Department of Bioengineering, Henry Samueli School of Engineering and Applied Sciences, University of California-Los Angeles, Los Angeles, CA, 90095, USA.
Center for Minimally Invasive Therapeutics (C-MIT), University of California-Los Angeles, Los Angeles, CA, 90095, USA.
Small. 2021 Apr;17(14):e2007425. doi: 10.1002/smll.202007425. Epub 2021 Mar 9.
Despite considerable efforts in modeling liver disease in vitro, it remains difficult to recapitulate the pathogenesis of the advanced phases of non-alcoholic fatty liver disease (NAFLD) with inflammation and fibrosis. Here, a liver-on-a-chip platform with bioengineered multicellular liver microtissues is developed, composed of four major types of liver cells (hepatocytes, endothelial cells, Kupffer cells, and stellate cells) to implement a human hepatic fibrosis model driven by NAFLD: i) lipid accumulation in hepatocytes (steatosis), ii) neovascularization by endothelial cells, iii) inflammation by activated Kupffer cells (steatohepatitis), and iv) extracellular matrix deposition by activated stellate cells (fibrosis). In this model, the presence of stellate cells in the liver-on-a-chip model with fat supplementation showed elevated inflammatory responses and fibrosis marker up-regulation. Compared to transforming growth factor-beta-induced hepatic fibrosis models, this model includes the native pathological and chronological steps of NAFLD which shows i) higher fibrotic phenotypes, ii) increased expression of fibrosis markers, and iii) efficient drug transport and metabolism. Taken together, the proposed platform will enable a better understanding of the mechanisms underlying fibrosis progression in NAFLD as well as the identification of new drugs for the different stages of NAFLD.
尽管在体外模拟肝脏疾病方面已经做出了相当大的努力，但仍然难以重现非酒精性脂肪性肝病 (NAFLD) 炎症和纤维化等晚期阶段的发病机制。在这里，开发了一种具有生物工程化多细胞肝微组织的肝芯片平台，由四种主要类型的肝脏细胞（肝细胞、内皮细胞、库普弗细胞和星状细胞）组成，以实现由 NAFLD 驱动的人类肝纤维化模型：i）肝细胞中的脂质积累（脂肪变性），ii）内皮细胞的新生血管形成，iii）激活的库普弗细胞的炎症（脂肪性肝炎），以及 iv）激活的星状细胞的细胞外基质沉积（纤维化）。在该模型中，在补充脂肪的肝芯片模型中存在星状细胞，显示出炎症反应和纤维化标志物的上调。与转化生长因子-β诱导的肝纤维化模型相比，该模型包括 NAFLD 的天然病理和时间步骤，其显示出 i）更高的纤维化表型，ii）纤维化标志物的表达增加，以及 iii）有效的药物转运和代谢。总之，该平台将有助于更好地了解 NAFLD 纤维化进展的机制，并鉴定用于 NAFLD 不同阶段的新药。
