Skip to main content
SpringerLink
Log in

Introduction to the Molecular Basis of Liver Stiffness and Its Relation to Mechano-signaling

  • Chapter
  • First Online:
Liver Elastography

  • 612 Accesses

Abstract

This chapter introduces to the book part “Molecular Basis of Liver Stiffness and Cell Biology.” The molecular basis of liver stiffness (LS) is complex and multifactorially controlled at the systemic, cellular, and intracellular level. In addition, all cells including liver cells sense and respond to their environmental stiffness through mechano-signaling processes. Principally, stiffness is modulated either by structural conditions, e.g., matrix deposition such as collagen, the degree of perfusion or pressure-related conditions that are all inter-related. Pressure itself is controlled in a complex manner. While the static component of pressure is mainly affected by the vascular bed with its elastic properties and water filling status, the dynamic component is related to blood flow, hepatic resistance, and the hemorheology. At the intracellular level, stiffness is affected by intracellular pressure and stretch forces on the cellular membranes and intermediary filaments. The intracellular pressure is likewise controlled by many conditions including transport proteins to control osmotic pressure, or water influx, e.g., by aquaporins. We are still at the beginning to understand how liver cells, fibroblasts and hepatic stellate cells sense environmental stiffness. Quantitative in vitro studies of cells adhering to gels of varying adjustable stiffness are a useful tool in order to elucidate these mechanisms. Other chapters of this book part will introduce to the role of stiffness for hepatocyte function in vitro, to liver mechanics and the profibrotic response at the cellular level and, finally, to the role of sinusoidal pressure and hepatic arterialization in driving hepatic fibrosis. It is expected that biomechanic concepts will be instrumental for our future understanding of stiffness, fibrosis development and liver diseases.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Fåhraeus R. The suspension stability of the blood. Physiol Rev. 1929;9(2):241–74.

    Article  Google Scholar 

  2. Wells RE Jr, Merrill EW. Influence of flow properties of blood upon viscosity-hematocrit relationships. J Clin Invest. 1962;41(8):1591–8.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Humphrey JD, Schwartz MA, Tellides G, Milewicz DM. Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ Res. 2015;116(8):1448–61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Hinz B. Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep. 2009;11(2):120–6.

    Article  PubMed  CAS  Google Scholar 

  5. Mueller S. Does pressure cause liver cirrhosis? The sinusoidal pressure hypothesis. World J Gastroenterol. 2016;22(48):10482.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Anwar MA, Shalhoub J, Lim CS, Gohel MS, Davies AH. The effect of pressure-induced mechanical stretch on vascular wall differential gene expression. J Vasc Res. 2012;49(6):463–78.

    Article  PubMed  CAS  Google Scholar 

  7. Niessen CM, Leckband D, Yap AS. Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation. Physiol Rev. 2011;91(2):691–731.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Yap AS, Brieher WM, Gumbiner BM. Molecular and functional analysis of cadherin-based adherens junctions. Annu Rev Cell Dev Biol. 1997;13:119–46.

    Article  PubMed  CAS  Google Scholar 

  9. Balda MS, Matter K. Tight junctions and the regulation of gene expression. Biochim Biophys Acta. 2009;1788(4):761–7.

    Article  PubMed  CAS  Google Scholar 

  10. Holczbauer A, Gyongyosi B, Lotz G, Torzsok P, Kaposi-Novak P, Szijarto A, et al. Increased expression of claudin-1 and claudin-7 in liver cirrhosis and hepatocellular carcinoma. Pathol Oncol Res. 2014;20(3):493–502.

    Article  PubMed  CAS  Google Scholar 

  11. Yeh TH, Krauland L, Singh V, Zou B, Devaraj P, Stolz DB, et al. Liver-specific beta-catenin knockout mice have bile canalicular abnormalities, bile secretory defect, and intrahepatic cholestasis. Hepatology. 2010;52(4):1410–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Hatzfeld M. Plakophilins: multifunctional proteins or just regulators of desmosomal adhesion? Biochim Biophys Acta. 2007;1773(1):69–77.

    Article  PubMed  CAS  Google Scholar 

  13. Moll R, Franke WW. Intermediate filaments and their interaction with membranes. The desmosome-cytokeratin filament complex and epithelial differentiation. Pathol Res Pract. 1982;175(2–3):146–61.

    Article  PubMed  CAS  Google Scholar 

  14. Kroger C, Loschke F, Schwarz N, Windoffer R, Leube RE, Magin TM. Keratins control intercellular adhesion involving PKC-alpha-mediated desmoplakin phosphorylation. J Cell Biol. 2013;201(5):681–92.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Song JY, Van Noorden CJ, Frederiks WM. Alterations of hepatocellular intermediate filaments during extrahepatic cholestasis in rat liver. Virchows Arch. 1997;430(3):253–60.

    Article  PubMed  CAS  Google Scholar 

  16. Windoffer R, Beile B, Leibold A, Thomas S, Wilhelm U, Leube RE. Visualization of gap junction mobility in living cells. Cell Tissue Res. 2000;299(3):347–62.

    Article  PubMed  CAS  Google Scholar 

  17. Hernandez-Guerra M, Gonzalez-Mendez Y, de Ganzo ZA, Salido E, Garcia-Pagan JC, Abrante B, et al. Role of gap junctions modulating hepatic vascular tone in cirrhosis. Liver Int. 2014;34(6):859–68.

    Article  PubMed  CAS  Google Scholar 

  18. Discher DE. Tissue cells feel and respond to the stiffness of their substrate. Science. 2005;310(5751):1139–43.

    Article  PubMed  CAS  Google Scholar 

  19. Suresh Babu S, Wojtowicz A, Freichel M, Birnbaumer L, Hecker M, Cattaruzza M. Mechanism of stretch-induced activation of the mechanotransducer zyxin in vascular cells. Sci Signal. 2012;5(254):ra91.

    Article  PubMed  CAS  Google Scholar 

  20. Kuipers AJ, Middelbeek J, van Leeuwen FN. Mechanoregulation of cytoskeletal dynamics by TRP channels. Eur J Cell Biol. 2012;91(11–12):834–46.

    Article  PubMed  CAS  Google Scholar 

  21. Myers KA, Rattner JB, Shrive NG, Hart DA. Hydrostatic pressure sensation in cells: integration into the tensegrity model. Biochem Cell Biol. 2007;85(5):543–51.

    Article  PubMed  CAS  Google Scholar 

  22. Abhilash PA, Harikrishnan R, Indira M. Ascorbic acid suppresses endotoxemia and NF-kappaB signaling cascade in alcoholic liver fibrosis in guinea pigs: a mechanistic approach. Toxicol Appl Pharmacol. 2014;274(2):215–24.

    Article  PubMed  CAS  Google Scholar 

  23. Nekouzadeh A, Pryse KM, Elson EL, Genin GM. Stretch-activated force shedding, force recovery, and cytoskeletal remodeling in contractile fibroblasts. J Biomech. 2008;41(14):2964–71.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Morsiani E, Aleotti A, Ricci D. Haemodynamic and ultrastructural observations on the rat liver after two-thirds partial hepatectomy. J Anat. 1998;192(Pt 4):507–15.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Morsiani E, Mazzoni M, Aleotti A, Gorini P, Ricci D. Increased sinusoidal wall permeability and liver fatty change after two-thirds hepatectomy: an ultrastructural study in the rat. Hepatology. 1995;21(2):539–44.

    PubMed  CAS  Google Scholar 

  26. Gatmaitan Z, Varticovski L, Ling L, Mikkelsen R, Steffan AM, Arias IM. Studies on fenestral contraction in rat liver endothelial cells in culture. Am J Pathol. 1996;148(6):2027–41.

    PubMed  PubMed Central  CAS  Google Scholar 

  27. DeLeve LD. Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology. 2015;61(5):1740–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349–63.

    Article  PubMed  CAS  Google Scholar 

  29. Tamariz E, Grinnell F. Modulation of fibroblast morphology and adhesion during collagen matrix remodeling. Mol Biol Cell. 2002;13(11):3915–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Yeung T, Georges PC, Flanagan LA, Marg B, Ortiz M, Funaki M, et al. Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion. Cell Motil Cytoskeleton. 2005;60(1):24–34.

    Article  PubMed  Google Scholar 

  31. Wells RG. The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J Clin Gastroenterol. 2005;39(4 Suppl 2):S158–61.

    Article  PubMed  CAS  Google Scholar 

  32. Georges PC, Hui JJ, Gombos Z, McCormick ME, Wang AY, Uemura M, et al. Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am J Physiol Gastrointest Liver Physiol. 2007;293(6):G1147–54.

    Article  PubMed  CAS  Google Scholar 

  33. Kawada N, Tran-Thi TA, Klein H, Decker K. The contraction of hepatic stellate (Ito) cells stimulated with vasoactive substances. Possible involvement of endothelin 1 and nitric oxide in the regulation of the sinusoidal tonus. Eur J Biochem. 1993;213(2):815–23.

    Article  PubMed  CAS  Google Scholar 

  34. Ng CP, Hinz B, Swartz MA. Interstitial fluid flow induces myofibroblast differentiation and collagen alignment in vitro. J Cell Sci. 2005;118(Pt 20):4731–9.

    Article  PubMed  CAS  Google Scholar 

  35. Sakata R, Ueno T, Nakamura T, Ueno H, Sata M. Mechanical stretch induces TGF-beta synthesis in hepatic stellate cells. Eur J Clin Invest. 2004;34(2):129–36.

    Article  PubMed  CAS  Google Scholar 

  36. Ingber DE. Tensegrity: the architectural basis of cellular mechanotransduction. Annu Rev Physiol. 1997;59:575–99.

    Article  PubMed  CAS  Google Scholar 

  37. Sagir A, Erhardt A, Schmitt M, Haussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology. 2008;47(2):592–5.

    Article  PubMed  CAS  Google Scholar 

  38. Millonig G, Friedrich S, Adolf S, Fonouni H, Golriz M, Mehrabi A, et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol. 2010;52(2):206–10.

    Article  PubMed  Google Scholar 

  39. Kanoldt V, Fischer L, Grashoff C. Unforgettable force—crosstalk and memory of mechanosensitive structures. Biol Chem. 2019;400(6):687–98.

    Article  PubMed  CAS  Google Scholar 

  40. Buscemi L, Ramonet D, Klingberg F, Formey A, Smith-Clerc J, Meister JJ, et al. The single-molecule mechanics of the latent TGF-beta1 complex. Curr Biol. 2011;21(24):2046–54.

    Article  PubMed  CAS  Google Scholar 

  41. Wipff PJ, Rifkin DB, Meister JJ, Hinz B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J Cell Biol. 2007;179(6):1311–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Humphrey JD. Mechanisms of arterial remodeling in hypertension: coupled roles of wall shear and intramural stress. Hypertension. 2008;52(2):195–200.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Atta HM. Varicose veins: role of mechanotransduction of venous hypertension. Int J Vasc Med. 2012;2012:538627.

    PubMed  PubMed Central  Google Scholar 

  44. Pfisterer L, Konig G, Hecker M, Korff T. Pathogenesis of varicose veins—lessons from biomechanics. Vasa. 2014;43(2):88–99.

    Article  PubMed  Google Scholar 

  45. Mueller S, Sandrin L. Liver stiffness: a novel parameter for the diagnosis of liver disease. Hepat Med. 2010;2:49–67.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine and Center for Alcohol Research and Liver Diseases, Salem Medical Center, University of Heidelberg, Heidelberg, Germany

    Sebastian Mueller

Authors
  1. Sebastian Mueller
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sebastian Mueller .

Editor information

Editors and Affiliations

  1. Department of Medicine and Center for Alcohol Research and Liver Diseases, Salem Medical Center, University of Heidelberg, Heidelberg, Germany

    Sebastian Mueller

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Mueller, S. (2020). Introduction to the Molecular Basis of Liver Stiffness and Its Relation to Mechano-signaling. In: Mueller, S. (eds) Liver Elastography. Springer, Cham. https://doi.org/10.1007/978-3-030-40542-7_54

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-40542-7_54

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-40541-0

  • Online ISBN: 978-3-030-40542-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation