• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of amjpatholAmerican Journal of Pathology For AuthorsAmerican Journal of Pathology SubscribeAmerican Journal of Pathology SearchAmerican Journal of Pathology Current IssueAmerican Journal of Pathology About the JournalAmerican Journal of Pathology
Am J Pathol. Aug 1996; 149(2): 449–462.
PMCID: PMC1865318

Cell-type-specific expression of neural cell adhesion molecule (N-CAM) in Ito cells of rat liver. Up-regulation during in vitro activation and in hepatic tissue repair.

Abstract

Ito cells (lipocytes, stellate cells) are regarded as the principle matrix-producing cell of the liver and have been shown recently to express glial fibrillary acidic protein, an intermediate filament typically found in glia cells of the nervous system. The present study examines 1) whether Ito cells of rat liver express central nervous system typical adhesion molecules, namely, neural cell adhesion molecule (N-CAM), in a cell-type-specific manner and 2) whether N-CAM expression is affected by activation of Ito cells in vitro and during rat liver injury in vivo. As assessed by reverse transcriptase polymerase chain reaction, Northern blotting, Western blotting, and immunocytochemistry of freshly isolated and cultivated hepatic cells, N-CAM expression was restricted to Ito cells and was absent in hepatocytes, Kupffer cells, and sinusoidal endothelial cells. Ito cells expressed predominantly N-CAM-coding transcripts of 6.1 and 4.8 kb in size and 140-kd isoforms of the N-CAM protein, which was localized on the cell surface membrane of Ito cells. In parallel to glial fibrillary acidic protein down-regulation and smooth muscle alpha-actin up-regulation, N-CAM expression was increased during in vitro transformation of Ito cells from resting to activated (myofibroblast-like) cells and by the fibrogenic mediator transforming growth factor-beta 1. By immunohistochemistry, N-CAM was detected in normal rat liver in the portal field as densely packed material and in a spot as well as fiber-like pattern probably representing nerve structures. However, after liver injury, N-CAM expression became detectable in mesenchymal cells within and around the necrotic area and within fibrotic septae. In serially cut tissue sections, N-CAM-positive cells were predominantly co-distributed with smooth muscle alpha-actin-positive cells rather than glial fibrillary acidic protein-positive cells, especially in fibrotic livers. The experimental results illustrate that N-CAM positivity in the liver cannot be solely ascribed to nerve endings as, among the different types of resident liver cells, Ito cells specifically express N-CAM in vitro and presumably in vivo. In addition to its role as potential cell-type-specific marker protein for activated Ito cells, the induction of N-CAM expression might illustrate a mechanism by which mesenchymal cell proliferation might be inhibited when tissue repair is concluded.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (3.8M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Cunningham BA. Cell adhesion molecules as morphoregulators. Curr Opin Cell Biol. 1995 Oct;7(5):628–633. [PubMed]
  • Edelman GM, Crossin KL. Cell adhesion molecules: implications for a molecular histology. Annu Rev Biochem. 1991;60:155–190. [PubMed]
  • Cole GJ, Akeson R. Identification of a heparin binding domain of the neural cell adhesion molecule N-CAM using synthetic peptides. Neuron. 1989 Feb;2(2):1157–1165. [PubMed]
  • Kallapur SG, Akeson RA. The neural cell adhesion molecule (NCAM) heparin binding domain binds to cell surface heparan sulfate proteoglycans. J Neurosci Res. 1992 Dec;33(4):538–548. [PubMed]
  • Friedlander DR, Milev P, Karthikeyan L, Margolis RK, Margolis RU, Grumet M. The neuronal chondroitin sulfate proteoglycan neurocan binds to the neural cell adhesion molecules Ng-CAM/L1/NILE and N-CAM, and inhibits neuronal adhesion and neurite outgrowth. J Cell Biol. 1994 May;125(3):669–680. [PMC free article] [PubMed]
  • Milev P, Friedlander DR, Sakurai T, Karthikeyan L, Flad M, Margolis RK, Grumet M, Margolis RU. Interactions of the chondroitin sulfate proteoglycan phosphacan, the extracellular domain of a receptor-type protein tyrosine phosphatase, with neurons, glia, and neural cell adhesion molecules. J Cell Biol. 1994 Dec;127(6 Pt 1):1703–1715. [PMC free article] [PubMed]
  • Reyes AA, Small SJ, Akeson R. At least 27 alternatively spliced forms of the neural cell adhesion molecule mRNA are expressed during rat heart development. Mol Cell Biol. 1991 Mar;11(3):1654–1661. [PMC free article] [PubMed]
  • Eckhardt M, Mühlenhoff M, Bethe A, Koopman J, Frosch M, Gerardy-Schahn R. Molecular characterization of eukaryotic polysialyltransferase-1. Nature. 1995 Feb 23;373(6516):715–718. [PubMed]
  • Frei T, von Bohlen und Halbach F, Wille W, Schachner M. Different extracellular domains of the neural cell adhesion molecule (N-CAM) are involved in different functions. J Cell Biol. 1992 Jul;118(1):177–194. [PMC free article] [PubMed]
  • Sunshine J, Balak K, Rutishauser U, Jacobson M. Changes in neural cell adhesion molecule (NCAM) structure during vertebrate neural development. Proc Natl Acad Sci U S A. 1987 Aug;84(16):5986–5990. [PMC free article] [PubMed]
  • Møller CJ, Christgau S, Williamson MR, Madsen OD, Niu ZP, Bock E, Baekkeskov S. Differential expression of neural cell adhesion molecule and cadherins in pancreatic islets, glucagonomas, and insulinomas. Mol Endocrinol. 1992 Aug;6(8):1332–1342. [PubMed]
  • Mizutani H, Roswit W, Hemperly J, Lawley T, Compton C, Swerlick R, Kupper TS. Human dermal microvascular endothelial cells express the 140-kD isoform of neural cell adhesion molecule. Biochem Biophys Res Commun. 1994 Aug 30;203(1):686–693. [PubMed]
  • Tavella S, Raffo P, Tacchetti C, Cancedda R, Castagnola P. N-CAM and N-cadherin expression during in vitro chondrogenesis. Exp Cell Res. 1994 Dec;215(2):354–362. [PubMed]
  • Roubin R, Deagostini-Bazin H, Hirsch MR, Goridis C. Modulation of NCAM expression by transforming growth factor-beta, serum, and autocrine factors. J Cell Biol. 1990 Aug;111(2):673–684. [PMC free article] [PubMed]
  • Gulbenkian S, Santos J, Gordon L, Wharton J, Polak JM, David-Ferreira JF. Neural cell adhesion molecule is expressed by smooth muscle cells during the development of the rat vascular system. J Neurocytol. 1989 Dec;18(6):809–817. [PubMed]
  • Nouwen EJ, Dauwe S, van der Biest I, De Broe ME. Stage- and segment-specific expression of cell-adhesion molecules N-CAM, A-CAM, and L-CAM in the kidney. Kidney Int. 1993 Jul;44(1):147–158. [PubMed]
  • Lanier LL, Testi R, Bindl J, Phillips JH. Identity of Leu-19 (CD56) leukocyte differentiation antigen and neural cell adhesion molecule. J Exp Med. 1989 Jun 1;169(6):2233–2238. [PMC free article] [PubMed]
  • Moolenaar CE, Pieneman C, Walsh FS, Mooi WJ, Michalides RJ. Alternative splicing of neural-cell-adhesion molecule mRNA in human small-cell lung-cancer cell line H69. Int J Cancer. 1992 May 8;51(2):238–243. [PubMed]
  • Dickson G, Peck D, Moore SE, Barton CH, Walsh FS. Enhanced myogenesis in NCAM-transfected mouse myoblasts. Nature. 1990 Mar 22;344(6264):348–351. [PubMed]
  • Krushel LA, Sporns O, Cunningham BA, Crossin KL, Edelman GM. Neural cell adhesion molecule (N-CAM) inhibits astrocyte proliferation after injury to different regions of the adult rat brain. Proc Natl Acad Sci U S A. 1995 May 9;92(10):4323–4327. [PMC free article] [PubMed]
  • Smith DV, Klevitsky R, Akeson RA, Shipley MT. Expression of the neural cell adhesion molecule (NCAM) and polysialic acid during taste bud degeneration and regeneration. J Comp Neurol. 1994 Sep 8;347(2):187–196. [PubMed]
  • Chuong CM, Chen HM. Enhanced expression of neural cell adhesion molecules and tenascin (cytotactin) during wound healing. Am J Pathol. 1991 Feb;138(2):427–440. [PMC free article] [PubMed]
  • Zocchi MR, Ferrero E, Toninelli E, Castellani P, Poggi A, Rugarli C. Expression of N-CAM by human renal cell carcinomas correlates with growth rate and adhesive properties. Exp Cell Res. 1994 Oct;214(2):499–509. [PubMed]
  • Ramadori G. The stellate cell (Ito-cell, fat-storing cell, lipocyte, perisinusoidal cell) of the liver. New insights into pathophysiology of an intriguing cell. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;61(3):147–158. [PubMed]
  • Pinzani M. Novel insights into the biology and physiology of the Ito cell. Pharmacol Ther. 1995 May;66(2):387–412. [PubMed]
  • Tsutsumi M, Takada A, Takase S. Characterization of desmin-positive rat liver sinusoidal cells. Hepatology. 1987 Mar-Apr;7(2):277–284. [PubMed]
  • Ramadori G, Veit T, Schwögler S, Dienes HP, Knittel T, Rieder H, Meyer zum Büschenfelde KH. Expression of the gene of the alpha-smooth muscle-actin isoform in rat liver and in rat fat-storing (ITO) cells. Virchows Arch B Cell Pathol Incl Mol Pathol. 1990;59(6):349–357. [PubMed]
  • Dijkstra CD, Döpp EA, Joling P, Kraal G. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in the rat recognized by monoclonal antibodies ED1, ED2 and ED3. Immunology. 1985 Mar;54(3):589–599. [PMC free article] [PubMed]
  • Schwartz RJ, Haron JA, Rothblum KN, Dugaiczyk A. Regulation of muscle differentiation: cloning of sequences from alpha-actin messenger ribonucleic acid. Biochemistry. 1980 Dec 9;19(25):5883–5890. [PubMed]
  • McHugh KM, Lessard JL. The nucleotide sequence of a rat vascular smooth muscle alpha-actin cDNA. Nucleic Acids Res. 1988 May 11;16(9):4167–4167. [PMC free article] [PubMed]
  • Chen WJ, Liem RK. Reexpression of glial fibrillary acidic protein rescues the ability of astrocytoma cells to form processes in response to neurons. J Cell Biol. 1994 Nov;127(3):813–823. [PMC free article] [PubMed]
  • Barbu V, Dautry F. Northern blot normalization with a 28S rRNA oligonucleotide probe. Nucleic Acids Res. 1989 Sep 12;17(17):7115–7115. [PMC free article] [PubMed]
  • Small SJ, Shull GE, Santoni MJ, Akeson R. Identification of a cDNA clone that contains the complete coding sequence for a 140-kD rat NCAM polypeptide. J Cell Biol. 1987 Nov;105(5):2335–2345. [PMC free article] [PubMed]
  • Arcari P, Martinelli R, Salvatore F. The complete sequence of a full length cDNA for human liver glyceraldehyde-3-phosphate dehydrogenase: evidence for multiple mRNA species. Nucleic Acids Res. 1984 Dec 11;12(23):9179–9189. [PMC free article] [PubMed]
  • Knittel T, Armbrust T, Schwögler S, Schuppan D, Ramadori G. Distribution and cellular origin of undulin in rat liver. Lab Invest. 1992 Dec;67(6):779–787. [PubMed]
  • Spencer CI, Lab MJ, Seed WA. Mechanical restitution during alternans in guinea pig papillary muscles. Cardiovasc Res. 1992 Aug;26(8):779–782. [PubMed]
  • Knittel T, Neubauer K, Armbrust T, Ramadori G. Expression of von Willebrand factor in normal and diseased rat livers and in cultivated liver cells. Hepatology. 1995 Feb;21(2):470–476. [PubMed]
  • Knittel T, Schuppan D, Meyer zum Büschenfelde KH, Ramadori G. Differential expression of collagen types I, III, and IV by fat-storing (Ito) cells in vitro. Gastroenterology. 1992 May;102(5):1724–1735. [PubMed]
  • Neubauer K, Knittel T, Armbrust T, Ramadori G. Accumulation and cellular localization of fibrinogen/fibrin during short-term and long-term rat liver injury. Gastroenterology. 1995 Apr;108(4):1124–1135. [PubMed]
  • Ramadori G, Lenzi M, Dienes HP, Meyer zum Büschenfelde KH. Binding properties of mechanically and enzymatically isolated hepatocytes for IgG and C3. Liver. 1983 Dec;3(6):358–368. [PubMed]
  • Ramadori G, Rieder H, Knittel T, Dienes HP, Meyer zum Büschenfelde KH. Fat storing cells (FSC) of rat liver synthesize and secrete fibronectin. Comparison with hepatocytes. J Hepatol. 1987 Apr;4(2):190–197. [PubMed]
  • Ramadori G, Schwögler S, Veit T, Rieder H, Chiquet-Ehrismann R, Mackie EJ, Meyer zum Büschenfelde KH. Tenascin gene expression in rat liver and in rat liver cells. In vivo and in vitro studies. Virchows Arch B Cell Pathol Incl Mol Pathol. 1991;60(3):145–153. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. [PMC free article] [PubMed]
  • Theveniau M, Guo XJ, Rage P, Rougon G. Removal of C6 astrocytoma cell surface molecules with phosphatidylinositol phospholipase C: effect on regulation of neural cell adhesion molecule isoforms. J Neurochem. 1991 Jul;57(1):67–74. [PubMed]
  • Fantini J, Guo XJ, Marvaldi J, Rougon G. Suramin inhibits proliferation of rat glioma cells and alters N-CAM cell surface expression. Int J Cancer. 1990 Mar 15;45(3):554–561. [PubMed]
  • Ramadori G, Knittel T, Odenthal M, Schwögler S, Neubauer K, Meyer zum Büschenfelde KH. Synthesis of cellular fibronectin by rat liver fat-storing (Ito) cells: regulation by cytokines. Gastroenterology. 1992 Oct;103(4):1313–1321. [PubMed]
  • Czaja MJ, Weiner FR, Flanders KC, Giambrone MA, Wind R, Biempica L, Zern MA. In vitro and in vivo association of transforming growth factor-beta 1 with hepatic fibrosis. J Cell Biol. 1989 Jun;108(6):2477–2482. [PMC free article] [PubMed]
  • Nakatsukasa H, Nagy P, Evarts RP, Hsia CC, Marsden E, Thorgeirsson SS. Cellular distribution of transforming growth factor-beta 1 and procollagen types I, III, and IV transcripts in carbon tetrachloride-induced rat liver fibrosis. J Clin Invest. 1990 Jun;85(6):1833–1843. [PMC free article] [PubMed]
  • Milani S, Herbst H, Schuppan D, Stein H, Surrenti C. Transforming growth factors beta 1 and beta 2 are differentially expressed in fibrotic liver disease. Am J Pathol. 1991 Dec;139(6):1221–1229. [PMC free article] [PubMed]
  • Scoazec JY, Racine L, Couvelard A, Moreau A, Flejou JF, Bernuau D, Feldmann G. Parenchymal innervation of normal and cirrhotic human liver: a light and electron microscopic study using monoclonal antibodies against the neural cell-adhesion molecule. J Histochem Cytochem. 1993 Jun;41(6):899–908. [PubMed]
  • Roskams T, van den Oord JJ, De Vos R, Desmet VJ. Neuroendocrine features of reactive bile ductules in cholestatic liver disease. Am J Pathol. 1990 Nov;137(5):1019–1025. [PMC free article] [PubMed]
  • Volpes R, van den Oord JJ, Desmet VJ. Integrins as differential cell lineage markers of primary liver tumors. Am J Pathol. 1993 May;142(5):1483–1492. [PMC free article] [PubMed]
  • Sporns O, Edelman GM, Crossin KL. The neural cell adhesion molecule (N-CAM) inhibits proliferation in primary cultures of rat astrocytes. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):542–546. [PMC free article] [PubMed]
  • Devereux J, Haeberli P, Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. [PMC free article] [PubMed]

Articles from The American Journal of Pathology are provided here courtesy of American Society for Investigative Pathology

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Compound
    Compound
    PubChem Compound links
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...