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Stiffness and Hepatocytes Function In Vitro

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Liver Elastography

Abstract

Liver fibrosis is a wound-healing response to chronic liver injury such as alcoholic/nonalcoholic fatty liver disease, and viral hepatitis with no FDA-approved treatments. Liver fibrosis results in a continual accumulation of extracellular matrix (ECM) proteins and paves the way for replacement of parenchyma with non-functional scar tissue. During liver fibrosis, alterations in hepatocytes phenotype including apoptosis, oxidative stress, and loss of metabolic function have been shown to precede fibrosis and promote hepatic stellate cell activation. Specifically, hepatocyte death, as part of the original injury, triggers a cascade of events, including pathological accumulation of ECM leading to the increased tissue stiffness during liver injury. This chapter provides an overview of the interplay of hepatocytes with stiffness using in vitro models mimicking physiological and pathological matrix rigidity to provide insight into the pivotal changes in hepatocytes physiology and the extent to which it mediates the progression of liver fibrosis. Establishing the molecular aspects of hepatocytes in the light of fibrotic liver stiffness is valuable towards development of novel therapeutic and diagnostic targets of liver fibrosis.

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References

  1. Asrani SK, Larson JJ, Yawn B, Therneau TM, Kim WR. Underestimation of liver-related mortality in the United States. Gastroenterology. 2013;145(2):375–82.e1–2.

    Article  PubMed  Google Scholar 

  2. Liver disease in Europe. Lancet. 2013;381(9866):508.

    Google Scholar 

  3. Iredale JP, Thompson A, Henderson NC. Extracellular matrix degradation in liver fibrosis: biochemistry and regulation. Biochim Biophys Acta. 2013;1832(7):876–83.

    Article  CAS  PubMed  Google Scholar 

  4. Mederacke I. Liver fibrosis—mouse models and relevance in human liver diseases. Z Gastroenterol. 2013;51(1):55–62.

    Article  CAS  PubMed  Google Scholar 

  5. Ramachandran P, Iredale JP. Liver fibrosis: a bidirectional model of fibrogenesis and resolution. QJM. 2012;105(9):813–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Foucher J, Chanteloup E, Vergniol J, Castera L, Le Bail B, Adhoute X, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut. 2006;55(3):403–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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  CAS  PubMed  Google Scholar 

  8. Yin M, Kolipaka A, Woodrum DA, Glaser KJ, Romano AJ, Manduca A, et al. Hepatic and splenic stiffness augmentation assessed with MR elastography in an in vivo porcine portal hypertension model. J Magn Reson Imaging. 2013;38(4):809–15.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Yin M, Talwalkar JA, Glaser KJ, Manduca A, Grimm RC, Rossman PJ, et al. Assessment of hepatic fibrosis with magnetic resonance elastography. Clin Gastroenterol Hepatol. 2007;5(10):1207–13.e2.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Takeda T, Yasuda T, Nakayama Y, Nakaya M, Kimura M, Yamashita M, et al. Usefulness of noninvasive transient elastography for assessment of liver fibrosis stage in chronic hepatitis C. World J Gastroenterol. 2006;12(48):7768–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 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 

  12. Henderson NC, Forbes SJ. Hepatic fibrogenesis: from within and outwith. Toxicology. 2008;254(3):130–5.

    Article  CAS  PubMed  Google Scholar 

  13. Lozoya OA, Wauthier E, Turner RA, Barbier C, Prestwich GD, Guilak F, et al. Regulation of hepatic stem/progenitor phenotype by microenvironment stiffness in hydrogel models of the human liver stem cell niche. Biomaterials. 2011;32(30):7389–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology. 2008;47(4):1394–400.

    Article  CAS  PubMed  Google Scholar 

  15. Arias I, Wolkoff A, Boyer J, Shafritz D, Fausto N, Alter H, et al. The liver: biology and pathobiology. Chichester: Wiley; 2011.

    Google Scholar 

  16. Arias IM, Boyer J, Shafritz D, Fausto N, Alter H, Cohen DE, Wolkoff A. The liver: biology and pathology. Hoboken: Wiley Blackwell; 2010. 1216 p.

    Google Scholar 

  17. Rouiller C. The liver: morphology, biochemistry, physiology. New York: Academic; 2013.

    Google Scholar 

  18. Zakim D, Boyer T, Hepatology A. Textbook of liver disease. Philadelphia: WB Saunders Company; 1996.

    Google Scholar 

  19. Pinzani M, Marra F, Carloni V. Signal transduction in hepatic stellate cells. Liver. 1998;18(1):2–13.

    Article  CAS  PubMed  Google Scholar 

  20. Van den Eynden GG, Majeed AW, Illemann M, Vermeulen PB, Bird NC, Høyer-Hansen G, et al. The multifaceted role of the microenvironment in liver metastasis: biology and clinical implications. Cancer Res. 2013;73(7):2031–43.

    Article  PubMed  CAS  Google Scholar 

  21. Kidambi S, Yarmush RS, Novik E, Chao P, Yarmush ML, Nahmias Y. Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance. Proc Natl Acad Sci. 2009;106(37):15714–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bhatia S, Balis U, Yarmush M, Toner M. Effect of cell–cell interactions in preservation of cellular phenotype: cocultivation of hepatocytes and nonparenchymal cells. FASEB J. 1999;13(14):1883–900.

    Article  CAS  PubMed  Google Scholar 

  23. Uygun BE, Soto-Gutierrez A, Yagi H, Izamis M-L, Guzzardi MA, Shulman C, et al. Organ reengineering through development of a transplantable recellularized liver graft using decellularized liver matrix. Nat Med. 2010;16(7):814–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wong SF, Choi YY, Kim DS, Chung BG, Lee S-H. Concave microwell based size-controllable hepatosphere as a three-dimensional liver tissue model. Biomaterials. 2011;32(32):8087–96.

    Article  CAS  PubMed  Google Scholar 

  25. Bhandari RN, Riccalton LA, Lewis AL, Fry JR, Hammond AH, Tendler SJ, et al. Liver tissue engineering: a role for co-culture systems in modifying hepatocyte function and viability. Tissue Eng. 2001;7(3):345–57.

    Article  CAS  PubMed  Google Scholar 

  26. Kidambi S, Sheng LF, Yarmush ML, Toner M, Lee I, Chan C. Patterned co-culture of primary hepatocytes and fibroblasts using polyelectrolyte multilayer templates. Macromol Biosci. 2007;7(3):344–53.

    Article  CAS  PubMed  Google Scholar 

  27. Kidambi S, Lee I, Chan C. Controlling primary hepatocyte adhesion and spreading on protein-free polyelectrolyte multilayer films. J Am Chem Soc. 2004;126(50):16286–7.

    Article  CAS  PubMed  Google Scholar 

  28. Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115(2):209–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Friedman SL. Liver fibrosis–from bench to bedside. J Hepatol. 2003;38:38–53.

    Article  Google Scholar 

  30. Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol. 2011;6:425–56.

    Article  CAS  PubMed  Google Scholar 

  31. Mammoto T, Ingber DE. Mechanical control of tissue and organ development. Development. 2010;137(9):1407–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ferraioli G, Tinelli C, Dal Bello B, Zicchetti M, Filice G, Filice C. Accuracy of real-time shear wave elastography for assessing liver fibrosis in chronic hepatitis C: a pilot study. Hepatology. 2012;56(6):2125–33.

    Article  PubMed  Google Scholar 

  33. Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology. 2008;134(4):960–74.e8.

    Article  PubMed  Google Scholar 

  34. Yin M, Woollard J, Wang X, Torres VE, Harris PC, Ward CJ, et al. Quantitative assessment of hepatic fibrosis in an animal model with magnetic resonance elastography. Magn Reson Med. 2007;58(2):346–53.

    Article  PubMed  Google Scholar 

  35. Wang H-B, Dembo M, Wang Y-L. Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. Am J Physiol Cell Physiol. 2000;279(5):C1345–C50.

    Article  CAS  PubMed  Google Scholar 

  36. Hsiong SX, Carampin P, Kong HJ, Lee KY, Mooney DJ. Differentiation stage alters matrix control of stem cells. J Biomed Mater Res A. 2008;85(1):145–56.

    Article  PubMed  Google Scholar 

  37. Park JS, Chu JS, Tsou AD, Diop R, Tang Z, Wang A, et al. The effect of matrix stiffness on the differentiation of mesenchymal stem cells in response to TGF-β. Biomaterials. 2011;32(16):3921–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Discher DE, Janmey P, Wang YL. Tissue cells feel and respond to the stiffness of their substrate. Science. 2005;310(5751):1139–43.

    Article  CAS  PubMed  Google Scholar 

  39. Ingber DE. Cellular mechanotransduction: putting all the pieces together again. FASEB J. 2006;20(7):811–27.

    Article  CAS  PubMed  Google Scholar 

  40. McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS. Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell. 2004;6(4):483–95.

    Article  CAS  PubMed  Google Scholar 

  41. Desmoulière A, Darby I, Costa A, Raccurt M, Tuchweber B, Sommer P, et al. Extracellular matrix deposition, lysyl oxidase expression, and myofibroblastic differentiation during the initial stages of cholestatic fibrosis in the rat. Lab Invest. 1997;76(6):765–78.

    PubMed  Google Scholar 

  42. Brenner DA, Waterboer T, Choi SK, Lindquist JN, Stefanovic B, Burchardt E, et al. New aspects of hepatic fibrosis. J Hepatol. 2000;32:32–8.

    Article  CAS  PubMed  Google Scholar 

  43. Li Z, Dranoff JA, Chan EP, Uemura M, Sevigny J, Wells RG. Transforming growth factor-beta and substrate stiffness regulate portal fibroblast activation in culture. Hepatology. 2007;46(4):1246–56.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  45. Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem. 2007;282(32):23337–47.

    Article  CAS  PubMed  Google Scholar 

  46. Schrader J, Gordon-Walker TT, Aucott RL, van Deemter M, Quaas A, Walsh S, et al. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology. 2011;53(4):1192–205.

    Article  CAS  PubMed  Google Scholar 

  47. Tateno C, Yoshizato K. Long-term cultivation of adult rat hepatocytes that undergo multiple cell divisions and express normal parenchymal phenotypes. Am J Pathol. 1996;148(2):383.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Clayton DF, Darnell J. Changes in liver-specific compared to common gene transcription during primary culture of mouse hepatocytes. Mol Cell Biol. 1983;3(9):1552–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Griffith LG, Swartz MA. Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol. 2006;7(3):211–24.

    Article  CAS  PubMed  Google Scholar 

  50. Sawada H, Takami K, Asahi S. A toxicogenomic approach to drug-induced phospholipidosis: analysis of its induction mechanism and establishment of a novel in vitro screening system. Toxicol Sci. 2005;83(2):282–92.

    Article  CAS  PubMed  Google Scholar 

  51. Natarajan V, Berglund EJ, Chen DX, Kidambi S. Substrate stiffness regulates primary hepatocyte functions. RSC Adv. 2015;5(99):80956–66.

    Article  CAS  PubMed  Google Scholar 

  52. Dunn JC, Yarmush ML, Koebe HG, Tompkins RG. Hepatocyte function and extracellular matrix geometry: long-term culture in a sandwich configuration. FASEB J. 1989;3(2):174–7.

    Article  CAS  PubMed  Google Scholar 

  53. Youssef J, Chen P, Shenoy VB, Morgan JR. Mechanotransduction is enhanced by the synergistic action of heterotypic cell interactions and TGF-β1. FASEB J. 2012;26(6):2522–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. You J, Park SA, Shin DS, Patel D, Raghunathan VK, Kim M, et al. Characterizing the effects of heparin gel stiffness on function of primary hepatocytes. Tissue Eng Part A. 2013;19(23–24):2655–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. LeCluyse E, Bullock P, Madan A, Carroll K, Parkinson A. Influence of extracellular matrix overlay and medium formulation on the induction of cytochrome P-450 2B enzymes in primary cultures of rat hepatocytes. Drug Metab Dispos. 1999;27(8):909–15.

    CAS  PubMed  Google Scholar 

  56. Lin P, Chan WC, Badylak SF, Bhatia SN. Assessing porcine liver-derived biomatrix for hepatic tissue engineering. Tissue Eng. 2004;10(7–8):1046–53.

    Article  CAS  PubMed  Google Scholar 

  57. Guillouzo A. Liver cell models in in vitro toxicology. Environ Health Perspect. 1998;106(Suppl 2):511–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Perepelyuk M, Chin L, Cao X, van Oosten A, Shenoy VB, Janmey PA, et al. Normal and fibrotic rat livers demonstrate shear strain softening and compression stiffening: a model for soft tissue mechanics. PLoS One. 2016;11(1):e0146588.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Zustiak S, Nossal R, Sackett DL. Multiwell stiffness assay for the study of cell responsiveness to cytotoxic drugs. Biotechnol Bioeng. 2014;111(2):396–403.

    Article  CAS  PubMed  Google Scholar 

  60. 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 

  61. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs stem cell lineage specification. Cell. 2006;126(4):677–89.

    Article  CAS  PubMed  Google Scholar 

  62. Regehr KJ, Domenech M, Koepsel JT, Carver KC, Ellison-Zelski SJ, Murphy WL, et al. Biological implications of polydimethylsiloxane-based microfluidic cell culture. Lab Chip. 2009;9(15):2132–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Deegan DB, Zimmerman C, Skardal A, Atala A, Shupe TD. Stiffness of hyaluronic acid gels containing liver extracellular matrix supports human hepatocyte function and alters cell morphology. J Mech Behav Biomed Mater. 2015;55:87–103.

    Article  PubMed  CAS  Google Scholar 

  64. Xia T, Zhao R, Liu W, Huang Q, Chen P, Waju YN, et al. Effect of substrate stiffness on hepatocyte migration and cellular Young’s modulus. J Cell Physiol. 2018;233(9):6996–7006.

    Article  CAS  PubMed  Google Scholar 

  65. Mata A, Fleischman AJ, Roy S. Characterization of polydimethylsiloxane (PDMS) properties for biomedical micro/nanosystems. Biomed Microdevices. 2005;7(4):281–93.

    Article  CAS  PubMed  Google Scholar 

  66. Dario P, Carrozza MC, Benvenuto A, Menciassi A. Micro-systems in biomedical applications. J Micromech Microeng. 2000;10(2):235.

    Article  CAS  Google Scholar 

  67. Tzvetkova-Chevolleau T, Stéphanou A, Fuard D, Ohayon J, Schiavone P, Tracqui P. The motility of normal and cancer cells in response to the combined influence of the substrate rigidity and anisotropic microstructure. Biomaterials. 2008;29(10):1541–51.

    Article  CAS  PubMed  Google Scholar 

  68. Natarajan V, Moeller M, Casey CA, Harris EN, Kidambi S. Matrix Stiffness Regulates Liver Sinusoidal Endothelial Cell Function Mimicking Responses in Fatty Liver Disease. bioRXiv, 2020, https://doi.org/10.1101/2020.01.27.921353.

  69. Daverey A, Mytty A, Kidambi S. Topography mediated regulation of HER-2 expression in breast cancer cells. Nano LIFE. 2012;2(3):1241009.

    Article  CAS  Google Scholar 

  70. Kidambi S, Udpa N, Schroeder SA, Findlan R, Lee I, Chan C. Cell adhesion on polyelectrolyte multilayer coated polydimethylsiloxane surfaces with varying topographies. Tissue Eng. 2007;13(8):2105–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Huang X, Hang R, Wang X, Lin N, Zhang X, Tang B. Matrix stiffness in three-dimensional systems effects on the behavior of C3A cells. Artif Organs. 2013;37(2):166–74.

    Article  CAS  PubMed  Google Scholar 

  72. Ben-Ze’ev A, Robinson GS, Bucher N, Farmer SR. Cell-cell and cell-matrix interactions differentially regulate the expression of hepatic and cytoskeletal genes in primary cultures of rat hepatocytes. Proc Natl Acad Sci. 1988;85(7):2161–5.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Mooney D, Hansen L, Vacanti J, Langer R, Farmer S, Ingber D. Switching from differentiation to growth in hepatocytes: control by extracellular matrix. J Cell Physiol. 1992;151(3):497–505.

    Article  CAS  PubMed  Google Scholar 

  74. Hansen LK, Wilhelm J, Fassett JT. Regulation of hepatocyte cell cycle progression and differentiation by type I collagen structure. Curr Top Dev Biol. 2006;72:205–36, 1 plate.

    Article  CAS  PubMed  Google Scholar 

  75. Fassett J, Tobolt D, Hansen LK. Type I collagen structure regulates cell morphology and EGF signaling in primary rat hepatocytes through cAMP-dependent protein kinase A. Mol Biol Cell. 2005;17(1):345–56.

    Article  PubMed  Google Scholar 

  76. Nagaki M, Sugiyama A, Naiki T, Ohsawa Y, Moriwaki H. Control of cyclins, cyclin-dependent kinase inhibitors, p21 and p27, and cell cycle progression in rat hepatocytes by extracellular matrix. J Hepatol. 2000;32(3):488–96.

    Article  CAS  PubMed  Google Scholar 

  77. Nagaki M, Shidoji Y, Yamada Y, Sugiyama A, Tanaka M, Akaike T, et al. Regulation of hepatic genes and liver transcription factors in rat hepatocytes by extracellular matrix. Biochem Biophys Res Commun. 1995;210(1):38–43.

    Article  CAS  PubMed  Google Scholar 

  78. DiPersio CM, Jackson DA, Zaret KS. The extracellular matrix coordinately modulates liver transcription factors and hepatocyte morphology. Mol Cell Biol. 1991;11(9):4405–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Brill S, Zvibel I, Halpern Z, Oren R. The role of fetal and adult hepatocyte extracellular matrix in the regulation of tissue-specific gene expression in fetal and adult hepatocytes. Eur J Cell Biol. 2002;81(1):43–50.

    Article  CAS  PubMed  Google Scholar 

  80. Desai SS, Tung JC, Zhou VX, Grenert JP, Malato Y, Rezvani M, et al. Physiological ranges of matrix rigidity modulate primary mouse hepatocyte function in part through hepatocyte nuclear factor 4 alpha. Hepatology. 2016;64(1):261–75.

    Article  CAS  PubMed  Google Scholar 

  81. Wilson CL, Hayward SL, Kidambi S. Astrogliosis in a dish: substrate stiffness induces astrogliosis in primary rat astrocytes. RSC Adv. 2016;6(41):34447–57.

    Article  CAS  PubMed  Google Scholar 

  82. Cozzolino AM, Noce V, Battistelli C, Marchetti A, Grassi G, Cicchini C, et al. Modulating the substrate stiffness to manipulate differentiation of resident liver stem cells and to improve the differentiation state of hepatocytes. Stem Cells Int. 2016;2016:5481493.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Chen AA, Khetani SR, Lee S, Bhatia SN, Van Vliet KJ. Modulation of hepatocyte phenotype in vitro via chemomechanical tuning of polyelectrolyte multilayers. Biomaterials. 2009;30(6):1113–20.

    Article  CAS  PubMed  Google Scholar 

  84. Semler EJ, Lancin PA, Dasgupta A, Moghe PV. Engineering hepatocellular morphogenesis and function via ligand-presenting hydrogels with graded mechanical compliance. Biotechnol Bioeng. 2005;89(3):296–307.

    Article  CAS  PubMed  Google Scholar 

  85. Xia T, Zhao R, Feng F, Song Y, Zhang Y, Dong L, et al. Gene expression profiling of human hepatocytes grown on differing substrate stiffness. Biotechnol Lett. 2018;40(5):809–18.

    Article  CAS  PubMed  Google Scholar 

  86. Bowler BE. Thermodynamics of protein denatured states. Mol BioSyst. 2007;3(2):88–99.

    Article  CAS  PubMed  Google Scholar 

  87. Battle AR, Ridone P, Bavi N, Nakayama Y, Nikolaev YA, Martinac B. Lipid-protein interactions: lessons learned from stress. Biochim Biophys Acta. 2015;1848(9):1744–56.

    Article  CAS  PubMed  Google Scholar 

  88. Bordeleau F, Califano JP, Negron Abril YL, Mason BN, LaValley DJ, Shin SJ, et al. Tissue stiffness regulates serine/arginine-rich protein-mediated splicing of the extra domain B-fibronectin isoform in tumors. Proc Natl Acad Sci U S A. 2015;112(27):8314–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Saha K, Kim J, Irwin E, Yoon J, Momin F, Trujillo V, et al. Surface creasing instability of soft polyacrylamide cell culture substrates. Biophys J. 2010;99(12):L94–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Moeller M, Thulasingam S, Narasimhan M, Kidambi S. Stiffness Induces NAFLD-Like Metabolic Dysfunction in Primary Hepatocytes, Hepatology. 2019;70:119A.

    Google Scholar 

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Kidambi, S. (2020). Stiffness and Hepatocytes Function In Vitro. In: Mueller, S. (eds) Liver Elastography. Springer, Cham. https://doi.org/10.1007/978-3-030-40542-7_55

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