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Substrate stiffness regulates primary hepatocyte functions

机译：衬底刚度调节原发性肝细胞功能

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摘要

Liver fibrosis occurs as a consequence of chronic injuries from viral infections, metabolic disorders, and alcohol abuse. Fibrotic liver microenvironment (LME) is characterized by excessive deposition and aberrant turnover of extracellular matrix proteins, which leads to increased tissue stiffness. Liver stiffness acts as a vital cue in the regulation of hepatic responses in both healthy and diseased states; however, the effect of varying stiffness on liver cells is not well understood. There is a critical need to engineer in vitro models that mimic the liver stiffness corresponding to various stages of disease progression in order to elucidate the role of individual cellular responses. Here we employed polydimethyl siloxane (PDMS) based substrates with tunable mechanical properties to investigate the effect of substrate stiffness on the behavior of primary rat hepatocytes. To recreate physiologically relevant stiffness, we designed soft substrates (2 kPa) to represent the healthy liver and stiff substrates (55 kPa) to represent the diseased liver. Tissue culture plate surface (TCPS) served as the control substrate. We observed that hepatocytes cultured on soft substrates displayed a more differentiated and functional phenotype for a longer duration as compared to stiff substrates and TCPS. We demonstrated that hepatocytes on soft substrates exhibited higher urea and albumin synthesis. Cytochrome P450 (CYP) activity, another critical marker of hepatocytes, displayed a strong dependence on substrate stiffness, wherein hepatocytes on soft substrates retained 2.7 fold higher CYP activity on day 7 in culture, as compared to TCPS. We further observed that an increase in stiffness induced downregulation of key drug transporter genes (NTCP, UGT1A1, and GSTM-2). In addition, we observed that the epithelial cell phenotype was better maintained on soft substrates as indicated by higher expression of hepatocyte nuclear factor 4 alpha, cytokeratin 18, and connexin 32. These results indicate that the substrate stiffness plays a significant role in modulating hepatocyte behavior. Our PDMS based liver model can be utilized to investigate the signaling pathways mediating the hepatocyte-LME communication to understand the progression of liver diseases.
机译：肝纤维化的发生是由于从病毒感染，代谢障碍，酗酒慢性损伤的结果。肝纤维化的微环境（LME）的特征在于过度沉积和细胞外基质蛋白的异常的营业额，这导致增加的组织硬度。肝脏硬度充当在健康和患病状态肝反应的调节至关重要的线索;然而，变化的刚度对肝细胞的作用还不是很清楚。还有关键的是需要在体外​​模型来设计模仿与疾病进展的不同阶段，以便在肝脏硬度阐明的个体细胞反应的作用。这里我们利用聚二甲基硅氧烷（PDMS）基的衬底具有可调的机械性能调查基板刚度对原代大鼠肝的行为的影响。要重新生理有关刚度，我们设计了软基片（2千帕），以代表健康的肝脏和僵硬的基材（55千帕）表示受损肝脏。组织培养板表面（TCPS）作为控制基板。我们观察到，相比于硬衬底和TCPS上软衬底培养肝细胞显示更长的持续时间的更分化和功能性表型。我们证实在底物柔软该肝细胞显示出较高的尿素和白蛋白的合成。细胞色素P450（CYP）活性，肝细胞的另一个重要标志，显示在衬底的刚度有很强的依赖性，其中，在软衬底的肝细胞在培养物中保留的2.7倍高的CYP活性在第7天，与TCPS。我们进一步观察到增加的刚度诱导的关键药物转运蛋白基因（NTCP，UGT1A1，和GSTM-2）下调。此外，我们观察到上皮细胞表型更好的软衬底保持由肝细胞核因子4的α的更高表达所指示的，细胞角蛋白18，和连接蛋白32这些结果表明，基片的刚度在调节肝细胞行为显著作用。我们的基于PDMS肝模型可用于调查信号转导途径介导的肝细胞LME通信了解肝脏疾病的进展。

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  • 来源
    《RSC Advances》 |2015年第99期|共11页
  • 作者

    Natarajan Vaishaali; Berglund Eric J.; Chen Dorothy X.; Kidambi Srivatsan;

  • 作者单位

    Univ Nebraska Dept Chem &

    Biomol Engn Lincoln NE 68588 USA;

    Univ Nebraska Dept Chem &

    Biomol Engn Lincoln NE 68588 USA;

    Univ Nebraska Dept Chem &

    Biomol Engn Lincoln NE 68588 USA;

    Univ Nebraska Dept Chem &

    Biomol Engn Lincoln NE 68588 USA;

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  • 正文语种 eng
  • 中图分类 化学;
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