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. 2007 May 1;9(1):169–190. doi: 10.1111/j.1582-4934.2005.tb00347.x

Interstitial cells of Cajal in pancreas

L M Popescu 1,2,✉, M E Hinescu 1,2, N Ionescu 1, Sanda M Ciontea 1, D Cretoiu 1,2, Carmen Ardeleanu 2
PMCID: PMC6741310  PMID: 15784175

Abstract

We show here (presumably for the first time) a special type of cell in the human and rat exocrine pancreas. These cells have phenotypic characteristics of the enteric interstitial cells of Cajal (ICC). To identify pancreatic interstitial cells of Cajal (pICC) we used routine light microscopy, non‐conventional light microscopy (less than 1 μm semi‐thin sections of Epon‐embedded specimens cut by ultramicrotomy and stained with Toluidine blue), transmission electron microscopy (TEM), and immunocytochemistry. The results showed that pICC can be recognized easily by light microscopy, particularly on semi‐thin sections, as well as by TEM. Two‐dimensional reconstructions from serial photos suggest a network‐like spatial distribution of pICC. pICC represent 3.3±0.5% of all pancreatic cells, and seem to establish close spatial relationships with: capillaries (43%), acini (40%), stellate cells (14%), nerve fibres (3%). Most of pICC (88%) have 2 or 3 long processes (tens of μm) emerging from the cell body. TEM data show that pICC meet the criteria for positive diagnosis as ICC (e.g. numerous mitochondria, 8.7±0.8% of cytoplasm). Immunocytochemistry revealed that pICC are CD117/c‐kit and CD34 positive. We found pICC positive (40–50%) for smooth muscle α‐actin or S‐100, and, occasionally, for CD68, NK1 neurokinin receptor and vimentin. The reactions for desmin and chromogranin A were negative in pICC. At present, only hypotheses and speculations can be formulated on the possible role of the pICC (e.g., juxtacrine and/or paracrine roles).

In conclusion, the quite‐established dogma: “ICC only in cavitary organs” is overpassed.

Keywords: interstitial cells of Cajal, CD117/c‐kit, CD34, CD68, smooth muscle actin, desmin, vimentin, NK1 neurokinin receptor, exocrine pancreas, pancreatic stellate cells

References

  • 1. Cajal S.R., Les preuves objectives de l'unite anatomique des cellules nerveuses, Trav. Lab. Rech. Biol. Univ. Madrid 29: 1–137, 1934. [Google Scholar]
  • 2. Thuneberg L., One hundred years of interstitial cells of Cajal, Microsc. Res. Tech. 47: 223–238, 1999. [DOI] [PubMed] [Google Scholar]
  • 3. Kobayashi S., The centenary of the problem of the interstitial cells of Cajal, J. Anat. 71: 629–637, 1996. [PubMed] [Google Scholar]
  • 4. Faussone Pellegrini M.S., Thuneberg L., Guide to the identification of interstitial cells of Cajal, Microsc. Res. Tech. 47: 248–266, 1999. [DOI] [PubMed] [Google Scholar]
  • 5. Young H.M., Embryological origin of interstitial cells of Cajal, Microsc. Res. Tech. 47: 303–308, 1999. [DOI] [PubMed] [Google Scholar]
  • 6. Faussone Pellegrini M.S., Cortesini C., Ultrastructural features and localization of the interstitial cells of Cajal in the smooth muscle coat of human esophagus, J. Submicrosc. Cytol. 17: 187–197, 1985. [PubMed] [Google Scholar]
  • 7. Faussone Pellegrini M.S., Pantalone D., Cortesini C., An ultrastructural study of the interstitial cells of Cajal of the human stomach, J. Submicrosc. Cytol. Pathol. 21: 439–460, 1989. [PubMed] [Google Scholar]
  • 8. Daniel E.E., Berezin I., Interstitial cells of Cajal are they major player in control of gastrointestinal motility J. Gastrointest. Motil. 4: 1–24, 1992. [Google Scholar]
  • 9. Rumessen J.J., Peters S., Thuneberg L., Light‐and electron microscopical studies of interstitial cells of Cajal (ICC) and muscle cells at the submucosal border of human colon, Lab. Invest. 68: 481–495, 1993. [PubMed] [Google Scholar]
  • 10. Rumessen J.J., Identification of interstitial cells of Cajal. Significance for studies of human small intestine and colon, Dan. Med. Bull. 41: 275–293, 1994. [PubMed] [Google Scholar]
  • 11. Thuneberg L., Rumessen J.J., Mikkelsen H.B., Peters S., Jessen H., Structural aspects of interstital cells of Cajal as intestinal pacemaker cells, In: Huizinga J.D. (Ed.), Pacemaker Activity and Intercellular Communication. CRC Press, Boca Raton , FL , USA , 1995, pp. 193–222. [Google Scholar]
  • 12. Sanders K.M., A case for interstitial cells of Cajal as pacemakers and mediators of neurotransmission in the gastrointestinal tract, Gastroenterol., 111: 492–515, 1996. [DOI] [PubMed] [Google Scholar]
  • 13. Hagger R., Gharaie S., Finlayson C., Kumar D., Distribution of the interstitial cells of Cajal in the human anorectum, J. Auton. Nerv. Syst., 73: 75–79, 1998. [DOI] [PubMed] [Google Scholar]
  • 14. Huizinga J.D., Thuneberg L., Vanderwinden J.M., Rumessen J.J, Interstitial cells of Cajal as targets for pharmacological intervention in gastrointestinal motor disorders, Trends Pharmacol. Sci. 18: 393–403, 1997. [DOI] [PubMed] [Google Scholar]
  • 15. Koh S.D., Sanders K.M., Ward S.M., Spontaneous electrical rhythmicity in cultured interstitial cells of Cajal, isolated from the murine small intestine, J. Physiol. (Lond.), 513: 203–213, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Thomsen L., Robinson T.L., Lee J.C.F., Farraway L.A., Hughes M.J.G., Andrews D.W., Huizinga J.D., Interstitial cells of Cajal generate a rhythmic pacemaker current, Nature Med., 4: 848–851, 1998. [DOI] [PubMed] [Google Scholar]
  • 17. Maeda H., Yamagata A., Nishikawa S., Yoshinaga K., Kobayashi S., Nishi K., Nishikawa S.I., Requirement of c‐kit for development of intestinal pacemaker system, Development 116: 369–375, 1992. [DOI] [PubMed] [Google Scholar]
  • 18. Hirota S., Isozaki K., Moriyama Y., Hashimoto K., Nishida T., Ishiguro S., Kawano K., Hanada N., Kurata A., Takeda M., Muhammad T.G., Matsuzawa Y., Kanakura Y., Shinomura Y., Kitamura Y., Gain‐of‐function mutations of c‐kit in human gastrointestinal stromal tumors, Science 279: 577–580, 1998. [DOI] [PubMed] [Google Scholar]
  • 19. Grider J.R., Focus on “Molecular markers expressed in cultured and freshly isolated interstitial cells of Cajal”, Am. J. Physiol. Cell Physiol. 279: C284–C285, 2000. [DOI] [PubMed] [Google Scholar]
  • 20. Chan J.K., Mesenchymal tumors of the gastrointestinal tract: a paradise for acronyms (STUMP, GIST, GANT, and now GIPACT), implication of c‐kit in genesis, and yet another of the many emerging roles of the interstitial cell of Cajal in the pathogenesis of gastrointestinal diseases Adv. Anat. Pathol. 6: 19–40, 1999. [DOI] [PubMed] [Google Scholar]
  • 21. Robinson T.L., Sircar K., Hewlett B.R., Chorneyko K., Riddell R.H., Huizinga J.D., Gastrointestinal stromal tumors may originate from a subset of CD34‐positive interstitial cells of Cajal, Am. J. Pathol. 156: 1157–1163, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Nishida T., Hirota S., Biological and clinical review of stromal tumors in the gastrointestinal tract, Histol. Histopathol. 15: 1293–1301, 2000. [DOI] [PubMed] [Google Scholar]
  • 23. Van Roggen J.F.G., Van Velthuysen M.L.F., Hogendoorn P.C.W., The histopathological diferential diagnosis of gastrointestinal stromal tumors, J. Clin. Pathol. 54: 96–103, 2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Miettinen M., Majidi M., Lasota J., Pathology and diagnostic criteria of gastrointestinal stromal tumors (GISTs): a review, Eur. J. Canc. 38: S39–S51, 2002. [DOI] [PubMed] [Google Scholar]
  • 25. Huizinga J.D., Thuneberg L., Kluppel M., Malysz J., Mickkelsen H.B., Bernstein A., W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity, Nature 373: 347–349, 1995. [DOI] [PubMed] [Google Scholar]
  • 26. Suzuki H., Cellular mechanisms of myogenic activity in gastric smooth muscle, Jpn. J. Physiol., 50: 289–301, 2000. [DOI] [PubMed] [Google Scholar]
  • 27. Daniel E.E., Physiology and pathophysiology of the interstitial cell of Cajal: From bench to bedside III. Interaction of interstitial cells of Cajal with neuromediators: an interim assessment, Am. J. Physiol. Gastrointest. Liver Physiol. 281: G1329–G1323, 2001. [DOI] [PubMed] [Google Scholar]
  • 28. Takaki M., Gut pacemaker cells: the interstitial cells of Cajal (ICC), J. Smooth Muscle Res. 39: 137–161, 2003. [DOI] [PubMed] [Google Scholar]
  • 29. Burton L.D., Housley G.D., Salih S.G., Jaeenwood D., P2X2 receptor expression by interstitial cells of Cajal in vas deferens implicated in semen emission, Auton. Neurosci. Basic Clin. 84: 147–161, 2000. [DOI] [PubMed] [Google Scholar]
  • 30. Sergeant G.P., Hollywood M.A., McCloskey K.D., Thornbury K.D., McHale N.G., Specialized pacemaking cells in the rabbit urethra, J. Physiol 526: 359–366, 2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. McCloskey K.D., Gurney A.M., Kit positive cells in the guinea‐pig bladder, J. Urol. 168: 832–836, 2002. [PubMed] [Google Scholar]
  • 32. Pezzone M.A., Watkins S.C., Alber S.M., King W.E., De Groat C.W., Chancellor M.B., Fraser M.O., 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, 2003. [DOI] [PubMed] [Google Scholar]
  • 33. Metzger R., Schuster T., Till H., Franke F.E., Dietz H.G., Cajal‐like cells in the upper urinary tract: comparative study in various species, Pediatr: Surg. Int., 21: 169–174, 2005. [DOI] [PubMed] [Google Scholar]
  • 34. Duquette R.A., Shmygol A., Vaillant C., Mobasheri A., Pope M., Burdyga T., Wray S., Vimentin‐positive, c‐KIT‐negative interstitial cells in human and rat uterus: A role in pacemaking Biol. Reprod. 72: 276–283, 2005. [DOI] [PubMed] [Google Scholar]
  • 35. Pucovsky V., Moss R.F., Bolton T.B., Non‐contractile cells with thin processes resembling interstitial cells of Cajal found in the wall of guinea‐pig mesenteric arteries, J. Physiol. 552: 119–133, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Harhun M.I., Gordienko D.V., Povstyan O.V., Moss R.F., Bolton T.B., Function of interstitial cells of Cajal in the rabbit portal vein, Circ. Res. 95: 619–626, 2004. [DOI] [PubMed] [Google Scholar]
  • 37. McCloskey K.D., Hollywood M.A., Thornbury K.D., Ward S.M., McHale N.G., Kit‐like immunopositive cells in sheap mesenteric lymphatic vessels, Cell Tissue Res. 310: 77–84, 2002. [DOI] [PubMed] [Google Scholar]
  • 38. Bolton T.B., Gordienko D.V., Povstyan O.V., Harhun M.I., Pucovsky V., Smooth muscle cells and interstitial cells of blood vessels, Cell Calcium, 35: 643–657, 2004. [DOI] [PubMed] [Google Scholar]
  • 39. Weibel E.R., Practical methods for biological morphometry. Stereological methods, London , Academic Press, 1979. [Google Scholar]
  • 40. Hsu S.M, Rainel L., Fanger H., “Use of ABC und unlabeled antibody (PAP) procedures”, J. Histoch. Cytochem. 29: 577–580, 1981. [DOI] [PubMed] [Google Scholar]
  • 41. Bussolati G., Gugliotta P.: Nonspecific staining of mast cells by avidin ‐ biotin ‐ peroxidase complexes (ABC), J. Histochem. Cytochem, 31: 1419–1421, 1983. [DOI] [PubMed] [Google Scholar]
  • 42. Miller K., Immunocytochemical techniques, In: Bancroft J.D., Gamble M., Theory and Practice of Histological Techniques, 5th ed., Churchill Livingstone, London , 2002, pp. 421–464. [Google Scholar]
  • 43. Apte M.V., Haber P.S., Applegate T.L., Norton I.D., McCaughan G.W., Korsten M.A., Pirola R.C., Wilson J.S., Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture, Gut, 43: 128–133, 1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Bachem M.G., Schneider E., Gross H., Weidenbach H., Schmid R.M., Menke A., Siech M., Beger H., Grunert A., Adler G., Identification, culture, and characterization of pancreatic stellate cells in rats and humans, Gastroenterology, 115: 421–432, 1998. [DOI] [PubMed] [Google Scholar]
  • 45. Popescu L.M., Diculescu I., Zelck U., Ionescu N., Ultrastructural distribution of calcium in smooth muscle cells of guinea‐pig taenia coli. A correlated electron microscopic and quantitative study, Cell Tissue Res. 154: 357–78, 1974. [DOI] [PubMed] [Google Scholar]
  • 46. Popescu L.M., A conceptual model of the excitation‐contraction coupling in smooth muscle: the possible role of the surface microvesicles, Studia Biophys., 44: 141–153, 1974. [Google Scholar]
  • 47. Kitamura Y., Hirota S., Kit as human oncogenic tyrosine kinase, Cell. Mol. Life Sci. 62: 2924–2931, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Kuroda N., Toi M., Nakayama H., Miyazaki E., Yamamoto M., Hayashi Y., Hiroi M., Enzan H., The distribution and role of myofibroblasts and CD34‐positive stromal cells in normal pancreas and various pancreatic lesions, Histol. Histopathol. 19: 59–67, 2004. [DOI] [PubMed] [Google Scholar]
  • 49. Vannucchi M.G., De Giorgio R., Faussone‐Pellegrini M.S., NK1 receptor expression in the interstitial cells of Cajal and neurons and tachykinins ditribution in rat ileum during development, J. Comp. Neurol. 383: 153–162, 1997. [DOI] [PubMed] [Google Scholar]
  • 50. Epperson A., Hatton W.J., Callaghan B., Doherty P., Walker R.L., Sanders K.M., Ward S.M., Horowitz B., Molecular markers expressed in cultured and freshly isolated interstitial cells of Cajal, Am. J. Physiol. Cell Physiol., 279: C529–C539, 2000. [DOI] [PubMed] [Google Scholar]
  • 51. Ushiki T., Ide C., Autonomic nerve networks in the rat exocrine pancreas as revealed by scanning and transmission electron microscopy, Arch. Histol. Cytol., 51: 71–81, 1998. [DOI] [PubMed] [Google Scholar]
  • 52. Kumar M., Melton D., Pancreas specification: a budding question, Curr. Opin. Genet. Dev., 13: 401–407, 2003. [DOI] [PubMed] [Google Scholar]
  • 53. Gu G., Brown J.R., Melton D.A., Direct lineage tracing reveals the ontogeny of pancreatic cell fates during mouse embryogenesis, Mech. Dev. 120: 35–43, 2003. [DOI] [PubMed] [Google Scholar]
  • 54. Hu M.C., Rosenblum N.D., Genetic regulation of branching morphogenesis: Lessons learned from loss‐of‐function phenotype, Ped. Res. 54: 433–438, 2003. [DOI] [PubMed] [Google Scholar]
  • 55. Hebrok M., Hedgehog signaling in pancreas development, Mech. Dev., 120: 45–57, 2003. [DOI] [PubMed] [Google Scholar]
  • 56. Murtaugh L.C., Melton D.A., Genes, signals, and lineages in pancreas development, Annu. Rev. Cell Dev. Biol., 19: 71–89, 2003. [DOI] [PubMed] [Google Scholar]
  • 57. Apelqvist Å., Ahlgren U., Edlund H., Sonic hedgehog directs specialized mesoderm differentiation in the intestine and pancreas. Curr. Biol., 7: 810–804, 1997. [DOI] [PubMed] [Google Scholar]
  • 58. Grompe M., Pancreatic‐hepatic switches in vivo , Mech. Dev. 120: 99–106, 2003. [DOI] [PubMed] [Google Scholar]
  • 59. Shen C.N., Horb M.E., Stack J.M.W., Tosh D., Transdifferentiation of pancreas to liver, Mech. Dev. 120: 107–116, 2003. [DOI] [PubMed] [Google Scholar]
  • 60. Corless C.L., Fletcher J.A., Heinrich M.C., Biology of gastrointestinal stromal tumors, J. Clin. Oncol., 22: 3813–3825, 2004. [DOI] [PubMed] [Google Scholar]
  • 61. Yamaura K., Kato K., Miyazawa M., Haba Y., Muramatsu A., Miyata K., Koide N., Stromal tumor of the pancreas with expression of c‐kit protein: report of a case, J. Gastroenterol. Hepatol., 19: 467–470, 2004. [DOI] [PubMed] [Google Scholar]
  • 62. Jaster R., Molecular regulation of pancreatic stellate cell function, Mol. Cancer, 3: 26, 2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Phillips P.A, McCarroll, J.A. , Park S., Wu M.‐J., Pirola R., Korsten M., Wilson J.S., Apte M.V., Rat pancreatic stellate cells secrete matrix metalloproteinases: implications for extracellular matrix turnover, Gut, 52: 275–282, 2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Klöppel G., Perren A., Heitz P.U., The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification, Ann. N.Y. Acad. Sci., 1014: 13–27, 2004. [DOI] [PubMed] [Google Scholar]
  • 65. Rindi G., Leiter A.B, Kopin A. S., Bordi C., Solcia E., The “normal” endocrine cell of the gut changing concepts and new evidences, Ann. N.Y. Acad. Sci., 1014: 1–12, 2004. [DOI] [PubMed] [Google Scholar]

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