肝纤维化3D共培养体外模型的研究进展

摘要/Abstract

摘要： 肝纤维化是慢性肝病的晚期阶段,最终可能导致肝硬化、肝功能衰竭甚至肝细胞癌。肝纤维化是细胞外基质(ECM)在肝脏过度沉积和异常分布的病理生理过程。肝星状细胞(HSC)活化是肝纤维化的核心事件,其被激活并分化为肌成纤维细胞,可以分泌大量的细胞外基质。肝脏巨噬细胞和其他免疫细胞的参与以及各种炎症因子和促纤维化因子的共同作用决定了肝纤维化进程的复杂性。尽管目前已有各种病因诱导的肝纤维化动物模型用于研究,但是依然缺乏有效的体外模型来深入探究肝纤维化发病机制及药物研发。因此,迫切需要开发一种更接近在体的肝纤维化体外模型,作为了解疾病和筛选新药的有效手段。本文将对近年来发展起来的肝纤维化3D共培养体外模型作一概述。

关键词: 肝纤维化, 细胞外基质, 肝星状细胞, 体外共培养模型

黄龙, 王雪, 丛敏. 肝纤维化3D共培养体外模型的研究进展[J]. 肝脏, 2023, 28(12): 1492-1496.

参考文献

[1] Kisseleva T, Brenner D. Molecular and cellular mechanisms of liver fibrosis and its regression. Nat Rev Gastroenterol Hepatol, 2021,18(3):151-166.
[2] Wang FD, Zhou J, Chen EQ. Molecular mechanisms and potential new therapeutic drugs for liver fibrosis. Front Pharmacol, 2022,13:787748.
[3] Prestigiacomo V, Weston A, Suter-Dick L. Rat multicellular 3D liver microtissues to explore TGF-β1 induced effects. J Pharmacol Toxicol Methods, 2020,101:106650.
[4] Collins SD, Yuen G, Tu T, et al. In vitro models of the liver: disease modeling, drug discovery and clinical applications. Tirnitz-Parker JEE. Hepatocellular Carcinoma [Internet]. Brisbane (AU): Codon Publications, 2019.
[5] Farzaneh Z, Khojastehpour F, Keivan M, et al. Co-culture of liver parenchymal cells with non-parenchymal cells under 2D and 3D culture systems; a review paper. Curr Stem Cell Res Ther, 2023,18(7):904-916..
[6] Prestigiacomo V, Weston A, Messner S, et al. Pro-fibrotic compounds induce stellate cell activation, ECM-remodelling and Nrf2 activation in a human 3D-multicellular model of liver fibrosis. PLoS One, 2017 ,12(6):e0179995.
[7] Lauschke VM, Shafagh RZ, Hendriks DFG, et al. 3D primary hepatocyte culture systems for analyses of liver diseases, drug metabolism, and toxicity: emerging culture paradigms and applications. Biotechnol J, 2019, 14(7):e1800347.
[8] Lee SA, No da Y, Kang E, et al. Spheroid-based three-dimensional liver-on-a-chip to investigate hepatocyte-hepatic stellate cell interactions and flow effects. Lab Chip, 2013, 13(18):3529-3537.
[9] Thomas RJ, Bhandari R, Barrett DA, et al. The effect of three-dimensional co-culture of hepatocytes and hepatic stellate cells on key hepatocyte functions in vitro. Cells Tissues Organs, 2005, 181(2):67-79.
[10] Bell CC, Hendriks DF, Moro SM, et al. Characterization of primary human hepatocyte spheroids as a model system for drug-induced liver injury, liver function and disease. Sci Rep, 2016, 6:25187.
[11] Baze A, Parmentier C, Hendriks DFG, 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.
[12] Mannaerts I, Eysackers N, Anne van Os E, et al. The fibrotic response of primary liver spheroids recapitulates in vivo hepatic stellate cell activation. Biomaterials, 2020, 261:120335.
[13] Lee HJ, Mun SJ, Jung CR, et al. In vitro modeling of liver fibrosis with 3D co-culture system using a novel human hepatic stellate cell line. Biotechnol Bioeng, 2023,120(5):1241-1253.
[14] Ma L, Wu Y, Li Y, et al. Current advances on 3D-bioprinted liver tissue models. Adv Healthc Mater, 2020, 9(24):e2001517.
[15] Cui X, Li J, Hartanto Y, et al. Advances in extrusion 3D bioprinting: a focus on multicomponent hydrogel-based bioinks. Adv Healthc Mater, 2020, 9(15):e1901648.
[16] Yan Y, Wang X, Pan Y, et al. Fabrication of viable tissue-engineered constructs with 3D cell-assembly technique. Biomaterials, 2005, 26(29):5864-5871.
[17] Nguyen DG, Funk J, Robbins JB, 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.
[18] Norona LM, Nguyen DG, Gerber DA, et al. Editor's highlight: modeling compound-induced fibrogenesis in vitro using three-dimensional bioprinted human liver tissues. Toxicol Sci, 2016, 154(2):354-367.
[19] Cuvellier M, Ezan F, Oliveira H, et al. 3D culture of HepaRG cells in GelMa and its application to bioprinting of a multicellular hepatic model. Biomaterials, 2021, 269:120611.
[20] Wang T, Lü S, Hao Y, et al. Influence of microflow on hepatic sinusoid blood flow and red blood cell deformation. Biophys J, 2021, 120(21):4859-4873.
[21] Orbach SM, Ford AJ, Saverot SE, et al. Multi-cellular transitional organotypic models to investigate liver fibrosis. Acta Biomater, 2018, 82:79-92.
[22] Du Y, Li N, Yang H, et al. Mimicking liver sinusoidal structures and functions using a 3D-configured microfluidic chip. Lab Chip, 2017, 17(5):782-794.
[23] Li W, Li P, Li N, et al. Matrix stiffness and shear stresses modulate hepatocyte functions in a fibrotic liver sinusoidal model. Am J Physiol Gastrointest Liver Physiol, 2021, 320(3):G272-G282.
[24] Kabirian F, Mozafari M. Decellularized ECM-derived bioinks: prospects for the future. Methods, 2020, 171:108-118.
[25] Dai Q, Jiang W, Huang F, et al. Recent advances in liver engineering with decellularized scaffold. Front Bioeng Biotechnol, 2022, 10:831477.
[26] Hoshiba T. Decellularized extracellular matrix for cancer research. Materials (Basel), 2019, 12(8):1311.
[27] Zhang X, Chen X, Hong H, et al. Decellularized extracellular matrix scaffolds: Recent trends and emerging strategies in tissue engineering. Bioact Mater, 2021, 10:15-31.
[28] Caralt M, Uzarski JS, Iacob S, et al. Optimization and critical evaluation of decellularization strategies to develop renal extracellular matrix scaffolds as biological templates for organ engineering and transplantation. Am J Transplant, 2015, 15(1):64-75.
[29] Thanapirom K, Caon E, Papatheodoridi M, et al. Optimization and validation of a novel three-dimensional co-culture system in decellularized human liver scaffold for the study of liver fibrosis and cancer. Cancers (Basel), 2021, 13(19):4936.
[30] Palma E, Doornebal EJ, Chokshi S. Precision-cut liver slices: a versatile tool to advance liver research. Hepatol Int, 2019, 13(1):51-57.
[31] Mazza G, Al-Akkad W, Rombouts K. Engineering in vitro models of hepatofibrogenesis. Adv Drug Deliv Rev, 2017, 121:147-157.
[32] Dewyse L, Reynaert H, van Grunsven LA. Best practices and progress in precision-cut liver slice cultures. Int J Mol Sci, 2021, 22(13):7137.
[33] Dewyse L, De Smet V, Verhulst S, et al. Improved precision-cut liver slice cultures for testing drug-induced liver fibrosis. Front Med (Lausanne), 2022, 9:862185.
[34] Paish HL, Reed LH, Brown H, et al. A bioreactor technology for modeling fibrosis in human and rodent precision-cut liver slices. Hepatology, 2019, 70(4):1377-1391.
[35] Sun L, Hui L. Progress in human liver organoids. J Mol Cell Biol, 2020, 12(8):607-617.
[36] Artegiani B, Clevers H. Use and application of 3D-organoid technology. Hum Mol Genet, 2018, 27(R2):R99-R107.
[37] Harrison SP, Baumgarten SF, Verma R, et al. Liver organoids: recent developments, limitations and potential. Front Med (Lausanne), 2021, 8:574047.
[38] Arjmand B, Rabbani Z, Soveyzi F, et al. Advancement of organoid technology in regenerative medicine. Regen Eng Transl Med, 2023, 9(1):83-96.
[39] Leite SB, Roosens T, El Taghdouini A, et al. Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro. Biomaterials, 2016, 78:1-10.
[40] Brovold M, Keller D, Soker S. Differential fibrotic phenotypes of hepatic stellate cells within 3D liver organoids. Biotechnol Bioeng, 2020, 117(8):2516-2526.
[41] Ouchi R, Togo S, Kimura M, et al. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metab, 2019, 30(2):374-384.e6.