Abstract
In vitro and in vivo studies suggest that liver fat-storing cells (FSC) may play an important role in the development of liver fibrosis. We explored the effects of platelet-derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor (TGF)-alpha and TGF-beta, and basic fibroblast growth factor (bFGF) on DNA synthesis and growth of rat liver FSC. PDGF, EGF, TGF-alpha, and bFGF induced a dose-dependent increase in DNA synthesis with a peak effect at 24 h. PDGF produced the most striking effect with a maximum 18-fold increase over control. EGF, TGF-alpha, and bFGF elicited a maximum three- to fourfold increase in DNA synthesis. Analysis of growth curves revealed a similar pattern of potency of the growth factors. TGF-beta did not affect DNA synthesis of FSC; however, TGF-beta markedly potentiated the stimulatory effects of both EGF and PDGF. FSC showed high specific binding of 125I-PDGF and Scatchard analysis revealed high affinity receptors with an apparent Kd of 2.3 x 10(-10) M. Our data suggest that PDGF is a key mitogen for FSC and that the coordinate release of other growth factors together with PDGF by inflammatory cells represents a potent potential stimulus for FSC proliferation in conditions of chronic self-perpetuating liver inflammation.
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- Arenson D. M., Friedman S. L., Bissell D. M. Formation of extracellular matrix in normal rat liver: lipocytes as a major source of proteoglycan. Gastroenterology. 1988 Aug;95(2):441–447. doi: 10.1016/0016-5085(88)90502-1. [DOI] [PubMed] [Google Scholar]
- Assoian R. K. Biphasic effects of type beta transforming growth factor on epidermal growth factor receptors in NRK fibroblasts. Functional consequences for epidermal growth factor-stimulated mitosis. J Biol Chem. 1985 Aug 15;260(17):9613–9617. [PubMed] [Google Scholar]
- Assoian R. K., Grotendorst G. R., Miller D. M., Sporn M. B. Cellular transformation by coordinated action of three peptide growth factors from human platelets. 1984 Jun 28-Jul 4Nature. 309(5971):804–806. doi: 10.1038/309804a0. [DOI] [PubMed] [Google Scholar]
- Ballardini G., Degli Esposti S., Bianchi F. B., de Giorgi L. B., Faccani A., Biolchini L., Busachi C. A., Pisi E. Correlation between Ito cells and fibrogenesis in an experimental model of hepatic fibrosis. A sequential stereological study. Liver. 1983 Feb;3(1):58–63. doi: 10.1111/j.1600-0676.1983.tb00850.x. [DOI] [PubMed] [Google Scholar]
- Bauer E. A., Cooper T. W., Huang J. S., Altman J., Deuel T. F. Stimulation of in vitro human skin collagenase expression by platelet-derived growth factor. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4132–4136. doi: 10.1073/pnas.82.12.4132. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blomhoff R., Rasmussen M., Nilsson A., Norum K. R., Berg T., Blaner W. S., Kato M., Mertz J. R., Goodman D. S., Eriksson U. Hepatic retinol metabolism. Distribution of retinoids, enzymes, and binding proteins in isolated rat liver cells. J Biol Chem. 1985 Nov 5;260(25):13560–13565. [PubMed] [Google Scholar]
- Bowen-Pope D. F., Hart C. E., Seifert R. A. Sera and conditioned media contain different isoforms of platelet-derived growth factor (PDGF) which bind to different classes of PDGF receptor. J Biol Chem. 1989 Feb 15;264(5):2502–2508. [PubMed] [Google Scholar]
- Bowen-Pope D. F., Ross R. Platelet-derived growth factor. II. Specific binding to cultured cells. J Biol Chem. 1982 May 10;257(9):5161–5171. [PubMed] [Google Scholar]
- Braun L., Mead J. E., Panzica M., Mikumo R., Bell G. I., Fausto N. Transforming growth factor beta mRNA increases during liver regeneration: a possible paracrine mechanism of growth regulation. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1539–1543. doi: 10.1073/pnas.85.5.1539. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chua C. C., Geiman D. E., Keller G. H., Ladda R. L. Induction of collagenase secretion in human fibroblast cultures by growth promoting factors. J Biol Chem. 1985 May 10;260(9):5213–5216. [PubMed] [Google Scholar]
- Clement B., Grimaud J. A., Campion J. P., Deugnier Y., Guillouzo A. Cell types involved in collagen and fibronectin production in normal and fibrotic human liver. Hepatology. 1986 Mar-Apr;6(2):225–234. doi: 10.1002/hep.1840060212. [DOI] [PubMed] [Google Scholar]
- Deuel T. F., Huang J. S. Platelet-derived growth factor. Structure, function, and roles in normal and transformed cells. J Clin Invest. 1984 Sep;74(3):669–676. doi: 10.1172/JCI111482. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Friedman S. L., Roll F. J., Boyles J., Arenson D. M., Bissell D. M. Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem. 1989 Jun 25;264(18):10756–10762. [PubMed] [Google Scholar]
- Friedman S. L., Roll F. J., Boyles J., Bissell D. M. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver. Proc Natl Acad Sci U S A. 1985 Dec;82(24):8681–8685. doi: 10.1073/pnas.82.24.8681. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Friedman S. L., Roll F. J. Isolation and culture of hepatic lipocytes, Kupffer cells, and sinusoidal endothelial cells by density gradient centrifugation with Stractan. Anal Biochem. 1987 Feb 15;161(1):207–218. doi: 10.1016/0003-2697(87)90673-7. [DOI] [PubMed] [Google Scholar]
- Garbisa S., Ballin M., Daga-Gordini D., Fastelli G., Naturale M., Negro A., Semenzato G., Liotta L. A. Transient expression of type IV collagenolytic metalloproteinase by human mononuclear phagocytes. J Biol Chem. 1986 Feb 15;261(5):2369–2375. [PubMed] [Google Scholar]
- Globus R. K., Patterson-Buckendahl P., Gospodarowicz D. Regulation of bovine bone cell proliferation by fibroblast growth factor and transforming growth factor beta. Endocrinology. 1988 Jul;123(1):98–105. doi: 10.1210/endo-123-1-98. [DOI] [PubMed] [Google Scholar]
- Gronwald R. G., Seifert R. A., Bowen-Pope D. F. Differential regulation of expression of two platelet-derived growth factor receptor subunits by transforming growth factor-beta. J Biol Chem. 1989 May 15;264(14):8120–8125. [PubMed] [Google Scholar]
- Heldin C. H., Westermark B., Wasteson A. Demonstration of an antibody against platelet-derived growth factor. Exp Cell Res. 1981 Dec;136(2):255–261. doi: 10.1016/0014-4827(81)90003-3. [DOI] [PubMed] [Google Scholar]
- Heldin C. H., Westermark B., Wasteson A. Specific receptors for platelet-derived growth factor on cells derived from connective tissue and glia. Proc Natl Acad Sci U S A. 1981 Jun;78(6):3664–3668. doi: 10.1073/pnas.78.6.3664. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kawase T., Shiratori Y., Sugimoto T. Collagen production by rat liver fat-storing cells in primary culture. Exp Cell Biol. 1986;54(4):183–192. doi: 10.1159/000163355. [DOI] [PubMed] [Google Scholar]
- Kent G., Gay S., Inouye T., Bahu R., Minick O. T., Popper H. Vitamin A-containing lipocytes and formation of type III collagen in liver injury. Proc Natl Acad Sci U S A. 1976 Oct;73(10):3719–3722. doi: 10.1073/pnas.73.10.3719. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maher J. J., Bissell D. M., Friedman S. L., Roll F. J. Collagen measured in primary cultures of normal rat hepatocytes derives from lipocytes within the monolayer. J Clin Invest. 1988 Aug;82(2):450–459. doi: 10.1172/JCI113618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Maher J. J., Friedman S. L., Roll F. J., Bissell D. M. Immunolocalization of laminin in normal rat liver and biosynthesis of laminin by hepatic lipocytes in primary culture. Gastroenterology. 1988 Apr;94(4):1053–1062. doi: 10.1016/0016-5085(88)90566-5. [DOI] [PubMed] [Google Scholar]
- Mak K. M., Leo M. A., Lieber C. S. Alcoholic liver injury in baboons: transformation of lipocytes to transitional cells. Gastroenterology. 1984 Jul;87(1):188–200. [PubMed] [Google Scholar]
- Mak K. M., Lieber C. S. Lipocytes and transitional cells in alcoholic liver disease: a morphometric study. Hepatology. 1988 Sep-Oct;8(5):1027–1033. doi: 10.1002/hep.1840080508. [DOI] [PubMed] [Google Scholar]
- Matsuoka M., Pham N. T., Tsukamoto H. Differential effects of interleukin-1 alpha, tumor necrosis factor alpha, and transforming growth factor beta 1 on cell proliferation and collagen formation by cultured fat-storing cells. Liver. 1989 Apr;9(2):71–78. doi: 10.1111/j.1600-0676.1989.tb00382.x. [DOI] [PubMed] [Google Scholar]
- McGee J. O., Patrick R. S. The role of perisinusoidal cells in hepatic fibrogenesis. An electron microscopic study of acute carbon tetrachloride liver injury. Lab Invest. 1972 Apr;26(4):429–440. [PubMed] [Google Scholar]
- Mead J. E., Fausto N. Transforming growth factor alpha may be a physiological regulator of liver regeneration by means of an autocrine mechanism. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1558–1562. doi: 10.1073/pnas.86.5.1558. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Milani S., Herbst H., Schuppan D., Hahn E. G., Stein H. In situ hybridization for procollagen types I, III and IV mRNA in normal and fibrotic rat liver: evidence for predominant expression in nonparenchymal liver cells. Hepatology. 1989 Jul;10(1):84–92. doi: 10.1002/hep.1840100117. [DOI] [PubMed] [Google Scholar]
- Popper H., Uenfriend S. Hepatic fibrosis. Correlation of biochemical and morphologic investigations. Am J Med. 1970 Nov;49:707–721. doi: 10.1016/s0002-9343(70)80135-8. [DOI] [PubMed] [Google Scholar]
- Raines E. W., Dower S. K., Ross R. Interleukin-1 mitogenic activity for fibroblasts and smooth muscle cells is due to PDGF-AA. Science. 1989 Jan 20;243(4889):393–396. doi: 10.1126/science.2783498. [DOI] [PubMed] [Google Scholar]
- Ross R., Raines E. W., Bowen-Pope D. F. The biology of platelet-derived growth factor. Cell. 1986 Jul 18;46(2):155–169. doi: 10.1016/0092-8674(86)90733-6. [DOI] [PubMed] [Google Scholar]
- Shimokado K., Raines E. W., Madtes D. K., Barrett T. B., Benditt E. P., Ross R. A significant part of macrophage-derived growth factor consists of at least two forms of PDGF. Cell. 1985 Nov;43(1):277–286. doi: 10.1016/0092-8674(85)90033-9. [DOI] [PubMed] [Google Scholar]
- Shultz P. J., DiCorleto P. E., Silver B. J., Abboud H. E. Mesangial cells express PDGF mRNAs and proliferate in response to PDGF. Am J Physiol. 1988 Oct;255(4 Pt 2):F674–F684. doi: 10.1152/ajprenal.1988.255.4.F674. [DOI] [PubMed] [Google Scholar]
- Sporn M. B., Roberts A. B. Peptide growth factors and inflammation, tissue repair, and cancer. J Clin Invest. 1986 Aug;78(2):329–332. doi: 10.1172/JCI112580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Stein G. H., Yanishevsky R. Autoradiography. Methods Enzymol. 1979;58:279–292. doi: 10.1016/s0076-6879(79)58143-9. [DOI] [PubMed] [Google Scholar]
- Stiles C. D., Capone G. T., Scher C. D., Antoniades H. N., Van Wyk J. J., Pledger W. J. Dual control of cell growth by somatomedins and platelet-derived growth factor. Proc Natl Acad Sci U S A. 1979 Mar;76(3):1279–1283. doi: 10.1073/pnas.76.3.1279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takase S., Leo M. A., Nouchi T., Lieber C. S. Desmin distinguishes cultured fat-storing cells from myofibroblasts, smooth muscle cells and fibroblasts in the rat. J Hepatol. 1988 Jun;6(3):267–276. doi: 10.1016/s0168-8278(88)80042-4. [DOI] [PubMed] [Google Scholar]
- Wisse E. Observations on the fine structure and peroxidase cytochemistry of normal rat liver Kupffer cells. J Ultrastruct Res. 1974 Mar;46(3):393–426. doi: 10.1016/s0022-5320(74)90064-1. [DOI] [PubMed] [Google Scholar]
- Yokoi Y., Namihisa T., Kuroda H., Komatsu I., Miyazaki A., Watanabe S., Usui K. Immunocytochemical detection of desmin in fat-storing cells (Ito cells). Hepatology. 1984 Jul-Aug;4(4):709–714. doi: 10.1002/hep.1840040425. [DOI] [PubMed] [Google Scholar]
- de Leeuw A. M., McCarthy S. P., Geerts A., Knook D. L. Purified rat liver fat-storing cells in culture divide and contain collagen. Hepatology. 1984 May-Jun;4(3):392–403. doi: 10.1002/hep.1840040307. [DOI] [PubMed] [Google Scholar]