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On-line Access: 2021-02-08

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Bio-Design and Manufacturing  2021 Vol.4 No.2 P.157-170

http://doi.org/10.1007/s42242-020-00121-4


3D human nonalcoholic hepatic steatosis and fibrosis models


Author(s):  Sushila Maharjan, Diana Bonilla, Princy Sindurakar, Hongbin Li, Wanlu Li, Sergio Duarte, Ali Zarrinpar & Y. Shrike Zhang

Affiliation(s):  Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, 65 Landsdowne St, Cambridge, MA 02139, USA; more

Corresponding email(s):   ali.zarrinpar@surgery.uf.edu, yszhang@research.bwh.harvard.edu

Key Words:  Nonalcoholic fatty liver disease (NAFLD), Gelatin methacryloyl (GelMA), Photocrosslinking, Steatosis, Fibrosis, Free fatty acids, Transforming growth factor-β1 (TGF-β1)


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Sushila Maharjan, Diana Bonilla, Princy Sindurakar, Hongbin Li, Wanlu Li, Sergio Duarte, Ali Zarrinpar & Y. Shrike Zhang . 3D human nonalcoholic hepatic steatosis and fibrosis models[J]. Journal of Zhejiang University Science D, 2021, 4(2): 157-170.

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author="Sushila Maharjan, Diana Bonilla, Princy Sindurakar, Hongbin Li, Wanlu Li, Sergio Duarte, Ali Zarrinpar & Y. Shrike Zhang ",
journal="Journal of Zhejiang University Science D",
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pages="157-170",
year="2021",
publisher="Zhejiang University Press & Springer",
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Abstract: 
This study presents a simple and robust three-dimensional human hepatic tissue model to emulate steatotic and fibrotic conditions and provide an in vitro model for drug testing and mechanistic studies. Using a photolithographic biofabrication method with a photomask featuring hexagonal units, liver cells, including a human hepatic cell line (HepG2-C3A) and a human hepatic stellate cell line (LX-2) were embedded in gelatin methacryloyl hydrogel. Hepatic steatosis was induced by supraphysiological concentration of free fatty acids; hepatic fibrosis was induced by transforming growth factor-β1. Induction of steatosis was confirmed by Oil Red O and BODIPY staining and was inhibited with toyocamycin and obeticholic acid. Induction of fibrosis was confirmed by immunostaining for collagen type I and alpha smooth muscle actin and inhibited by rapamycin and curcumin treatment. This model was further preliminarily validated using primary human hepatocytes in a similar setup. These constructs provide a viable, biologically relevant, and higher throughput model of hepatic steatosis and fibrosis and may facilitate the study of the mechanisms of disease and testing of liver-directed drugs.

哈佛大学张宇等 | 三维人类非酒精性肝脂肪变性和纤维化模型

本研究论文提出了一个简单而强大的三维人肝组织模型,以模拟脂肪变性和纤维化状况,并为药物测试和机制研究提供体外模型。使用具有六边形单元掩模的光刻生物制造方法,将肝细胞(包括人肝细胞系 (HepG2-C3A) 和人肝星状细胞系 (LX-2) )嵌入甲基丙烯酰化明胶水凝胶中。肝脏脂肪变性是由游离脂肪酸的超生理浓度引起的;转化生长因子-β1 诱导肝纤维化。通过Oil Red O和BODIPY染色证实了脂肪变性的诱导,并被丰加霉素和贝替胆酸抑制。通过I型胶原和α平滑肌肌动蛋白免疫染色证实纤维化的诱导,并被雷帕霉素和姜黄素处理抑制。在类似的设置中使用原代人肝细胞进一步验证该模型。这些构建体提供了一个可行的、生物学相关的和更高通量的肝脂肪变性和纤维化模型,并可能促进疾病机制的研究和肝脏导向药物的测试。

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