Abstract
Hepatic stellate cells (HSCs) play an important role in liver fibrogenesis. Morphologically similar cells have been found at extrahepatic sites such as pancreas, kidney and colon. The true phenotypic relationship between these cells has not been fully established. We carried out immunohistochemical staining in normal tissues from liver, kidney, colon, pancreas, lung and heart, obtained from a range of species. Immunoreactivity to antibodies directed to synemin, glial fibrillary acidic protein (GFAP), nestin, neurofilament-L, β-tubulin, protein gene product 9.5 (PGP9.5), S100, desmin, alpha-smooth muscle actin (α-SMA) and vimentin was examined. Synemin was identified in HSCs, pancreatic stellate cells, mesangial cells and in peribronchiolar stellate-shaped fibroblasts. GFAP positivity was detected in HSCs and peribronchiolar stellate-shaped fibroblasts. Desmin immunoreactivity was detected in HSCs, pancreatic stellate cells, mesangial cells, periglomerular and peritubular fibroblasts, subepithelial fibroblasts, as well as in peribronchiolar stellate-shaped fibroblasts. Vimentin expression was evident in HSCs, periductal fibroblasts, pancreatic stellate cells, fibroblasts within the fibroconnective tissue capsule, mesangial cells, subepithelial fibroblasts and the interstitial cells of Cajal, as well as in peribronchiolar fibroblasts. Mesangial cells and peritubular fibroblasts showed nestin immunoreactivity. Our data indicates that mesenchymal cells at extrahepatic sites express many of the neural and muscle-associated proteins seen in HSCs; there are however species differences in the expression pattern of these proteins. The findings support the concept of a diffuse stellate cell system in mammals.
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References
Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS (1998) Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut 43:128–133
Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H, Grunert A, Adler G (1998) Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 115:421–432
Bauer P, Wake K (1996) Mesangial cells of the lamprey, Lampetra japonica, store vitamin A. Arch Histol Cytol 59:71–78
Bioulac-Sage P, Lafon ME, Saric J, Balabaud C (1990) Nerves and perisinusoidal cells in human liver. J Hepatol 10:105–112
Blomhoff R, Wake K (1991) Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J 5:271–277
Burt AD, Le Bail B, Balabaud C, Bioulac-Sage P (1993) Morphologic investigation of sinusoidal cells Semin. Liver Dis 13:21–38
Burt AD, Robertson JL, Heir J, MacSween RN (1986) Desmin-containing stellate cells in rat liver; distribution in normal animals and response to experimental acute liver injury. J Pathol 150:29–35
Burt AD, Tiniakos D, MacSween RN, Griffiths MR, Wisse E, Polak JM (1989) Localization of adrenergic and neuropeptide tyrosine-containing nerves in the mammalian liver. Hepatology 9:839–845
Cassiman D, Denef C, Desmet VJ, Roskams T (2001) Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Hepatology 33:148–158
Cassiman D, van Pelt J, De Vos R, Van Lommel F, Desmet V, Yap SH, Roskams T (1999) Synaptophysin: a novel marker for human and rat hepatic stellate cells. Am J Pathol 155:1831–1839
de Leeuw AM, McCarthy SP, Geerts A, Knook DL (1984) Purified rat liver fat-storing cells in culture divide and contain collagen. Hepatology 4: 392–403
Friedman SL (1996) Hepatic stellate cells. Prog Liver Dis 14: 101–130
Gard AL, White FP, Dutton GR (1985) Extra-neural glial fibrillary acidic protein (GFAP) immunoreactivity in perisinusoidal stellate cells of rat liver. J Neuroimmunol 8:359–375
Geerts A, Lazou JM, De Bleser P, Wisse E (1991) Tissue distribution, quantitation and proliferation kinetics of fat-storing cells in carbon tetrachloride-injured rat liver. Hepatology 13:1193–1202
Granger BL, Lazarides E (1980) Synemin: a new high molecular weight protein associated with desmin and vimentin filaments in muscle. Cell 22:727–738
Granger BL, Lazarides E (1982) Structural associations of synemin and vimentin filaments in avian erythrocytes revealed by immunoelectron microscopy. Cell 30:263–275
Handharyani E, Ochiai K, Iwata N, Umemura T (2001) Immunohistochemical and ultrastructural study of ito cells (fat-storing cells) in response to extrahepatic bile duct ligation in broiler chickens. J Vet Med Sci 63:547–552
Hautekeete ML, Niki T, Van den Berg K, Delvaux G, Geerts A (1996) A fraction of stellate cells in human liver express glial fibrillary acidic protein (GFAP). J Hepatol 25:112
Ikejiri N (1990) The vitamin A-storing cells in the human and rat pancreas. Kurume Med J 37:67–81
Jing R, Pizzolato G, Robson R, Gabbiani G, Skalli (2005) Intermediate filament protein synemin is present in human reactive and malignant astrocytes and associated with ruffled membranes in astrocytoma cells. Glia 50:107–120
Lee JA, Ahmed Q, Hines JE, Burt AD (1992) Disappearance of hepatic parenchymal nerves in human liver cirrhosis. Gut 33:87–91
Nagy NE, Holven KB, Roos N, Senoo H, Kojima N, Norum KR, Blomhoff R (1997) Storage of vitamin A in extrahepatic stellate cells in normal rats. J Lipid Res 38:645–658
Nakatani K, Seki S, Kawada N, Kobayashi K, Kaneda K (1996) Expression of neural cell adhesion molecule (N-CAM) in perisinusoidal stellate cells of the human liver. Cell Tissue Res 283:159–165
Niki T, De Bleser PJ, Xu G, Van Den Berg K, Wisse E, Geerts A (1996) Comparison of glial fibrillary acidic protein and desmin staining in normal and CCl4-induced fibrotic rat livers. Hepatology 23:1538–1545
Niki T, Pekny M, Hellemans K, Bleser PD, Berg KV, Vaeyens F, Quartier E, Schuit F, Geerts A (1999) Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells. Hepatology 29:520–527
Norton AJ, Jordan S, Yeomans P (1994) Brief, high-temperature heat denaturation (pressure cooking): a simple and effective method of antigen retrieval for routinely processed tissues. J Pathol 173:371–379
O’Neill A, Williams MW, Resneck WG, Milner DJ, Capetanaki Y, Bloch RJ (2002) Sarcolemmal organization in skeletal muscle lacking desmin: evidence for cytokeratins associated with the membrane skeleton at costameres. Mol Biol Cell 13:2347–2359
Powell DW, Mifflin RC, Valentich JD, Crowe SE, Saada JI, West AB (1999) Myofibroblasts. II. Intestinal subepithelial myofibroblasts. Am J Physiol Cell Physiol 277:C183–201
Reichelt J, Bussow H, Grund C, Magin TM (2001) Formation of a normal epidermis supported by increased stability of keratins 5 and 14 in keratin 10 null mice. Mol Biol Cell 12:1557–1568
Sam M, Shah S, Friden J, Milner DJ, Capetanaki Y, Lieber RL (2000) Desmin knockout muscles generate lower stress and are less vulnerable to injury compared with wild-type muscles. Am J Physiol Cell Physiol 279:C1116–1122
Saotome T, Inoue H, Fujimiya M, Fujiyama Y, Bamba T (1997) Morphological and immunocytochemical identification of periacinar fibroblast-like cells derived from human pancreatic acini. Pancreas 14:373–382
Sato K, Hirano M, Nakashima T (2001) Stellate cells in the human vocal fold. Ann Otol Rhinol Laryngol 110:319–325
Sato K, Hirano M, Nakashima T (2003) Vitamin A-storing stellate cells in the human vocal fold. Acta Otolaryngol 123:106–110
Schmitt-Graff A, Kruger S, Bochard F, Gabbiani G, Denk H (1991) Modulation of alpha smooth muscle actin and desmin expression in perisinusoidal cells of normal and diseased human livers. Am J Pathol 138:1233–1242
Schousboe A (2003) Role of astrocytes in the maintenance and modulation of glutamatergic and GABAergic neurotransmission. Neurochem Res 28:347–352
Senda T, Nomura R (2003) The expression of cytokeratin in hepatic stellate cells of the cod. Arch Histol Cytol 66:437–444
Streefkerk JG (1972) Inhibition of erythrocyte pseudoperoxidase activity by treatment with hydrogen peroxide following methanol. J Histochem Cytochem 20:829–831
Sultana S, Sernett SW, Bellin RM, Robson RM, Skalli O (2000) Intermediate filament protein synemin is transiently expressed in a subset of astrocytes during development. Glia 30:143–153
Tiniakos DG, Lee JA, Burt AD (1996) Innervation of the liver: morphology and function. Liver 16:151–160
Uyama N, Zhao L, Van Rossen E, Hirako Y, Reynaert H, Adams DH, Xue Z, Li Z, Robson R, Pekny M, Geerts A (2006) Hepatic stellate cells express synemin, a protein bridging intermediate filaments to focal adhesions. Gut 55:1276–1289
Wake K (1980) Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids, and vitamin A-storing cells in extrahepatic organs. Int Rev Cytol 66:303–353
Wake K, Sato T (1993) Intralobular heterogeneity of perisinusoidal stellate cells in porcine liver. Cell Tissue Res 273:227–237
Watari N, Hotta Y, Mabuchi Y (1982) Morphological studies on a vitamin A-storing cell and its complex with macrophage observed in mouse pancreatic tissues following excess vitamin A administration. Okajimas Folia Anat Jpn 58:837–858
Wold HL, Wake K, Higashi N, Wang D, Kojima N, Imai K, Blomhoff R, Senoo H (2004) Vitamin A distribution and content in tissues of the lamprey, Lampetra japonica. Anat Rec A Discov Mol Cell Evol Biol 276:134–142
Yokoi Y, Namihisa T, Kuroda H, Komatsu I, Miyazaki A, Watanabe S, Usui K (1984) Immunocytochemical detection of desmin in fat-storing cells (Ito cells). Hepatology 4:709–714
Acknowledgements
We are grateful to Dr Zhenlin Li (Department of Molecular Biology, University Denis Diderot Paris 7, France) for his donation of anti-human synemin antibody. We thank Dr Rakesh Rai (Freeman Hospital, Newcastle upon Tyne, UK) for providing frozen pig liver tissue.
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Zhao, L., Burt, A.D. The diffuse stellate cell system. J Mol Hist 38, 53–64 (2007). https://doi.org/10.1007/s10735-007-9078-5
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DOI: https://doi.org/10.1007/s10735-007-9078-5