofibroblast characteristics. J Urol 169: 1573–1576

    Article  Google Scholar 

  33. Wu C et al. (2004) Purinergic regulation of guinea pig suburothelial myofibroblasts. J Physiol 559: 231–243

    Article  CAS  Google Scholar 

  34. Wiseman OJ et al. (2003) The role of the human bladder lamina propria myofibroblast. BJU Int 91: 89–93

    Article  CAS  Google Scholar 

  35. Powell DW et al. (1999) Myofibroblasts. I. Paracrine cells important in health and disease. Am J Physiol 277: 1–9

    Article  Google Scholar 

  36. Hashitani H et al. (1996) Properties of spontaneous depolarizations in circular smooth muscle cells of rabbit urethra. Br J Pharmacol 118: 1627–1632

    Article  CAS  Google Scholar 

  37. Cotton KD et al. (1997) Ca2+ current and Ca2+-activated chloride current in isolated smooth muscle cells of the sheep urethra. J Physiol 505: 121–131

    Article  CAS  Google Scholar 

  38. Turner WH and Brading AF (1997) Smooth muscle of the bladder in the normal and the diseased state: pathophysiology, diagnosis and treatment. Pharmacol Ther 75: 77–110

    Article  CAS  Google Scholar 

  39. Daniel EE et al. (1983) Structural bases for neural and myogenic control of human detrusor muscle. Can J Physiol Pharmacol 61: 1247–1273

    Article  CAS  Google Scholar 

  40. Bramich NJ and Brading AF (1996) Electrical properties of smooth muscle in the guinea-pig urinary bladder. J Physiol 492: 185–198

    Article  CAS  Google Scholar 

  41. Hanani M and Brading AF (2000) Electrical coupling in smooth muscles. Is it universal? J Basic Clin Physiol Pharmacol 11: 321–330

    Article  CAS  Google Scholar 

  42. Hashitani H and Brading AF (2003) Electrical properties of detrusor smooth muscles from the pig and human urinary bladder. Br J Pharmacol 140: 146–158

    Article  CAS  Google Scholar 

  43. Hashitani H and Brading AF (2003) Ionic basis for the regulation of spontaneous excitation in detrusor smooth muscle cells of the guinea-pig urinary bladder. Br J Pharmacol 140: 159–169

    Article  CAS  Google Scholar 

  44. Hashitani H et al. (2001) Origin and propagation of spontaneous excitation in smooth muscle of the guinea-pig urinary bladder. J Physiol 530: 273–286

    Article  CAS  Google Scholar 

  45. Kubota Y et al. (2004) Investigation of the effect of the c-kit inhibitor Glivec on isolated guinea-pig detrusor preparations. Auton Neurosci 115: 64–73

    Article  CAS  Google Scholar 

  46. Biers SM (2005) Novel pharmological treatments for detrusor overactivity [thesis]. Oxford: Oxford University.

    Google Scholar 

  47. Gillespie JI (2004) The autonomous bladder: a view of the origin of bladder overactivity and sensory urge. BJU Int 93: 478–483

    Article  CAS  Google Scholar 

  48. De Ridder D et al. (1999) Nitric oxide synthase expression in neurogenic bladder disease: a pilot study. Acta Neurol Belg 99: 57–60

    CAS  PubMed  Google Scholar 

  49. Moon A (2002) Influence of nitric oxide signalling pathways on pre-contracted human detrusor smooth muscle in vitro. BJU Int 89: 942–949

    Article  CAS  Google Scholar 

  50. Ost D et al. (2002) Topography of the vanilloid receptor in the human bladder: more than just the nerve fibers. J Urol 168: 293–297

    Article  Google Scholar 

  51. Fry CH et al. (2005) Cell biology. In Incontinence: 3rd International Consultation on Incontinence, 313–362 (Eds Abrams P et al.). Plymouth: Health Publication Ltd

    Google Scholar 

  52. Kubota Y et al.: The effects of imatinib mesylate (Glivec) as a c-kit tyrosine kinase inhibitor in the guinea-pig urinary bladder. Neurourol Urodyn, in press

  53. Piotrowska AP et al. (2004) Interstitial cells of Cajal in the human normal urinary bladder and in the bladder of patients with megacystis-microcolon intestinal hypoperistalsis syndrome. BJU Int 94: 143–146

    Article  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Professor Giorgio Gabella for helpful discussion.

Author information

Authors and Affiliations

  1. Professor in the Pharmacology Department of Oxford University, Oxford, UK

    Alison F Brading

  2. Senior Lecturer in the Physiology Department of Queen's University, Belfast, UK

    Karen D McCloskey

Authors
  1. Alison F Brading
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen D McCloskey
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alison F Brading.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Brading, A., McCloskey, K. Mechanisms of Disease: specialized interstitial cells of the urinary tract—an assessment of current knowledge. Nat Rev Urol 2, 546–554 (2005). https://doi.org/10.1038/ncpuro0340

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpuro0340

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing