A review on cell-based models of human liver disease in vitro_Journal of Biomedical Engineering

Authors：

LIU Ting ^1,2 ,  GE Yuqing ² ,  YUAN Min ¹ , XIONG Qiao ³ , ZHAO Jianlong ²

1. School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai 200093, P.R.China;
2. State Key Laboratory of Transducer Technology, Shanghai Institute of Microsystem and Information Technology, Chinese Academy of Sciences, Shanghai 200050, P.R.China;
3. Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai 200433, P.R.China;

Corresponding author：

GE Yuqing, Email: yqge@mail.sim.ac.cn; YUAN Min, Email: yuanmin986@126.com

Keywords：

liver diseases; model in vitro; microenvironment; liver function; protein biomarkers

DOI：

10.7507/1001-5515.202004027

Video：

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Abstract Full text Figures/Tables Video References Cited by

Unhealthy diet, habits and drug abuse cause a variety of liver diseases, including steatohepatitis, liver fibrosis, liver cirrhosis and liver cancer, which seriously affect human health. The fabrication of highly simulated cell models in vitro is important in the treatment of liver diseases and drug development. This article summarized the common strategies for the construction of liver pathology models in vitro. It introduced four typical cell models in vitro related to liver disease and provided a reference for the study of liver disease models.

Citation： LIU Ting, GE Yuqing, YUAN Min, XIONG Qiao, ZHAO Jianlong. A review on cell-based models of human liver disease in vitro. Journal of Biomedical Engineering, 2021, 38(1): 178-184. doi: 10.7507/1001-5515.202004027 Copy

1.	Casotti V, Lorenzo D. Basic principles of liver physiology. Berlin: Springer International Publishing, 2019: 21-39.
2.	de Boer Y S, Kosinski A S, Urban T J, et al. Features of autoimmune hepatitis in patients with drug-induced liver injury. Clin Gastroenterol Hepatol, 2017, 15(1): 103-112.
3.	Ramachandran P, Dobie R, Wilson-Kanamori J R, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature, 2019, 575(7783): 512-518.
4.	Cole B K, Feaver R E, Wamhoff B R, et al. Non-alcoholic fatty liver disease (NAFLD) models in drug discovery. Expert Opin Drug Discov, 2018, 13(2): 193-205.
5.	卢贤欢, 赵华琛, 王雪, 等. 体外肝脏 3D 模型在药物肝毒性评价中的优势. 药学学报, 2017, 52(12): 1859-1864.
6.	Williamson T, Sultanpuram N, Sendi H. The role of liver microenvironment in hepatic metastasis. Clin Transl Med, 2019, 8(1): 21.
7.	Utoh R, Komori J, Kuge H, et al. Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney. J Hepatol, 2018, 68(4): 744-753.
8.	Wang M, Liu S, Xu Z, et al. Characterizing poroelasticity of biological tissues by spherical indentation: an improved theory for large relaxation. J Mech Phys Solids, 2020, 138: 103920.
9.	Underhill G H, Khetani S R. Bioengineered liver models for drug testing and cell differentiation studies. Cell Mol Gastroenterol Hepatol, 2018, 5(3): 426-439.
10.	Vilas-Boas V, Cooreman A, Gijbels E, et al. Primary hepatocytes and their cultures for the testing of drug-induced liver injury. Adv Pharmacol, 2019, 85: 1-30.
11.	Xu J Y, Oda S, Yokoi T. Cell-based assay using glutathione-depleted HepaRG and HepG2 human liver cells for predicting drug-induced liver injury. Toxicol In Vitro, 2018, 48: 286-301.
12.	Abdellatef S A, Ohi A, Nabatame T, et al. The effect of physical and chemical cues on hepatocellular function and morphology. Int J Mol Sci, 2014, 15(3): 4299-4317.
13.	Seitz H K, Bataller R, Cortez-Pinto H, et al. Alcoholic liver disease. Nat Rev Dis Primers, 2018, 4(1): 16.
14.	Mahli A, Koch A, Fresse K, et al. Iso-alpha acids from hops (Humulus lupulus) inhibit hepatic steatosis, inflammation, and fibrosis. Lab Invest, 2018, 98(12): 1614-1626.
15.	Lee J, Choi B, No D Y, et al. A 3D alcoholic liver disease model on a chip. Integr Biol (Camb), 2016, 8(3): 302-308.
16.	Deng J, Chen Z, Zhang X, et al. A liver-chip-based alcoholic liver disease model featuring multi-non-parenchymal cells. Biomed Microdevices, 2019, 21(3): 57.
17.	Huang G, Li F, Zhao X, et al. Functional and biomimetic materials for engineering of the three-dimensional cell microenvironment. Chem Rev, 2017, 117(20): 12764-12850.
18.	Zhang Y, Wang C, Yu B, et al. Gastrodin protects against ethanol-induced liver injury and apoptosis in HepG2 cells and animal models of alcoholic liver disease. Biol Pharm Bull, 2018, 41(5): 670-679.
19.	Choi W M, Kim M H, Jeong W I. Functions of hepatic nonparenchymal cells in alcoholic liver disease. Liver Research, 2019, 3: 80-87.
20.	Kirchner V A, Tak E, Kim K, et al. The evolving microenvironment of the human hepatocyte: healthy vs. cirrhotic liver vs. isolated cells. Tissue Cell, 2020, 62: 101310.
21.	Bedossa P. Pathology of non-alcoholic fatty liver disease. Liver Int, 2017, 37(Suppl 1): 85-89.
22.	Friedman S L, Neuschwander-Tetri B A, Rinella M, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med, 2018, 24(7): 908-922.
23.	Kozyra M, Johansson I, Nordling Å, et al. Human hepatic 3D spheroids as a model for steatosis and insulin resistance. Sci Rep, 2018, 8(1): 14297.
24.	Bessone F, Razori M V, Roma M G. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci, 2019, 76(1): 99-128.
25.	Kostrzewski T, Cornforth T, Snow S A, et al. Three-dimensional perfused human in vitro model of non-alcoholic fatty liver disease. World J Gastroenterol, 2017, 23(2): 204-215.
26.	Suurmond C-a E, Lasli S, van den Dolder F W, et al. In vitro human liver model of nonalcoholic steatohepatitis by coculturing hepatocytes, endothelial cells, and kupffer cells. Adv Healthc Mater, 2019, 8(24): e1901379.
27.	Magee N, Zou A, Zhang Y X. Pathogenesis of nonalcoholic steatohepatitis: interactions between liver parenchymal and nonparenchymal cells. Biomed Res Int, 2016: 5170402.
28.	Hall Z, Bond N J, Ashmore T, et al. Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease. Hepatology, 2017, 65(4): 1165-1180.
29.	Bulutoglu B, Rey-Bedón C, Kang Y, et al. A microfluidic patterned model of non-alcoholic fatty liver disease: applications to disease progression and zonation. Lab Chip, 2019, 19(18): 3022-3031.
30.	Jang K J, Otieno M, Ronxhi J, et al. Reproducing human and cross-species drug toxicities using a liver-chip. Sci Transl Med, 2019, 11(517): eaax5516.
31.	Nguyen D G, Funk J, Robbins J B, et al. Bioprinted 3D primary liver tissues allow assessment of organ-level response to clinical drug induced toxicity in vitro. PLoS One, 2016, 11(7): e0158674.
32.	Mukherjee S, Zhelnin L, Sanfiz A, et al. Development and validation of an in vitro 3D model of NASH with severe fibrotic phenotype. Am J Transl Res, 2019, 11(3): 1531-1540.
33.	Underhill G H, Khetani S R. Emerging trends in modeling human liver disease in vitro. APL Bioeng, 2019, 3(4): 040902.
34.	Andrade R J, Chalasani N, Björnsson E S, et al. Drug-induced liver injury. Nat Rev Dis Primers, 2019, 5(1): 58.
35.	Zhou Y T, Shen J X, Lauschke V M. Comprehensive evaluation of organotypic and microphysiological liver models for prediction of drug-induced liver injury. Front Pharmacol, 2019, 10: 1093.
36.	Fey S J, Wrzesinski K. Determination of drug toxicity using 3D spheroids constructed from an immortal human hepatocyte cell line. Toxicological Sciences, 2012, 127(2): 403-411.
37.	Ewart L, Dehne E M, Fabre K, et al. Application of microphysiological systems to enhance safety assessment in drug discovery. Annu Rev Pharmacol Toxicol, 2018, 58: 65-82.
38.	Kuna L, Bozic I, Kizivat T, et al. Models of drug induced liver injury (Dili) - current issues and future perspectives. Curr Drug Metab, 2018, 19(10): 830-838.
39.	Ware B R, Durham M J, Monckton C P, et al. A cell culture platform to maintain long-term phenotype of primary human hepatocytes and endothelial cells. Cell Mol Gastroenterol Hepatol, 2018, 5(3): 187-207.
40.	Rizki-Safitri A, Shinohara M, Tanaka M, et al. Tubular bile duct structure mimicking bile duct morphogenesis for prospective in vitro liver metabolite recovery. J Biol Eng, 2020, 14(1): 11.
41.	Baze A, Parmentier C, Hendriks D, et al. Three-Dimensional spheroid primary human hepatocytes in monoculture and coculture with nonparenchymal cells. Tissue Eng Part C Methods, 2018, 24(9): 534-545.
42.	Corbett J L, Duncan S A. iPSC-Derived hepatocytes as a platform for disease modeling and drug discovery. Front Med (Lausanne), 2019, 6: 265.
43.	Ott L M, Ramachandran K, Stehno-Bittel L. An automated multiplexed hepatotoxicity and CYP induction assay using HepaRG cells in 2D and 3D. SLAS Discov, 2017, 22(5): 614-625.
44.	Kizawa H, Nagao E, Shimamura M, et al. Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery. Biochem Biophys Rep, 2017, 10: 186-191.
45.	Gural N, Mancio-Silva L, HE J, et al. Engineered livers for infectious diseases. Cell Mol Gastroenterol Hepatol, 2018, 5(2): 131-144.
46.	Li M, Wang Z Q, Zhang L, et al. Burden of cirrhosis and other chronic liver diseases caused by specific etiologies in China, 1990-2016: findings from the global burden of disease study 2016. Biomed Environ Sci: BES, 2020, 33(1): 1-10.
47.	Paran N, Geiger B, Shaul Y. HBV infection of cell culture: evidence for multivalent and cooperative attachment. EMBO J, 2001, 20(16): 4443-4453.
48.	Xia Y, Carpentier A, Cheng X, et al. Human stem cell-derived hepatocytes as a model for hepatitis B virus infection, spreading and virus-host interactions. J Hepatol, 2017, 66(3): 494-503.
49.	Shlomai A, Schwartz R E, Ramanan V, et al. Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems. Proc Natl Acad Sci U S A, 2014, 111(33): 12193-12198.
50.	March S, Ramanan V, Trehan K, et al. Micropatterned coculture of primary human hepatocytes and supportive cells for the study of hepatotropic pathogens. Nat Protoc, 2015, 10(12): 2027-2053.
51.	Ortega-Prieto A M, Skelton J K, Wai S N, et al. 3D microfluidic liver cultures as a physiological preclinical tool for hepatitis B virus infection. Nat Commun, 2018, 9(1): 682.
52.	World Health Organization. World malaria report 2016. Geneva Switzerland Who, 2016, 30(1): 189-206.
53.	Gural N, Mancio-Silva L, Miller A B, et al. In vitro culture, drug sensitivity, and transcriptome of plasmodium vivax hypnozoites. Cell Host Microbe, 2018, 23(3): 395-406.
54.	Talman A M, Blagborough A M, Sinden R E. A plasmodium falciparum strain expressing GFP throughout the parasite's life-cycle. PLoS One, 2010, 5(2): e9156.
55.	Bao C Y, Hung H C, Chen Y W, et al. Requirement of cyclin-dependent kinase function for hepatitis B virus cccDNA synthesis as measured by digital PCR. Ann Hepatol, 2020, 19(3): 280-286.

1. Casotti V, Lorenzo D. Basic principles of liver physiology. Berlin: Springer International Publishing, 2019: 21-39.
2. de Boer Y S, Kosinski A S, Urban T J, et al. Features of autoimmune hepatitis in patients with drug-induced liver injury. Clin Gastroenterol Hepatol, 2017, 15(1): 103-112.
3. Ramachandran P, Dobie R, Wilson-Kanamori J R, et al. Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature, 2019, 575(7783): 512-518.
4. Cole B K, Feaver R E, Wamhoff B R, et al. Non-alcoholic fatty liver disease (NAFLD) models in drug discovery. Expert Opin Drug Discov, 2018, 13(2): 193-205.
5. 卢贤欢, 赵华琛, 王雪, 等. 体外肝脏 3D 模型在药物肝毒性评价中的优势. 药学学报, 2017, 52(12): 1859-1864.
6. Williamson T, Sultanpuram N, Sendi H. The role of liver microenvironment in hepatic metastasis. Clin Transl Med, 2019, 8(1): 21.
7. Utoh R, Komori J, Kuge H, et al. Adult hepatocytes direct liver organogenesis through non-parenchymal cell recruitment in the kidney. J Hepatol, 2018, 68(4): 744-753.
8. Wang M, Liu S, Xu Z, et al. Characterizing poroelasticity of biological tissues by spherical indentation: an improved theory for large relaxation. J Mech Phys Solids, 2020, 138: 103920.
9. Underhill G H, Khetani S R. Bioengineered liver models for drug testing and cell differentiation studies. Cell Mol Gastroenterol Hepatol, 2018, 5(3): 426-439.
10. Vilas-Boas V, Cooreman A, Gijbels E, et al. Primary hepatocytes and their cultures for the testing of drug-induced liver injury. Adv Pharmacol, 2019, 85: 1-30.
11. Xu J Y, Oda S, Yokoi T. Cell-based assay using glutathione-depleted HepaRG and HepG2 human liver cells for predicting drug-induced liver injury. Toxicol In Vitro, 2018, 48: 286-301.
12. Abdellatef S A, Ohi A, Nabatame T, et al. The effect of physical and chemical cues on hepatocellular function and morphology. Int J Mol Sci, 2014, 15(3): 4299-4317.
13. Seitz H K, Bataller R, Cortez-Pinto H, et al. Alcoholic liver disease. Nat Rev Dis Primers, 2018, 4(1): 16.
14. Mahli A, Koch A, Fresse K, et al. Iso-alpha acids from hops (Humulus lupulus) inhibit hepatic steatosis, inflammation, and fibrosis. Lab Invest, 2018, 98(12): 1614-1626.
15. Lee J, Choi B, No D Y, et al. A 3D alcoholic liver disease model on a chip. Integr Biol (Camb), 2016, 8(3): 302-308.
16. Deng J, Chen Z, Zhang X, et al. A liver-chip-based alcoholic liver disease model featuring multi-non-parenchymal cells. Biomed Microdevices, 2019, 21(3): 57.
17. Huang G, Li F, Zhao X, et al. Functional and biomimetic materials for engineering of the three-dimensional cell microenvironment. Chem Rev, 2017, 117(20): 12764-12850.
18. Zhang Y, Wang C, Yu B, et al. Gastrodin protects against ethanol-induced liver injury and apoptosis in HepG2 cells and animal models of alcoholic liver disease. Biol Pharm Bull, 2018, 41(5): 670-679.
19. Choi W M, Kim M H, Jeong W I. Functions of hepatic nonparenchymal cells in alcoholic liver disease. Liver Research, 2019, 3: 80-87.
20. Kirchner V A, Tak E, Kim K, et al. The evolving microenvironment of the human hepatocyte: healthy vs. cirrhotic liver vs. isolated cells. Tissue Cell, 2020, 62: 101310.
21. Bedossa P. Pathology of non-alcoholic fatty liver disease. Liver Int, 2017, 37(Suppl 1): 85-89.
22. Friedman S L, Neuschwander-Tetri B A, Rinella M, et al. Mechanisms of NAFLD development and therapeutic strategies. Nat Med, 2018, 24(7): 908-922.
23. Kozyra M, Johansson I, Nordling Å, et al. Human hepatic 3D spheroids as a model for steatosis and insulin resistance. Sci Rep, 2018, 8(1): 14297.
24. Bessone F, Razori M V, Roma M G. Molecular pathways of nonalcoholic fatty liver disease development and progression. Cell Mol Life Sci, 2019, 76(1): 99-128.
25. Kostrzewski T, Cornforth T, Snow S A, et al. Three-dimensional perfused human in vitro model of non-alcoholic fatty liver disease. World J Gastroenterol, 2017, 23(2): 204-215.
26. Suurmond C-a E, Lasli S, van den Dolder F W, et al. In vitro human liver model of nonalcoholic steatohepatitis by coculturing hepatocytes, endothelial cells, and kupffer cells. Adv Healthc Mater, 2019, 8(24): e1901379.
27. Magee N, Zou A, Zhang Y X. Pathogenesis of nonalcoholic steatohepatitis: interactions between liver parenchymal and nonparenchymal cells. Biomed Res Int, 2016: 5170402.
28. Hall Z, Bond N J, Ashmore T, et al. Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease. Hepatology, 2017, 65(4): 1165-1180.
29. Bulutoglu B, Rey-Bedón C, Kang Y, et al. A microfluidic patterned model of non-alcoholic fatty liver disease: applications to disease progression and zonation. Lab Chip, 2019, 19(18): 3022-3031.
30. Jang K J, Otieno M, Ronxhi J, et al. Reproducing human and cross-species drug toxicities using a liver-chip. Sci Transl Med, 2019, 11(517): eaax5516.
31. Nguyen D G, Funk J, Robbins J B, et al. Bioprinted 3D primary liver tissues allow assessment of organ-level response to clinical drug induced toxicity in vitro. PLoS One, 2016, 11(7): e0158674.
32. Mukherjee S, Zhelnin L, Sanfiz A, et al. Development and validation of an in vitro 3D model of NASH with severe fibrotic phenotype. Am J Transl Res, 2019, 11(3): 1531-1540.
33. Underhill G H, Khetani S R. Emerging trends in modeling human liver disease in vitro. APL Bioeng, 2019, 3(4): 040902.
34. Andrade R J, Chalasani N, Björnsson E S, et al. Drug-induced liver injury. Nat Rev Dis Primers, 2019, 5(1): 58.
35. Zhou Y T, Shen J X, Lauschke V M. Comprehensive evaluation of organotypic and microphysiological liver models for prediction of drug-induced liver injury. Front Pharmacol, 2019, 10: 1093.
36. Fey S J, Wrzesinski K. Determination of drug toxicity using 3D spheroids constructed from an immortal human hepatocyte cell line. Toxicological Sciences, 2012, 127(2): 403-411.
37. Ewart L, Dehne E M, Fabre K, et al. Application of microphysiological systems to enhance safety assessment in drug discovery. Annu Rev Pharmacol Toxicol, 2018, 58: 65-82.
38. Kuna L, Bozic I, Kizivat T, et al. Models of drug induced liver injury (Dili) - current issues and future perspectives. Curr Drug Metab, 2018, 19(10): 830-838.
39. Ware B R, Durham M J, Monckton C P, et al. A cell culture platform to maintain long-term phenotype of primary human hepatocytes and endothelial cells. Cell Mol Gastroenterol Hepatol, 2018, 5(3): 187-207.
40. Rizki-Safitri A, Shinohara M, Tanaka M, et al. Tubular bile duct structure mimicking bile duct morphogenesis for prospective in vitro liver metabolite recovery. J Biol Eng, 2020, 14(1): 11.
41. Baze A, Parmentier C, Hendriks D, et al. Three-Dimensional spheroid primary human hepatocytes in monoculture and coculture with nonparenchymal cells. Tissue Eng Part C Methods, 2018, 24(9): 534-545.
42. Corbett J L, Duncan S A. iPSC-Derived hepatocytes as a platform for disease modeling and drug discovery. Front Med (Lausanne), 2019, 6: 265.
43. Ott L M, Ramachandran K, Stehno-Bittel L. An automated multiplexed hepatotoxicity and CYP induction assay using HepaRG cells in 2D and 3D. SLAS Discov, 2017, 22(5): 614-625.
44. Kizawa H, Nagao E, Shimamura M, et al. Scaffold-free 3D bio-printed human liver tissue stably maintains metabolic functions useful for drug discovery. Biochem Biophys Rep, 2017, 10: 186-191.
45. Gural N, Mancio-Silva L, HE J, et al. Engineered livers for infectious diseases. Cell Mol Gastroenterol Hepatol, 2018, 5(2): 131-144.
46. Li M, Wang Z Q, Zhang L, et al. Burden of cirrhosis and other chronic liver diseases caused by specific etiologies in China, 1990-2016: findings from the global burden of disease study 2016. Biomed Environ Sci: BES, 2020, 33(1): 1-10.
47. Paran N, Geiger B, Shaul Y. HBV infection of cell culture: evidence for multivalent and cooperative attachment. EMBO J, 2001, 20(16): 4443-4453.
48. Xia Y, Carpentier A, Cheng X, et al. Human stem cell-derived hepatocytes as a model for hepatitis B virus infection, spreading and virus-host interactions. J Hepatol, 2017, 66(3): 494-503.
49. Shlomai A, Schwartz R E, Ramanan V, et al. Modeling host interactions with hepatitis B virus using primary and induced pluripotent stem cell-derived hepatocellular systems. Proc Natl Acad Sci U S A, 2014, 111(33): 12193-12198.
50. March S, Ramanan V, Trehan K, et al. Micropatterned coculture of primary human hepatocytes and supportive cells for the study of hepatotropic pathogens. Nat Protoc, 2015, 10(12): 2027-2053.
51. Ortega-Prieto A M, Skelton J K, Wai S N, et al. 3D microfluidic liver cultures as a physiological preclinical tool for hepatitis B virus infection. Nat Commun, 2018, 9(1): 682.
52. World Health Organization. World malaria report 2016. Geneva Switzerland Who, 2016, 30(1): 189-206.
53. Gural N, Mancio-Silva L, Miller A B, et al. In vitro culture, drug sensitivity, and transcriptome of plasmodium vivax hypnozoites. Cell Host Microbe, 2018, 23(3): 395-406.
54. Talman A M, Blagborough A M, Sinden R E. A plasmodium falciparum strain expressing GFP throughout the parasite's life-cycle. PLoS One, 2010, 5(2): e9156.
55. Bao C Y, Hung H C, Chen Y W, et al. Requirement of cyclin-dependent kinase function for hepatitis B virus cccDNA synthesis as measured by digital PCR. Ann Hepatol, 2020, 19(3): 280-286.

Journal of Biomedical Engineering

A review on cell-based models of human liver disease in vitro

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