Skip to main content
Log in

Mechanical microenvironment as a key cellular regulator in the liver

  • Review Paper
  • Published:
Acta Mechanica Sinica Aims and scope Submit manuscript

Abstract

Tissue stiffness, shear stress, and interstitial pressure constitute major factors of the liver mechanical microenvironment that play a key regulatory role in controlling cell behavior in the liver and progression of liver diseases. In this review, we focus on the characteristics of the liver mechanical microenvironment and summarize cellular responses to mechanobiological changes during liver pathogenesis, especially in hepatic fibrosis and cirrhosis. A better understanding of the indispensable contribution of mechanical cues to liver homeostasis and pathogenesis is essential for identifying new therapeutic targets for liver diseases such as hepatic fibrosis or cirrhosis.

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

Access this article

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. Bogdanos, D.P., Gao, B., Gershwin, M.E.: Liver immunology. Comp. Physiol. 2, 567–598 (2013)

    Google Scholar 

  2. Eipel, C., Abshagen, K., Vollmar, B.: Regulation of hepatic blood flow: the hepatic arterial buffer response revisited. World J. Gastroenterol. 48, 6046–6057 (2010)

    Article  Google Scholar 

  3. Iwakiri, Y.: Pathophysiology of portal hypertension. Clin. Liver Dis. 2, 281–291 (2014)

    Article  Google Scholar 

  4. Wells, R.G.: Tissue mechanics and fibrosis. Biochim. Biophys. Acta 7, 884–890 (2013)

    Article  Google Scholar 

  5. Handorf, A.M., Zhou, Y., Halanski, M.A., et al.: Tissue stiffness dictates development, homeostasis, and disease progression. Organogenesis 1, 1–15 (2015)

    Article  Google Scholar 

  6. Wells, R.G.: The role of matrix stiffness in regulating cell behavior. Hepatology 4, 1394–1400 (2008)

    Article  Google Scholar 

  7. Cox, T.R., Erler, J.T.: Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis. Models Mech. 2, 165–178 (2011)

    Article  Google Scholar 

  8. Sporea, I., Sirli, R., Deleanu, A., et al.: Liver stiffness measurements in patients with HBV vs HCV chronic hepatitis: a comparative study. World J. Gastroenterol. 38, 4832–4837 (2010)

    Article  Google Scholar 

  9. Cassinotto, C., Boursier, J., de Ledinghen, V., et al.: Liver stiffness in nonalcoholic fatty liver disease: a comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology 6, 1817–1827 (2016)

    Article  Google Scholar 

  10. Gomez-Dominguez, E., Mendoza, J., Garcia-Buey, L., et al.: Transient elastography to assess hepatic fibrosis in primary biliary cirrhosis. Aliment. Pharmacol. Ther. 5, 441–447 (2008)

    Google Scholar 

  11. Qi, M., Chen, Y., Zhang, G.Q., et al.: Clinical significance of preoperative liver stiffness measurements in primary HBV-positive hepatocellular carcinoma. Fut. Oncol. 30, 2799–2810 (2017)

    Article  Google Scholar 

  12. Macias, J., Camacho, A., von Wichmann, M.A., et al.: Liver stiffness measurement versus liver biopsy to predict survival and decompensations of cirrhosis among HIV/hepatitis C virus-coinfected patients. AIDS 16, 2541–2549 (2013)

    Article  Google Scholar 

  13. Aykut, U.E., Akyuz, U., Yesil, A., et al.: A comparison of FibroMeter (TM) NAFLD Score, NAFLD fibrosis score, and transient elastography as noninvasive diagnostic tools for hepatic fibrosis in patients with biopsy-proven non-alcoholic fatty liver disease. Scand. J Gastroenterol. 11, 1343–1348 (2014)

    Article  Google Scholar 

  14. Mueller, S., Sandrin, L.: Liver stiffness: a novel parameter for the diagnosis of liver disease. Hepat. Med. Evid. Res. 2, 49–67 (2010)

    Article  Google Scholar 

  15. Sumida, Y., Nakajima, A., Itoh, Y.: Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J. Gastroenterol. 2, 475–485 (2014)

    Article  Google Scholar 

  16. Sandrin, L., Fourquet, B., Hasquenoph, J.M., et al.: Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med. Biol. 12, 1705–1713 (2003)

    Article  Google Scholar 

  17. Afdhal, N.H.: Fibroscan (transient elastography) for the measurement of liver fibrosis. Gastroenterol. Hepatol. 9, 605–607 (2012)

    Google Scholar 

  18. Castera, L., Forns, X., Alberti, A.: Non-invasive evaluation of liver fibrosis using transient elastography. J. Hepatol. 5, 835–847 (2008)

    Article  Google Scholar 

  19. Castera, L., Foucher, J., Bernard, P., et al.: Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 3, 828–835 (2010)

    Google Scholar 

  20. Deng, H., Wang, C., Lai, J., et al.: Noninvasive diagnosis of hepatic steatosis using fat attenuation parameter measured by FibroTouch and a new algorithm in CHB patients. Hepat. Mon. 16, e402639 (2016)

    Article  Google Scholar 

  21. Venkatesh, S.K., Yin, M., Ehman, R.L.: Magnetic resonance elastography of liver: technique, analysis, and clinical applications. J. Magn. Reson. Imaging 3, 544–555 (2013)

    Article  Google Scholar 

  22. Muthupillai, R., Lomas, D.J., Rossman, P.J., et al.: Magnetic resonance elastography by direct visualization of propagating acoustic strain waves. Science 5232, 1854–1857 (1995)

    Article  Google Scholar 

  23. Venkatesh, S.K., Yin, M., Ehman, R.L.: Magnetic resonance elastography of liver: clinical applications. J. Comput. Assist. Tomogr. 6, 887–896 (2013)

    Article  Google Scholar 

  24. Chang, W., Lee, J.M., Yoon, J.H., et al.: Liver fibrosis staging with MR elastography: comparison of diagnostic performance between patients with chronic hepatitis B and those with other etiologic causes. Radiology 1, 88–97 (2016)

    Article  Google Scholar 

  25. Kennedy, P., Wagner, M., Castera, L., et al.: Quantitative elastography methods in liver disease: current evidence and future directions. Radiology 3, 738–763 (2018)

    Article  Google Scholar 

  26. Nelissen, J.L., de Graaf, L., Traa, W.A., et al.: A MRI-compatible combined mechanical loading and MR elastography setup to study deformation-induced skeletal muscle damage in rats. PLoS ONE 16, e01698641 (2017)

    Google Scholar 

  27. Desai, S.S., Tung, J.C., Zhou, V.X., et al.: Physiological Ranges of Matrix Rigidity Modulate Primary Mouse Hepatocyte Function in Part Through Hepatocyte Nuclear Factor 4 Alpha. Hepatology 1, 261–275 (2016)

    Article  Google Scholar 

  28. Baiocchini, A., Montaldo, C., Conigliaro, A., et al.: Extracellular Matrix molecular remodeling in human liver fibrosis evolution. PLoS ONE 11, e01517363 (2016)

    Article  Google Scholar 

  29. Klaas, M., Kangur, T., Viil, J., et al.: The alterations in the extracellular matrix composition guide the repair of damaged liver tissue. Sci. Rep. 6, 27398 (2016)

    Article  Google Scholar 

  30. Georges, P.C., Hui, J., Gombos, Z., et al.: Increased stiffness of the rat liver precedes matrix deposition: implications for fibrosis. Am. J. Physiol. Gastrointest. Liver Physiol. 6, G1147–G1154 (2007)

    Article  Google Scholar 

  31. Kanta, J.: Elastin in the liver. Front. Physiol. 7, 491 (2016)

    Google Scholar 

  32. Nakayama, H., Itoh, H., Kunita, S., et al.: Presence of perivenular elastic fibers in nonalcoholic steatohepatitis Fibrosis Stage III. Histol. Histopathol. 4, 407–409 (2008)

    Google Scholar 

  33. Yasui, Y., Abe, T., Kurosaki, M., et al: Elastin fiber accumulation in liver correlates with the development of hepatocellular carcinoma. PLoS ONE 11, e0154558 (2016)

    Article  Google Scholar 

  34. Abe, T., Hashiguchi, A., Yamazaki, K., et al.: Quantification of collagen and elastic fibers using whole-slide images of liver biopsy specimens. Pathol. Int. 6, 305–310 (2013)

    Article  Google Scholar 

  35. Liu, X., Liu, R., Hou, F., et al.: Fibronectin expression is critical for liver fibrogenesis in vivo and in vitro. Mol. Med. Rep. 4, 3669–3675 (2016)

    Article  Google Scholar 

  36. Kolacna, L., Bakesova, J., Varga, F., et al.: Biochemical and biophysical aspects of collagen nanostructure in the extracellular matrix. Physiol. Res. 56, S51–S60 (2007)

    Google Scholar 

  37. Saneyasu, T., Akhtar, R., Sakai, T.: Molecular cues guiding matrix stiffness in liver fibrosis. Biomed. Res. Int. 2016, 2646212 (2016)

  38. Barry-Hamilton, V., Spangler, R., Marshall, D., et al.: Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat. Med. 9, 1009–1017 (2010)

    Article  Google Scholar 

  39. Gilad, G.M., Kagan, H.M., Gilad, V.H.: Evidence for increased lysyl oxidase, the extracellular matrix-forming enzyme, In Alzheimer’s disease brain. Neurosci. Lett. 3, 210–214 (2005)

    Article  Google Scholar 

  40. Liu, L., You, Z., Yu, H., et al.: Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis. Nat. Mater. 12, 1252–1261 (2017)

    Article  Google Scholar 

  41. Grenard, P., Bresson-Hadni, S., El Alaoui, S., et al.: Transglutaminase-mediated cross-linking is involved in the stabilization of extracellular matrix in human liver fibrosis. J. Hepatol. 3, 367–375 (2001)

    Article  Google Scholar 

  42. Steppan, J., Bergman, Y., Viegas, K., et al.: Tissue transglutaminase modulates vascular stiffness and function through crosslinking-dependent and crosslinking-independent functions. J. Am. Heart Assoc. 6, e0041612 (2017)

    Article  Google Scholar 

  43. Valero, C., Amaveda, H., Mora, M., et al.: Combined experimental and computational characterization of crosslinked collagen-based hydrogels. PLoS ONE 13, e01958204 (2018)

    Article  Google Scholar 

  44. Discher, D.E., Janmey, P., Wang, Y.L.: Tissue cells feel and respond to the stiffness of their substrate. Science 5751, 1139–1143 (2005)

    Article  Google Scholar 

  45. Natarajan, V., Berglund, E.J., Chen, D.X., et al.: Substrate stiffness regulates primary hepatocyte functions. RSC Adv. 99, 80956–80966 (2015)

    Article  Google Scholar 

  46. Schrader, J., Gordon-Walker, T.T., Aucott, R.L., et al.: Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 4, 1192–1205 (2011)

    Article  Google Scholar 

  47. Tsuchida, T., Friedman, S.L.: Mechanisms of hepatic stellate cell activation. Nat. Rev. Gastroenterol. Hepatol. 7, 397–411 (2017)

    Article  Google Scholar 

  48. Lee, Y.A., Wallace, M.C., Friedman, S.L.: Pathobiology of liver fibrosis: a translational success story. Gut 5, 830–841 (2015)

    Article  Google Scholar 

  49. Gandhi, C.R.: Hepatic stellate cell activation and pro-fibrogenic signals. J. Hepatol. 5, 1104–1105 (2017)

    Article  Google Scholar 

  50. Olsen, A.L., Bloomer, S.A., Chan, E.P., et al.: Hepatic stellate cells require a stiff environment for myofibroblastic differentiation. Am. J. Physiol. Gastrointest. Liver Physiol. 1, G110–G118 (2011)

    Article  Google Scholar 

  51. Braet, F., Wisse, E.: Structural and functional aspects of liver sinusoidal endothelial cell fenestrae: a review. Comp. Hepatol. 1, 1 (2002)

    Article  Google Scholar 

  52. Ford, A.J., Jain, G., Rajagopalan, P.: Designing a fibrotic microenvironment to investigate changes in human liver sinusoidal endothelial cell function. Acta Biomater. 24, 220–227 (2015)

    Article  Google Scholar 

  53. Kaplowitz, N.: Liver biology and pathobiology. Hepatology 2(Suppl 1), S235–S238 (2006)

    Article  Google Scholar 

  54. Kolios, G., Valatas, V., Kouroumalis, E.: Role of Kupffer cells in the pathogenesis of liver disease. World J. Gastroenterol. 46, 7413–7420 (2006)

    Article  Google Scholar 

  55. Chuang, Y., Chang, H., Chen, Y., et al.: Influence of extracellular matrix stiffness on modulating the phenotype of macrophage. Biophys. J. 3, 516A–516A (2018)

    Article  Google Scholar 

  56. Mcwhorter, F.Y., Davis, C.T., Liu, W.F.: Physical and mechanical regulation of macrophage phenotype and function. Cell. Mol. Life Sci. 7, 1303–1316 (2015)

    Article  Google Scholar 

  57. Patel, N.R., Bole, M., Chen, C., et al.: Cell elasticity determines macrophage function. PLoS ONE 79, e410249 (2012)

    Google Scholar 

  58. Janmey, P.A., Miller, R.T.: Mechanisms of mechanical signaling in development and disease. J. Cell Sci. 124(1), 9–18 (2011)

    Article  Google Scholar 

  59. Davies, P.F.: Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75(3), 519–560 (1995)

    Article  Google Scholar 

  60. Poisson, J., Lemoinne, S., Boulanger, C., et al.: Liver sinusoidal endothelial cells: physiology and role in liver diseases. J. Hepatol. 66(1), 212 (2016)

    Article  Google Scholar 

  61. Yamanaka, K., Hatano, E., Narita, M., et al.: Olprinone attenuates excessive shear stress through up-regulation of endothelial nitric oxide synthase in a rat excessive hepatectomy model. Liver Transpl. 17(1), 60–69 (2011)

    Article  Google Scholar 

  62. Fernandez, M.: Molecular pathophysiology of portal hypertension. Hepatology 61(4), 1406–1415 (2015)

    Article  Google Scholar 

  63. Parmar, K.M., Larman, H.B., Dai, G., et al.: Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2. J. Clin. Invest. 116(1), 49–58 (2006)

    Article  Google Scholar 

  64. Laurie, D.D., Wang, X., Guo, Y.: Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology 48(3), 920–930 (2010)

    Google Scholar 

  65. Braet, F., Shleper, M., Paizi, M., et al.: Liver sinusoidal endothelial cell modulation upon resection and shear stress in vitro. Comp. Hepatol. 3(1), 7 (2004)

    Article  Google Scholar 

  66. Du, Y., Li, N., Yang, H., et al.: Mimicking liver sinusoidal structures and functions using a 3d-configured microfluidic chip. Lab Chip 17(5), 782–794 (2017)

    Article  Google Scholar 

  67. Nishii, K., Brodin, E., Renshaw, T., et al.: Shear stress upregulates regeneration-related immediate early genes, in liver progenitors in 3D ECM-like microenvironments. J. Cellul. Physiol. 233, 4272–4281 (2018)

    Article  Google Scholar 

  68. Shah, V., Haddad, F.G., Garciacardena, G., et al.: Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids. J. Clin. Invest. 100(11), 2923–2930 (1997)

    Article  Google Scholar 

  69. Golse, N., Bucur, P.O., Adam, R., et al.: New paradigms in post-hepatectomy liver failure. J. Gastrointest. Surg. 17(3), 593–605 (2013)

    Article  Google Scholar 

  70. Sugawara, Y., Yamamoto, J., Shimada, K., et al.: Splenectomy in patients with hepatocellular carcinoma and hypersplenism. J. Am. Coll. Surg. 190(4), 446–450 (2000)

    Article  Google Scholar 

  71. Sato, Y., Kobayashi, T., Nakatsuka, H., et al.: Splenic arterial ligation prevents liver injury after a major hepatectomy by a reduction of surplus portal hypertension in hepatocellular carcinoma patients with cirrhosis. Hepatogastroenterology 48(39), 831–835 (2001)

    Google Scholar 

  72. Jain, R.K.: Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706), 58–62 (2005)

    Article  Google Scholar 

  73. Laine, G.A., Hall, J.T., Laine, S.H., et al.: Transsinusoidal fluid dynamics in canine liver during venous hypertension. Circ. Res. 45(3), 317–323 (1979)

    Article  Google Scholar 

  74. Polacheck, W.J., Charest, J.L., Kamm, R.D.: Interstitial flow influences direction of tumor cell migration through competing mechanisms. Proc. Nat. Acad. Sci. 108, 11115–11120 (2011)

    Article  Google Scholar 

  75. Bedossa, P., Poynard, T.: An algorithm for the grading of activity in chronic hepatitis C. Hepatology 24(2), 289–293 (1996)

    Article  Google Scholar 

  76. Debbaut, C., Vierendeels, J., Casteleyn, C., et al.: Perfusion characteristics of the human hepatic microcirculation based on three-dimensional reconstructions and computational fluid dynamic analysis. J. Biomech. Eng. 134(1), 011003 (2012)

    Article  Google Scholar 

  77. Puhl, G., Schaser, K.D., Vollmar, B., et al.: Noninvasive in vivo analysis of the human hepatic microcirculation using orthogonal polorization spectral imaging. Transplantation 75, 756–761 (2003)

    Article  Google Scholar 

  78. Genzel-Boroviczény, O., Strötgen, J., Harris, A.G., et al.: Orthogonal polarization spectral imaging (OPS): a novel method to measure the microcirculation in term and preterm infants transcutaneously. Pediatr. Res. 51, 386–391 (2002)

    Article  Google Scholar 

  79. Hu, J., Lü, S.Q., Feng, S., et al.: Flow dynamics analyses of pathophysiological liver lobules using porous media theory. Acta. Mech. Sin. 33(4), 823–832 (2017)

    Article  Google Scholar 

  80. Janmey, P.A., Miller, R.T.: Mechanisms of mechanical signaling in development and disease. J. Cell Sci. 124(Pt 1), 9 (2011)

    Article  Google Scholar 

Download references

Acknowledgements

This work was financially supported in part by the Beijing Natural Science Foundation (Grant 7162210) and National Key R&D Program of China (Grant 2016YFC1000810).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Chenyu Huang or Yanan Du.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

You, Z., Zhou, L., Li, W. et al. Mechanical microenvironment as a key cellular regulator in the liver. Acta Mech. Sin. 35, 289–298 (2019). https://doi.org/10.1007/s10409-019-00857-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10409-019-00857-y

Keywords

Navigation