Skip to main content
NCBI home page
Journal of Cellular and Molecular Medicine logoLink to Journal of Cellular and Molecular Medicine
. 2007 May 1;9(3):714–730. doi: 10.1111/j.1582-4934.2005.tb00502.x

The connective connection: interstitial cells of Cajal (ICC) and ICC‐like cells establish synapses with immunoreactive cells.: Electron microscope study in sity.

LM Popescu 1,2,✉, Mihaela Gherghiceanu 2, D Cretoiu 1,2, E Radu 1,2
PMCID: PMC6741637  PMID: 16202219

Abstract

We present transmission electron microscope (TEM) evidence that ICC and ICC‐like cells frequently establish close contacts (synapses) with several types of immunoreactive cells (IRC): lymphocytes, plasma cells, eosinophils, basophils, macrophages and mast cells. Such synapses were found in various organs: human mammary gland and myometrium, as well as rat stomach, gut, bladder and uterus. Specimens were observed by conventional TEM on ultrathin sections. Based on morphometric analyses and computer‐aided 3‐D reconstructions from serial sections, we propose an operational definition of ICC‐IRC synapses: cell‐to‐cell close contacts where the two cells are separated by only ∼15nm, equivalent to twice the plasmalemmal thickness. Two types of such synapses were found: (i) uniform (‘plain’) synapses (PS) ‐ close contact extending for >200 nm, and (ii) multicontact (‘kiss and run’) synapses (MS) ‐ with multiple, focal, close‐contact points alternating with regions of wider intermembrane distance. For instance, a typical PS between a rat bladder ICC‐like cell and an eosinophil was 2.48 μm long and 11±4nm wide. By contrast, a MS synapse in rat myometrium (between an ICC‐like cell and an eosinophil) was 8.64 μm long and had 13 contact points. The synaptic cleft measured 15±8nm at contact points and ∼100nm or more in wider areas. These synapses are different from gap junctions usually seen between ICC and between ICC and smooth muscle cells.

We previously proposed that ICC‐like cells might represent stromal progenitor cells, participate in juxtacrine/paracrine signaling and play a role in immune surveillance. The nanoscopic distances between the two contiguous membranes suggest a juxtacrine cell‐to‐cell signaling (chemical synapse), via juxtacrinins, a specific case of phenomenins. However, the (micro)vesicles found in the synaptic cleft may correspond to an exosome‐based mechanism.

Keywords: interstitial cells of Cajal, lymphocytes, eosinophils, basophils, plasma cells mast cells, macrophage, immune synapse, intercellular communication, exosomes

References

  • 1. Rumessen JJ, Vanderwinden JM. Interstitial cells in the musculature of the gastrointestinal tract: Cajal and beyond. Int Rev Cytol. 2003; 229:115–208. [DOI] [PubMed] [Google Scholar]
  • 2. Min KW, Seo IS. Interstitial cells of Cajal in the human small intestine: immunochemical and ultrastructural study. Ultrastruct Pathol. 2003; 27: 67–78. [DOI] [PubMed] [Google Scholar]
  • 3. Faussone‐Pellegrini MS. Interstitial cells of Cajal: once negligible players, now blazing protagonists. It J Anat Embryol. 2005; 110:11–31. [PubMed] [Google Scholar]
  • 4. Kitamura Y, Hirota S. Kit as a human oncogenic tyrosine kinase. Cell Mol Life Sci. 2004; 61:2924–31. [DOI] [PubMed] [Google Scholar]
  • 5. Huizinga JD, Golden CM, Zhu Y, White EJ. Ion channels in interstitial cells of Cajal as targets for neurotransmitter action. Neurogastroenterol Motil. 2004;16:106–11. [DOI] [PubMed] [Google Scholar]
  • 6. Ward SM, Sanders KM, Hirst GD. Role of interstitial cells of Cajal in neural control of gastrointestinal smooth muscles. Neurogastroenterol Motil. 2004;16 :112–7. [DOI] [PubMed] [Google Scholar]
  • 7. Hirst GD, Edwards FR. Role of interstitial cells of Cajal in the control of gastric motility. J Pharmacol Sci. 2004; 96:1–10. [DOI] [PubMed] [Google Scholar]
  • 8. Hanani M, Farrugia G, Komuro T. Intercellular coupling of interstitial cells of cajal in the digestive tract. Int Rev Cytol. 2005; 242:249–82. [DOI] [PubMed] [Google Scholar]
  • 9. Antonescu CR, Viale A, Sarran L, Tschernyavsky SJ, Gonen M, Segal NH, Maki RG, Socci ND, DeMatteo RP, Besmer P. Gene expression in gastrointestinal stromal tumors is distinguished by KIT genotype and anatomic site. Clin Cancer Res. 2004; 10:3282–90. [DOI] [PubMed] [Google Scholar]
  • 10. von Mehren M, Watson JC. Gastrointestinal stromal tumors. Hematol Oncol Clin North Am. 2005; 19:547–64, vii. [DOI] [PubMed] [Google Scholar]
  • 11. Prakash S, Sarran L, Socci N, DeMatteo RP, Eisenstat J, Greco AM, Maki RG, Wexler LH, LaQuaglia MP, Besmer P, Antonescu CR. Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J Pediatr Hematol Oncol. 2005; 27:179–87. [DOI] [PubMed] [Google Scholar]
  • 12. Huizinga JD, Faussone‐Pellegrini MS. About the presence of interstitial cells of Cajal outside the musculature of the gastrointestinal tract. J Cell Mol Med. 2005; 9:468–73. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Harhun MI, Pucovsky V, Povstyan OV, Gordienko DV, Bolton TB. Interstitial cells in the vasculature. J Cell Mol Med. 2005; 9:232–43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Lang RJ, Klemm MF. Interstitial cells of Cajal‐like cells in the upper urinary tract. J Cell Mol Med. 2005; 9:542–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15. Popescu LM, Hinescu ME, Ionescu N, Ciontea SM, Cretoiu D, Ardelean C. Interstitial cells of Cajal in pancreas. J Cell Mol Med. 2005;9:169–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Popescu LM, Hinescu ME, Radu E, Ciontea SM, Cretoiu D, Leabu M, Ardelean C. CD117/c‐kit positive interstitial (Cajal‐like) cells in human pancreas. J Cell Mol Med. 2005; 9:737–8. 16202221 [Google Scholar]
  • 17. Ciontea SM, Radu E, Regalia T, Ceafalan L, Cretoiu D, Gherghiceanu M, Braga RI, Malincenco M, Zagrean L, Hinescu ME, Popescu LM. C‐kit immunopositive interstitial cells (Cajal‐type) in human myometrium. J Cell Mol Med. 2005; 9:407–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Popescu LM, Ciontea SM, Cretoiu D, Hinescu ME, Radu E, Ionescu N, Ceausu M, Gherghiceanu M, Braga RI, Vasilescu F, Zagrean L, Ardeleanu C. Novel type of interstitial cell (Cajal‐like) in human fallopian tube. J Cell Mol Med. 2005; 9:479–523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Popescu LM, Andrei F, Hinescu ME. Snapshots of mammary gland interstitial cells: methylene‐blue vital staining and c‐kit immunopositivity. J Cell Mol Med. 2005; 9:476–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Radu E, Regalia T, Ceafalan L, Andrei F, Cretoiu D, Popescu LM. Cajal‐type cells from human mammary gland stroma: phenotype characteristics in cell culture. J Cell Mol Med. 2005; 9:748–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21. Faussone‐Pellegrini MS, Pantalone D, Cortesini C, Smooth muscle cells, interstitial cells of Cajal and myenteric plexus interrelationship in the human colon. Acta Anat. 1990; 139:31–44. [DOI] [PubMed] [Google Scholar]
  • 22. Mikkelsen HB. Macrophages in the external muscle layers of mammalian intestines. Histol Histopathol. 1995; 10:719–36. [PubMed] [Google Scholar]
  • 23. Rumessen JJ. Ultrastructure of interstitial cells of Cajal at the colonic submuscular border in patients with ulcerative colitis. Gastroenterology. 1996; 111:1447–55. [DOI] [PubMed] [Google Scholar]
  • 24. Wang XY, Berezin I, Mikkelsen HB, Der T, Bercik P, Collins SM, Huizinga JD. Pathology of Interstitial Cells of Cajal in relation to inflammation revealed by ultrastructure but not mmunohistochemistry. Am J Pathol. 2002; 160:1529–40. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Huppa JB, Davis MM. T‐cell‐antigen recognition and the immunological synapse. Nat Rev Immunol. 2003; 3:973–83. [DOI] [PubMed] [Google Scholar]
  • 26. Davis DM, Dustin ML. What is the importance of the immunological synapse Trends Immunol. 2004; 25:323–7. [DOI] [PubMed] [Google Scholar]
  • 27. Dustin ML. The immunological synapse In: Bradshaw RA, Dennis EA, editors. Handbook of cell signaling, vol. 1 Amsterdam : Academic Press; 2004. p. 79–82. [Google Scholar]
  • 28. Jacobelli J, Andres PG, Boisvert J, Krummel MF. New views of the immunological synapse: variations in assembly and function. Curr Opin Immunol. 2004; 16:345–52. [DOI] [PubMed] [Google Scholar]
  • 29. Friedl P, den Boer AT, Gunzer M. Tuning immune responses: diversity and adaptation of the immunological synapse. Nat Rev Immunol. 2005; 5:532–45. [DOI] [PubMed] [Google Scholar]
  • 30. Fiala JC. Reconstruct: a free editor for serial section microscopy, J Microsc. 2005; 218:52–61. [DOI] [PubMed] [Google Scholar]
  • 31. Faussone Pellegrini M.S., Thuneberg L. Guide to the identification of interstitial cells of Cajal. Microsc. Res. Tech. 1999; 47:248–66. [DOI] [PubMed] [Google Scholar]
  • 32. Komuro T, Seki K, Horiguchi K. Ultrastructural characterization of the interstitial cells of Cajal. Arch Histol Cytol. 1999; 62: 295–316. [DOI] [PubMed] [Google Scholar]
  • 33. Huizinga JD, Thuneberg L, Vanderwinden JM, Rumessen JJ. Interstitial cells of Cajal as targets for pharmacological intervention in gastrointestinal motor disorders. Trends Pharmacol Sci. 1997; 18: 393–403. [DOI] [PubMed] [Google Scholar]
  • 34. Tournier JN, Hellmann AQ. Neuro‐immune connections: evidence for a neuro‐immunological synapse. Trends Immunol. 2003; 24:114–5. [DOI] [PubMed] [Google Scholar]
  • 35. Nejmeddine M, Barnard AL, Tanaka Y, Taylor GP, Bangham CR. Human T‐lymphotropic virus, type 1, tax protein triggers microtubule reorientation in the virological synapse. J Biol Chem. 2005; 280:29653–60. [DOI] [PubMed] [Google Scholar]
  • 36. Brossard C, Feuillet V, Schmitt A, Randriamampita C, Romao M, Raposo G, Trautmann A. Multifocal structure of the T cell ‐ dendritic cell synapse. Eur J Immunol. 2005; 35:1741–53. [DOI] [PubMed] [Google Scholar]
  • 37. Dustin M.L., Colman D.R., Neuronal and immunological synaptic relations. Science, 2002; 298:785–789. [DOI] [PubMed] [Google Scholar]
  • 38. Fevrier B, Raposo G. Exosomes: endosomal‐derived vesicles shipping extracellular messages. Curr Opin Cell Biol. 2004; 16:415–21. [DOI] [PubMed] [Google Scholar]
  • 39. Thery C, Duban L, Segura E, Veron P, Lantz O, Amigorena S. Indirect activation of naive CD4+ T cells by dendritic cell‐derived exosomes. Nat Immunol. 2002; 3:1156–62. [DOI] [PubMed] [Google Scholar]
  • 40. Schartz NE, Chaput N, Andre F, Zitvogel L. From the antigen‐presenting cell to the antigen‐presenting vesicle: the exosomes. Curr Opin Mol Ther. 2002; 4:372–81. [PubMed] [Google Scholar]
  • 41. Taieb J, Chaput N, Zitvogel L. Dendritic cell‐derived exosomes as cell‐free peptide‐based vaccines. Crit Rev Immunol. 2005; 25:215–23. [DOI] [PubMed] [Google Scholar]
  • 42. Wang XY, Vannucchi MG, Nieuwmeyer F, Ye J, Faussone‐Pellegrini MS, Huizinga JD. Changes in interstitial cells of Cajal at the deep muscular plexus are associated with loss of distention‐induced burst‐type muscle activity in mice infected by Trichinella spiralis. Am J Pathol. 2005; 167:437–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43. Suzuki T, Won KJ, Horiguchi K, Kinoshita K, Hori M, Torihashi S, Momotani E, Itoh K, Hirayama K, Ward SM, Sanders KM, Ozaki H. Muscularis inflammation and the loss of interstitial cells of Cajal in the endothelin ETB receptor null rat. Am J Physiol Gastrointest Liver Physiol. 2004; 287:G638–46. [DOI] [PubMed] [Google Scholar]
  • 44. Vyas YM, Maniar H, Dupont B. Visualization of signaling pathways and cortical cytoskeleton in cytolytic and noncytolytic natural killer cell immune synapses. Immunol Rev. 2002; 189:161–78. [DOI] [PubMed] [Google Scholar]
  • 45. Skokos D, Goubran‐Botros H, Roa M, Mecheri S. Immunoregulatory properties of mast cell‐derived exosomes. Mol Immunol. 2002; 38:1359–62. [DOI] [PubMed] [Google Scholar]
  • 46. Skokos D, Botros HG, Demeure C, Morin J, Peronet R, Birkenmeier G, Boudaly S, Mecheri S. Mast cell‐derived exosomes induce phenotypic and functional maturation of dendritic cells and elicit specific immune responses in vivo. J Immunol. 2003; 170:3037–45. [DOI] [PubMed] [Google Scholar]
  • 47. Laulagnier K, Motta C, Hamdi S, Roy S, Fauvelle F, Pageaux JF, Kobayashi T, Salles JP, Perret B, Bonnerot C, Record M. Mast cell‐ and dendritic cell‐derived exosomes display a specific lipid composition and an unusual membrane organization. Biochem J. 2004; 380:161–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Tsibris JC, Segars J, Coppola D, Mane S, Wilbanks GD, O'Brien WF, Spellacy WN. Insights from gene arrays on the development and growth regulation of uterine leiomyomata. Fertil Steril. 2002; 78:114–21. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Onfelt B, Nedvetzki S, Yanagi K, Davis DM. Cutting edge: Membrane nanotubes connect immune cells. J Immunol. 2004; 173:1511–3. [DOI] [PubMed] [Google Scholar]
  • 50. Watkins SC, Salter RD. Functional connectivity between immune cells mediated by tunneling nanotubules. Immunity. 2005; 23:309–18. [DOI] [PubMed] [Google Scholar]
  • 51. Popescu LM. Phenomena and … phenomenins. J Cell Mol Med. 2005; 9:2. [Google Scholar]

Articles from Journal of Cellular and Molecular Medicine are provided here courtesy of Blackwell Publishing

RESOURCES