Modulation of hepatocyte phenotype in vitro via chemomechanical tuning of polyelectrolyte multilayers.
Modulation of hepatocyte phenotype in vitro via chemomechanical tuning of polyelectrolyte multilayers.
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DOI：
10.1016/j.biomaterials.2008.10.055
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发表时间：
2009-02
期刊：
影响因子：
14
通讯作者：
Van Vliet, Krystyn J.
中科院分区：
文献类型：
--
作者：
Chen, Alice A.;Khetani, Salman R.;Lee, Sunyoung;Bhatia, Sangeeta N.;Van Vliet, Krystyn J.
越来越多的人认识到，由于细胞和组织功能是由化学机械刺激调节的，因此对这种刺激的精确控制将改善组织模型的功能。然而，由于固有的困难解耦这些线索所提出的细胞外物质，很少有研究探讨了独立的调制生化和机械刺激对持续的细胞过程的操纵。在这里，我们证明了机械顺应性和配体介绍合成，弱的质子交换膜（PEM）可以独立调整，影响的粘附和肝脏特异性功能的原代大鼠肝细胞在延长体外培养（两周）。这些合成PEM表现出弹性模量E范围超过200 kPa -< E < 142 MPa，比组织培养聚苯乙烯（E <2.5 GPa）的顺应性高出一千倍。这些PEM基质中最柔顺的促进了肝细胞粘附和球形形态。随后修饰的PEM与I型胶原蛋白和蛋白多糖核心蛋白聚糖没有改变底物的依从性，但提高了表面上的球体的保留和稳定的肝功能（白蛋白和尿素分泌，CYP 450解毒活性）。核心蛋白聚糖对肝功能表现出独特的顺应性介导作用，当存在于高度顺应性的基质上时，下调肝细胞表型，而当存在于越来越硬的基质上时，上调肝细胞功能。这些结果表明，肝脏模型的表型功能可以通过利用合成聚合物来研究和优化细胞-材料界面处的生物化学和机械线索的相互作用来调节。更广泛地说，这些结果表明了一种系统设计功能性组织模型的方法，该模型适用于药物筛选，基于细胞的治疗以及发育，生理学和疾病的基础研究。
It is increasingly appreciated that since cell and tissue functions are regulated by chemomechanical stimuli, precise control over such stimuli will improve the functionality of tissue models. However, due to the inherent difficulty in decoupling these cues as presented by extracellular materials, few studies have explored the independent modulation of biochemical and mechanical stimuli towards the manipulation of sustained cellular processes. Here, we demonstrate that both mechanical compliance and ligand presentation of synthetic, weak polyelectrolyte multilayers (PEMs) can be tuned independently to influence the adhesion and liver-specific functions of primary rat hepatocytes over extended in vitro culture (two weeks). These synthetic PEMs exhibited elastic moduli E ranging over 200 kPa -< E < 142 MPa, as much as one thousand-fold more compliant than tissue-culture polystyrene (E ∼ 2.5 GPa). The most compliant of these PEM substrata promoted hepatocyte adhesion and spheroidal morphology. Subsequent modification of PEMs with type I collagen and the proteoglycan decorin did not alter substrata compliance, but enhanced the retention of spheroids on surfaces and stabilized hepatic functions (albumin and urea secretion, CYP450 detoxification activity). Decorin exhibited unique compliance-mediated effects on hepatic functions, down-regulating the hepatocyte phenotype when presented on highly compliant substrata while up-regulating hepatocyte functions when presented on increasingly stiffer substrata. These results show that phenotypic functions of liver models can be modulated by leveraging synthetic polymers to study and optimize the interplay of biochemical and mechanical cues at the cell–material interface. More broadly, these results suggest an enabling approach for the systematic design of functional tissue models applied to drug screening, cell-based therapies and fundamental studies in development, physiology and disease.
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影响因子：
15
作者：
Kidambi, S;Lee, I;Chan, C
通讯作者：
Chan, C
DOI：
10.1083/jcb.200405004
发表时间：
2004-09-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Engler AJ;Griffin MA;Sen S;Bönnemann CG;Sweeney HL;Discher DE
通讯作者：
Discher DE
影响因子：
14
作者：
Peyton, Shelly R.;Raub, Christopher B.;Putnam, Andrew J.
通讯作者：
Putnam, Andrew J.
影响因子：
4.6
作者：
Kidambi, Srivatsan;Sheng, Lufang;Chan, Christina
通讯作者：
Chan, Christina
DOI：
10.1073/pnas.0702668104
发表时间：
2007-06-05
影响因子：
11.1
作者：
Lee, Sunyoung;Mandic, Jelena;Van Vliet, Krystyn J.
通讯作者：
Van Vliet, Krystyn J.