Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112-5820, USA.
Biomaterials. 2012 Jun;33(18):4700-11. doi: 10.1016/j.biomaterials.2012.02.063. Epub 2012 Mar 22.
Cell-cell and cell-matrix interactions control cell phenotypes and functions in vivo. Maintaining these interactions in vitro is essential to both produce and retain cultured cell fidelity to normal phenotype and function in the context of drug efficacy and toxicity screening. Two-dimensional (2-D) cultures on culture plastics rarely recapitulate any of these desired conditions. Three dimensional (3-D) culture systems provide a critical junction between traditional, yet often irrelevant, in vitro cell cultures and more accurate, yet costly, in vivo models. This study describes development of an organoid-derived 3-D culture of kidney proximal tubules (PTs) that maintains native cellular interactions in tissue context, regulating phenotypic stability of primary cells in vitro for up to 6 weeks. Furthermore, unlike immortalized cells on plastic, these 3-D organoid kidney cultures provide a more physiologically-relevant response to nephrotoxic agent exposure, with production of toxicity biomarkers found in vivo. This biomimetic primary kidney model has broad applicability to high-throughput drug and biomarker nephrotoxicity screening, as well as more mechanistic drug toxicology, pharmacology, and metabolism studies.
细胞-细胞和细胞-基质相互作用控制着体内细胞的表型和功能。在体外维持这些相互作用对于产生和保留培养细胞的正常表型和功能的保真度至关重要，特别是在药物功效和毒性筛选方面。在培养塑料上的二维（2-D）培养很少能重现所有这些理想条件。三维（3-D）培养系统在传统的、但往往不相关的体外细胞培养和更准确的、但成本更高的体内模型之间提供了一个关键的连接点。本研究描述了一种来源于肾近端小管（PT）的器官样 3-D 培养物的开发，该培养物在组织环境中保持了天然的细胞相互作用，调节了原代细胞在体外的表型稳定性，最长可达 6 周。此外，与塑料上的永生化细胞不同，这些 3-D 器官样肾培养物对肾毒性剂暴露的反应更接近生理，产生了体内发现的毒性生物标志物。这种仿生原代肾模型具有广泛的适用性，可用于高通量药物和生物标志物肾毒性筛选，以及更具机制的药物毒理学、药理学和代谢研究。
