Abstract
We describe here an interstitial Cajal-like cell type (ICLC) in human gallbladder, resembling the archetypal enteric interstitial cells of Cajal. Gallbladder ICLC were demonstrated in fresh preparations (tissue cryosections) using methylene-blue, and fixed specimens in Epon semi-thin sections stained with toluidine blue or transmission electron microscopy (TEM). The positive diagnosis of gallbladder ICLC was further verified by immunohistochemistry: CD117/c-kit, CD34, and another 16 antigens: vimentin, desmin, nestin, α-smooth muscle actin, NK-1, S-100, PGP-9.5, tau protein, chromogranin A, NSE, GFAP, CD1a, CD62-P, CD68, estrogen and progesterone receptors. Double immunostaining was performed for CD117, CD34 and CD117 and nestin, respectively. In fresh specimens, the spatial density of gallbladder ICLC was 100–110 cells/mm2. ICLC mainly appeared beneath the epithelium and in muscularis (about 7%, and ∼5%, respectively). In toto, ICLC represent in gallbladder ∼5.5% of subepithelial cells. TEM showed that diagnostic criteria were fulfilled by ICLC. Moreover, TEM indicated that the main ultrastructural distinctive feature for ICLC, the cell processes, develop into the characteristic shape at a relatively early stage of development. It remains to be established if, in humans, ICLC are involved in gallbladder (dis)functions (e.g. pace-making, secretion (auto-, juxta- and/or paracrine), intercellular signaling, or stone formation).
Similar content being viewed by others
References
Bobryshev YV (2005) Subset of cells immunopositive for neurokinin-1 receptor identified as arterial interstitial cells of Cajal in human large arteries. Cell Tissue Res 321:45–55
Bussolati G (2005) Of GISTs and EGISTs, ICCs and Ics. Virchows Arch 447:907–908
Bussolati G, Gugliotta P (1983) Nonspecific staining of mast cells by avidin – biotin-peroxidase complexes (ABC). J Histochem Cytochem 31:1419–1421
Cajal RS (1911) Histologie du système nerveux de l’Homme et de Vertébrés. Grand sympathique, Paris, Maloine
Ciontea SM, Radu E, Regalia T, Ceafalan L, Cretoiu D, Gherghiceanu M, Braga RI, Malincenco M, Zagrean L, Hinescu ME Popescu LM (2005) C-kit immunopositive interstitial cells (Cajal-type) in human myometrium. J Cell Mol Med 9:407–420
Cretoiu D, Ciontea SM, Popescu LM, Ceafalan L, Ardeleanu C (2006) Interstitial Cajal-like cells (ICLC) as steroid hormone sensors in human myometrium: immunocytochemical approach. J Cell Mol Med 10:789–795
Dray X, Joly F, Reijasse D, Attar A, Alves A, Panis Y, Valleur P, Messing B (2007) Incidence, risk factors, and complications of cholelithiasis in patients with home parenteral nutrition. J Am Coll Surg 204:13–21
Faussone-Pellegrini MS (2006) Relationships between neurokinin receptor-expressing interstitial cells of Cajal and tachykininergic nerves in the gut. J Cell Mol Med 10:20–32
Faussone Pellegrini MS, Thuneberg L (1999) Guide to the identification of interstitial cells of Cajal. Microsc Res Tech 47:248–266
Faussone-Pellegrini MS, Vannucchi MG (2006) Substance P and neurokinin 1 receptor – expression is affected in the ileum of mice with mutation in the W locus. J Cell Mol Med 10:511–518
Faussone-Pellegrini MS, Vannucchi MG, Ledder O, Huang TY, Hanani M (2006) Plasticity of interstitial cells of Cajal: a study of mouse colon. Cell Tissue Res 325:211–217
Frossard JL (2005) Conversion of biliary system to pancreatic tissue: complete plasticity or same organ? J Hepatol 42:782–785
Furihata M, Fujimori T, Imura J, Ono Y, Furihata T, Shimoda M, Kato M, Kita J, Ohkura Y, Kubota K (2005) Malignant stromal tumor, so called ‘‘gastrointestinal stromal tumor’’, with rhabdomyomatous differentiation occurring in the gallbladder. Pathol Res Pract 201:609–613
Grimbaldeston MA, Chen CC, Piliponsky AM, Tsai M, See-Ying Tam S-Y, Galli SJ (2005) Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 167:835–848
Hakimian R, Korn D (2004) Ownership and use of tissue specimens for research. JAMA 292:2500–2505
Harhun MI, Pucovsky V, Povstyan OV, Gordienko DV, Bolton TB (2005) Interstitial cells in the vasculature. J Cell Mol Med 9:232–243
Heinrich MC, Corless CL (2005) Gastric GI stromal tumors (GISTs): the role of surgery in the era of targeted therapy. J Surg Oncol 90:195–207
Hinescu ME, Popescu LM (2005) Interstitial Cajal-like cells (ICLC) in human atrial myocardium. J Cell Mol Med 9:972–975
Hinescu ME, Gherghiceanu M, Mandache E, Ciontea SM, Popescu LM (2006) Interstitial Cajal-like cells (ICLC) in atrial myocardium: ultrastructural and immunohistochemical characterization. J Cell Mol Med 10:243–257
Hopwood D, Ross PE (1997) Biochemical and morphological correlations in human gallbladder with reference to membrane permeability. Microsc Res Tech 38:631–642
Hsu SM, Raniel L, Fanger H (1981) Use of ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem 29:577–580
Huizinga JD, Faussone-Pellegrini MS (2005) About the presence of interstitial cells of Cajal outside the musculature of the gastrointestinal tract. J Cell Mol Med 9:468–473
Huizinga JD, Thuneberg L, Vanderwinden JM, Rumessen JJ (1997) Interstitial cells of Cajal as targets for pharmacological intervention in gastrointestinal motor disorders. Trends Pharmacol Sci 18:393–403
Isozaki K, Hirota S, Nakama A, Miyagawa J, Shinomura Y, Xu Z, Nomura S, Kitamura Y (1995) Disturbed intestinal movement, bile reflux to the stomach, and deficiency of c-kit expressing cells in Ws/Ws mutant rats. Gastroenterology 109:456–464
Komuro T (1999) Comparative morphology of interstitial cells of Cajal: ultrastructural characterization. Microsc Res Tech 47:267–285
Kubota M, Kanda E, Ida K, Sakakihara Y, Hayashi M (2005) Severe gastrointestinal dysmotility in a patient with congenital myopathy: causal relationship to decrease of interstitial cells of Cajal. Brain Dev 27:447–450
Lang RJ, Klemm MF (2005) Interstitial cell of Cajal-like cells in the upper urinary tract. J Cell Mol Med 9:543–556
Langner C, Lemmerer M, Kornprat P (2004) Analysis of KIT (CD117) expression in gallbladder carcinomas by tissue microarray. Eur J Surg Oncol 30:847–850
Lardon J, De Breuck S, Rooman I, Van Lommel L, Kruhoffer M, Orntoft T, Schuit FF, Bouwens L (2004) Plasticity in the adult rat pancreas: transdifferentiation of exocrine to hepatocyte-like cells in primary culture. Hepatology 39:1499–1507
Lavoie BB, Onesmo B, Balemba OB, Mark T, Nelson MT, Sean M, Ward SM, Mawe GM (2007) Morphological and physiological evidence for interstitial cell of Cajal (ICC)-like cells in the guinea pig gallbladder. J Physiol 597:487–501
Lee H, Douglas-Jones AG, Morgan JM, Jasani B (2002) The effect of fixation and processing on the sensitivity of oestrogen receptor assay by immunohistochemistry in breast carcinoma. J Clin Pathol 55:236–238
Lyford GL, He CL, Soffer E, Hull TL, Strong SA, Senagore AJ, Burgart LJ, Young-Fadok T, Szurszewski JH, Farrugia G (2002) Pan-colonic decrease in interstitial cells of Cajal in patients with slow transit constipation. Gut 51:496–501
Maeda H, Yamagata A, Nishikawa S, Yoshinaga K, Kobayashi S, Nishi K, Nishikawa S-I (1992) Requirement of c-kit for development of intestinal pacemaker system. Development 116:369–375
McCloskey KD, Hollywood MA, Thornbury KD, Ward SM, McHale NG (2002) Kit-like immunopositive cells in sheep mesenteric lymphatic vessels. Cell Tissue Res 310:77–84
Mendoza-Marin M, Hoang MP, Albores-Saavedra J (2002) Malignant stromal tumor of the gallbladder with interstitial cells of Cajal phenotype. Arch Pathol Lab Med 126:481–483
Miller K (2002) Immunocytochemical techniques. In: Bancroft JD, Gamble M (eds) Theory and practice of histological techniques, 5th edn. Churchill Livingstone, London, pp 421–464
Nakanuma Y, Katayanagi K, Kawamura Y, Yoshida K (1997) Monolayer and three dimensional cell culture and living tissue culture of gallbladder epithelium. Microsc Res Tech 39:71–84
Oldham-Ott CK, Gilloteaux J (1997) Comparative morphology of the gallbladder and biliary tract in vertebrates: variation in structure, homology in function and gallstones. Microsc Res Tech 38:571–597
Ortiz-Hidalgo C, de Leon Bojorge B, Albores-Saavedra J (2000) Stromal tumor of the gallbladder with phenotype of interstitial cells of Cajal. A previously unrecognized neoplasm. Am J Surg Pathol 24:1420–1423
Park JK, Choi SH, Lee S, Min KO, Yun SS, Jeon HM (2004) Malignant gastrointestinal stromal tumor of the gallbladder. J Korean Med Sci 19:763–767
Parr EJ, Kennedy AL, Mawe GM (2003) Lack of evidence for the existence of interstitial cells of Cajal in the gallbladder. Gastroenterology 124(Suppl 1):A347
Popescu LM, Andrei F, Hinescu ME (2005a) Snapshots of mammary gland interstitial cells: methylene-blue vital staining and c-kit immunopositivity. J Cell Mol Med 9:476–477
Popescu LM, Ciontea SM, Cretoiu D, Hinescu ME, Radu E, Ionescu N, Ceausu M, Gherghiceanu M, Braga RI, Vasilescu F, Zagrean L, Ardeleanu C (2005b) Novel type of interstitial cell (Cajal-like) in human fallopian tube. J Cell Mol Med 9:479–523
Popescu LM, Gherghiceanu M, Cretoiu D, Radu E (2005c) The connective connection: interstitial cells of Cajal (ICC) and ICC-like cells establish synapses with immunoreactive cells. Electron microscope study in situ. J Cell Mol Med 9:714–730
Popescu LM, Hinescu ME, Ionescu N, Ciontea SM, Cretoiu D, Ardeleanu C (2005d) Interstitial cells of Cajal in pancreas. J Cell Mol Med 9:169–190
Popescu LM, Gherghiceanu M, Hinescu ME, Cretoiu D, Ceafalan L, Regalia T, Popescu AC, Ardeleanu C, Mandache E (2006a) Insights into the interstium of ventricular myocardium: interstitial Cajal-like cells (ICLC). J Cell Mol Med 10:429–458
Popescu LM, Vidulescu C, Curici A, Caravia L, Simionescu AA, Ciontea SM, Simion S (2006b) Imatinib inhibits spontaneous rhythmic contractions of human uterus and intestine. Eur J Pharmacol 546:177–181
Popescu LM, Ciontea SM, Cretoiu D (2007) Interstitial Cajal-like cells in human uterus and fallopian tube. Ann NY Acad Sci 1101:139–165
Porcher C, Baldo M, Henry M, Orsoni P, Jule Y, Ward SM (2002) Deficiency of interstitial cells of Cajal in the small intestine of patients with Crohn’s disease. Am J Gastroenterol 97:118–125
Radu E, Regalia T, Ceafalan L, Andrei F, Cretoiu D, Popescu LM (2005) Cajal-type cells from human mammary gland stroma: phenotype characteristics in cell culture. J Cell Mol Med 9:748–752
Robinson TL, Sircar K, Hewlett BR, Chorneyko K, Riddell RH, Huizinga JD (2000) Gastrointestinal stromal tumors may originate from a subset of CD34-positive interstitial cells of Cajal. Am J Pathol 56:1157–1163
Rumessen JJ, de Kerchove d’Exaerde A, Mignon S, Bernex F, Timmermans JP, Schiffmann SN, Panthier JJ, Vanderwinden JM (2001) Interstitial cells of Cajal in the striated musculature of the mouse esophagus. Cell Tissue Res 306:1–14
Sanders KM, Ordog T, Ward SM (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:G747–G756
Sanders KM, Ward SM (2006) Interstitial cells of Cajal: a new perspective on smooth muscle function. J Physiol 576:721–726
Sergeant GP, Thornbury KD, McHale NG, Hollywood MA (2006) Interstitial cells of Cajal in the urethra. J Cell Mol Med 10:280–291
Shen CN, Slack JMV, Tosh D (2002) Molecular basis of transdifferentiation of pancreas to liver. Nat Cell Biol 2:879–887
Solari V, Piotrowska AP, Puri P (2003) Altered expression of interstitial cells of Cajal in congenital ureteropelvic junction obstruction. J Urol 170:2420–2422
Streutker CJ, Huizinga JD, Driman DK, Riddell RH (2007) Interstitial cells of Cajal in health and disease. Part II: ICC and gastrointestinal tumors. Histopathology 50:190–202
Sumazaki R, Shiojiri N, Isoyama S, Masu M, Keino-Masu K, Osawa M, Nakauchi H, Kageyama R, Matsui A (2004) Conversion of biliary system to pancreatic tissue in Hes1-deficient mice. Nat Genet 36:83–87
Sun X, Yu B, Xu L, Dong W, Luo H (2006) Interstitial cells of Cajal in the murine gallbladder. Scand J Gastroenterol 41:1218–1226
Taguchi T, Suita S, Masumoto K, Nagasaki A (2005) An abnormal distribution of c-kit positive cells in the normoganglionic segment can predict a poor clinical outcome in patients with Hirschsprung’s disease. Eur J Pediatr Surg 15:153–158
Takahashi M (2001) GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev 12:361–373
Thomas MB (2007) Biological characteristics of cancers in the gallbladder and biliary tract and targeted therapy. Crit Rev Oncol Hematol 61:44–51
Tong WD, Liu BH, Zhang LY, Zhang SB, Lei Y (2004) Decreased interstitial cells of Cajal in the sigmoid colon of patients with slow transit constipation. Int J Colorectal Dis 19:467–473
Vannucchi MG (1999) Receptors in interstitial cells of Cajal: identification and possible physiological roles. Microsc Res Tech 47:325–335
Ye J, Zhu Y, Khan WI, Van Snick J, Huizinga JD (2006) IL-9 enhances growth of ICC, maintains network structure and strengthens rhythmicity of contraction in culture. J Cell Mol Med 10:687–694
Acknowledgements
Supported by CEEX 111/2006, CEEX 112/2006 and ‘Program Nucleu’ 06.26.01.02./2006, MCT Grants to ‘Victor Babes’ Institute of Pathology and “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania. We gratefully acknowlegde Mrs. Christine Lewis Radu for critical reading the manuscript and Dr. Dragos Cretoiu for experimental help and advice.
Author information
Authors and Affiliations
Corresponding author
Additional information
M. E. Hinescu and C. Ardeleanu contributed equally to this study.
Rights and permissions
About this article
Cite this article
Hinescu, M.E., Ardeleanu, C., Gherghiceanu, M. et al. Interstitial Cajal-like cells in human gallbladder. J Mol Hist 38, 275–284 (2007). https://doi.org/10.1007/s10735-007-9099-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10735-007-9099-0