Skip to main content
SpringerLink
Log in

Response of Hepatic Stellate Cells to TGFB1 Differs from the Response of Myofibroblasts. Decorin Protects against the Action of Growth Factor

  • Original Article
  • Published:
Pathology & Oncology Research

Abstract

Regardless to the exact nature of damage, hepatic stellate cells (HSCs) and other non-parenchymal liver cells transform to activated myofibroblasts, synthesizing the accumulating extracellular matrix (ECM) proteins, and transforming growth factor-β1 (TGF-β1) plays a crucial role in this process. Later it was discovered that decorin, member of the small leucin rich proteoglycan family is able to inhibit this action of TGF-β1. The aim of our present study was to clarify whether HSCs and activated myofibroblasts of portal region exert identical or different response to TGF-β1 exposure, and the inhibitory action of decorin against the growth factor is a generalized phenomenon on myofibroblast of different origin? To this end we measured mRNA expression and production of major collagen components (collagen type I, III and IV) of the liver after stimulation and co-stimulation with TGF-β1 and decorin in primary cell cultures of HSCs and myofibroblasts (MFs). Production of matrix proteins, decorin and members of the TGF-β1 signaling pathways were assessed on Western blots. Messenger RNA expression of collagens and TIEG was quantified by real-time RT-PCR. HSCs and MFs responded differently to TGF-β1 exposure. In contrast to HSCs in which TGF-β1 stimulated the synthesis of collagen type I, type III, and type IV, only the increase of collagen type IV was detected in portal MFs. However, in a combined treatment, decorin seemed to interfere with TGF-β1 and its stimulatory effect was abolished. The different mode of TGF-β1 action is mirrored by the different activation of signaling pathways in activated HSCs and portal fibroblasts. In HSCs the activation of pSMAD2 whereas in myofibroblasts the activation of MAPK pathway was detected. The inhibitory effect of decorin was neither related to the Smad-dependent nor to the Smad-independent signaling pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig 4

Similar content being viewed by others

References

  1. Blomhoff R, Wake K (1991) Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J: Off Publ Fed Am Soc Exp Biol 5(3):271–277

    CAS  Google Scholar 

  2. Ramadori G (1991) The stellate cell (Ito-cell, fat-storing cell, lipocyte, perisinusoidal cell) of the liver. New insights into pathophysiology of an intriguing cell. Virchows Archiv B, Cell Pathol Incl Mol Pathol 61(3):147–158

    CAS  Google Scholar 

  3. Neubauer K, Saile B, Ramadori G (2001) Liver fibrosis and altered matrix synthesis. Can J Gastroenterol = J Can de Gastroenterol 15(3):187–193

    Article  CAS  Google Scholar 

  4. Friedman SL (1990) Cellular sources of collagen and regulation of collagen production in liver. Semin Liver Dis 10(1):20–29. doi:10.1055/s-2008-1040454

    Article  CAS  PubMed  Google Scholar 

  5. Bhunchet E, Wake K (1992) Role of mesenchymal cell populations in porcine serum-induced rat liver fibrosis. Hepatology 16(6):1452–1473

    Article  CAS  PubMed  Google Scholar 

  6. Bataller R, Brenner DA (2005) Liver fibrosis. J Clin Invest 115(2):209–218. doi:10.1172/JCI24282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Arthur MJ (2000) Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol 279(2):G245–G249

    CAS  PubMed  Google Scholar 

  8. Nakatsukasa H, Nagy P, Evarts RP, Hsia CC, Marsden E, Thorgeirsson SS (1990) 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 85(6):1833–1843. doi:10.1172/JCI114643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Castilla A, Prieto J, Fausto N (1991) Transforming growth factors beta 1 and alpha in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med 324(14):933–940. doi:10.1056/NEJM199104043241401

    Article  CAS  PubMed  Google Scholar 

  10. Border WA, Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med 331(19):1286–1292. doi:10.1056/NEJM199411103311907

    Article  CAS  PubMed  Google Scholar 

  11. Saile B, Matthes N, Knittel T, Ramadori G (1999) Transforming growth factor beta and tumor necrosis factor alpha inhibit both apoptosis and proliferation of activated rat hepatic stellate cells. Hepatology 30(1):196–202. doi:10.1002/hep.510300144

    Article  CAS  PubMed  Google Scholar 

  12. Saile B, Matthes N, El Armouche H, Neubauer K, Ramadori G (2001) The bcl, NFkappaB and p53/p21WAF1 systems are involved in spontaneous apoptosis and in the anti-apoptotic effect of TGF-beta or TNF-alpha on activated hepatic stellate cells. Eur J Cell Biol 80(8):554–561

    Article  CAS  PubMed  Google Scholar 

  13. Guyot C, Lepreux S, Combe C, Doudnikoff E, Bioulac-Sage P, Balabaud C, Desmouliere A (2006) Hepatic fibrosis and cirrhosis: the (myo)fibroblastic cell subpopulations involved. Int J Biochem Cell Biol 38(2):135–151. doi:10.1016/j.biocel.2005.08.021

    CAS  PubMed  Google Scholar 

  14. Forbes SJ, Russo FP, Rey V, Burra P, Rugge M, Wright NA, Alison MR (2004) A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 126(4):955–963

    Article  PubMed  Google Scholar 

  15. Russo FP, Alison MR, Bigger BW, Amofah E, Florou A, Amin F, Bou-Gharios G, Jeffery R, Iredale JP, Forbes SJ (2006) The bone marrow functionally contributes to liver fibrosis. Gastroenterology 130(6):1807–1821. doi:10.1053/j.gastro.2006.01.036

    Article  PubMed  Google Scholar 

  16. Eyden B (2008) The myofibroblast: phenotypic characterization as a prerequisite to understanding its functions in translational medicine. J Cell Mol Med 12(1):22–37. doi:10.1111/j.1582-4934.2007.00213.x

    Article  CAS  PubMed  Google Scholar 

  17. Yamaguchi Y, Mann DM, Ruoslahti E (1990) Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature 346(6281):281–284. doi:10.1038/346281a0

    Article  CAS  PubMed  Google Scholar 

  18. Border WA, Noble NA, Yamamoto T, Harper JR, Yamaguchi Y, Pierschbacher MD, Ruoslahti E (1992) Natural inhibitor of transforming growth factor-beta protects against scarring in experimental kidney disease. Nature 360(6402):361–364. doi:10.1038/360361a0

    Article  CAS  PubMed  Google Scholar 

  19. Dudas J, Kovalszky I, Gallai M, Nagy JO, Schaff Z, Knittel T, Mehde M, Neubauer K, Szalay F, Ramadori G (2001) Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitis. Am J Clin Pathol 115(5):725–735. doi:10.1309/J8CD-E9C8-X4NG-GTVG

    Article  CAS  PubMed  Google Scholar 

  20. Jarmay K, Gallai M, Karacsony G, Ozsvar Z, Schaff Z, Lonovics J, Kovalszky I (2000) Decorin and actin expression and distribution in patients with chronic hepatitis C following interferon-alfa-2b treatment. J Hepatol 32(6):993–1002

    Article  CAS  PubMed  Google Scholar 

  21. Takeuchi Y, Kodama Y, Matsumoto T (1994) Bone matrix decorin binds transforming growth factor-beta and enhances its bioactivity. J Biol Chem 269(51):32634–32638

    CAS  PubMed  Google Scholar 

  22. Bi Y, Stuelten CH, Kilts T, Wadhwa S, Iozzo RV, Robey PG, Chen XD, Young MF (2005) Extracellular matrix proteoglycans control the fate of bone marrow stromal cells. J Biol Chem 280(34):30481–30489. doi:10.1074/jbc.M500573200

    Article  CAS  PubMed  Google Scholar 

  23. Cui X, Shimizu I, Lu G, Itonaga M, Inoue H, Shono M, Tamaki K, Fukuno H, Ueno H, Ito S (2003) Inhibitory effect of a soluble transforming growth factor beta type II receptor on the activation of rat hepatic stellate cells in primary culture. J Hepatol 39(5):731–737

    Article  CAS  PubMed  Google Scholar 

  24. Shi YF, Zhang Q, Cheung PY, Shi L, Fong CC, Zhang Y, Tzang CH, Chan BP, Fong WF, Chun J, Kung HF, Yang M (2006) Effects of rhDecorin on TGF-beta1 induced human hepatic stellate cells LX-2 activation. Biochim Biophys Acta 1760(11):1587–1595. doi:10.1016/j.bbagen.2006.09.012

    Article  CAS  PubMed  Google Scholar 

  25. Baghy K, Iozzo RV, Kovalszky I (2012) Decorin-TGFbeta axis in hepatic fibrosis and cirrhosis. J Histochem Cytochem 60(4):262–268. doi:10.1369/0022155412438104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Baghy K, Dezso K, Laszlo V, Fullar A, Peterfia B, Paku S, Nagy P, Schaff Z, Iozzo RV, Kovalszky I (2011) Ablation of the decorin gene enhances experimental hepatic fibrosis and impairs hepatic healing in mice. Lab Investig 91(3):439–451. doi:10.1038/labinvest.2010.172

    Article  CAS  PubMed  Google Scholar 

  27. de Leeuw AM, McCarthy SP, Geerts A, Knook DL (1984) Purified rat liver fat-storing cells in culture divide and contain collagen. Hepatology 4(3):392–403

    Article  PubMed  Google Scholar 

  28. Knittel T, Kobold D, Saile B, Grundmann A, Neubauer K, Piscaglia F, Ramadori G (1999) Rat liver myofibroblasts and hepatic stellate cells: different cell populations of the fibroblast lineage with fibrogenic potential. Gastroenterology 117(5):1205–1221

    Article  CAS  PubMed  Google Scholar 

  29. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  PubMed  Google Scholar 

  30. Sahin MB, Schwartz RE, Buckley SM, Heremans Y, Chase L, Hu WS, Verfaillie CM (2008) Isolation and characterization of a novel population of progenitor cells from unmanipulated rat liver. Liver Transplant: Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc 14(3):333–345. doi:10.1002/lt.21380

    Article  Google Scholar 

  31. Sanderson N, Factor V, Nagy P, Kopp J, Kondaiah P, Wakefield L, Roberts AB, Sporn MB, Thorgeirsson SS (1995) Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci U S A 92(7):2572–2576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Dudas J, Mansuroglu T, Batusic D, Saile B, Ramadori G (2007) Thy-1 is an in vivo and in vitro marker of liver myofibroblasts. Cell Tissue Res 329(3):503–514. doi:10.1007/s00441-007-0437-z

    Article  CAS  PubMed  Google Scholar 

  33. Dezso K, Jelnes P, Laszlo V, Baghy K, Bodor C, Paku S, Tygstrup N, Bisgaard HC, Nagy P (2007) Thy-1 is expressed in hepatic myofibroblasts and not oval cells in stem cell-mediated liver regeneration. Am J Pathol 171(5):1529–1537. doi:10.2353/ajpath.2007.070273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Weiss TS, Lichtenauer M, Kirchner S, Stock P, Aurich H, Christ B, Brockhoff G, Kunz-Schughart LA, Jauch KW, Schlitt HJ, Thasler WE (2008) Hepatic progenitor cells from adult human livers for cell transplantation. Gut 57(8):1129–1138. doi:10.1136/gut.2007.143321

    Article  CAS  PubMed  Google Scholar 

  35. Ueberham E, Low R, Ueberham U, Schonig K, Bujard H, Gebhardt R (2003) Conditional tetracycline-regulated expression of TGF-beta1 in liver of transgenic mice leads to reversible intermediary fibrosis. Hepatology 37(5):1067–1078. doi:10.1053/jhep.2003.50196

    Article  CAS  PubMed  Google Scholar 

  36. Schonherr E, Sunderkotter C, Iozzo RV, Schaefer L (2005) Decorin, a novel player in the insulin-like growth factor system. J Biol Chem 280(16):15767–15772. doi:10.1074/jbc.M500451200

    Article  PubMed  Google Scholar 

  37. Goldoni S, Iozzo RV (2008) Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs. Int J Cancer Journal Int du Cancer 123(11):2473–2479. doi:10.1002/ijc.23930

    Article  CAS  Google Scholar 

  38. Goldoni S, Humphries A, Nystrom A, Sattar S, Owens RT, McQuillan DJ, Ireton K, Iozzo RV (2009) Decorin is a novel antagonistic ligand of the met receptor. J Cell Biol 185(4):743–754. doi:10.1083/jcb.200901129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Baghy K, Horvath Z, Regos E, Kiss K, Schaff Z, Iozzo RV, Kovalszky I (2013) Decorin interferes with platelet-derived growth factor receptor signaling in experimental hepatocarcinogenesis. FEBS J 280(10):2150–2164. doi:10.1111/febs.12215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yu MC, Chen CH, Liang X, Wang L, Gandhi CR, Fung JJ, Lu L, Qian S (2004) Inhibition of T-cell responses by hepatic stellate cells via B7-H1-mediated T-cell apoptosis in mice. Hepatology 40(6):1312–1321. doi:10.1002/hep.20488

    Article  CAS  PubMed  Google Scholar 

  41. Chen CH, Kuo LM, Chang Y, Wu W, Goldbach C, Ross MA, Stolz DB, Chen L, Fung JJ, Lu L, Qian S (2006) In vivo immune modulatory activity of hepatic stellate cells in mice. Hepatology 44(5):1171–1181. doi:10.1002/hep.21379

    Article  CAS  PubMed  Google Scholar 

  42. Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhao JG, Lemarchand P, Pfeilschifter J, Schaefer RM, Iozzo RV, Schaefer L (2011) Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and MicroRNA-21. Sci Signal 4(199):ra75. doi:10.1126/scisignal.2001868

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Scientific Found (OTKA) 67925 and 100904, OM-8/2004 grants, by the Székelyhidi Miklós. Award of the Hungarian Liver Research Foundation, by the European Community Action Schemes for the Mobility of University Students (ERASMUS), and the DAAD/MÖB 2007/25 fellowship, NTP-FÖ-P-15-0903.

Author information

Authors and Affiliations

  1. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, Budapest, H-1085, Hungary

    Alexandra Fullár, Eszter Regős, Tibor Szarvas, Kornélia Baghy & Ilona Kovalszky

  2. 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary

    Gábor Firneisz

  3. Department of Otorhinolaryngology, Medical University Innsbruck, Innsbruck, Austria

    József Dudás

  4. Department of Gastroenterology and Endocrinology, George August University, Göttingen, Germany

    József Dudás & Giuliano Ramadori

Authors
  1. Alexandra Fullár
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gábor Firneisz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eszter Regős
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. József Dudás
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tibor Szarvas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kornélia Baghy
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Giuliano Ramadori
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ilona Kovalszky
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ilona Kovalszky.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Fullár, A., Firneisz, G., Regős, E. et al. Response of Hepatic Stellate Cells to TGFB1 Differs from the Response of Myofibroblasts. Decorin Protects against the Action of Growth Factor. Pathol. Oncol. Res. 23, 287–294 (2017). https://doi.org/10.1007/s12253-016-0095-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-016-0095-0

Keywords

Search

Navigation