3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake.
3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake.
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DOI：
10.1038/s41598-022-19293-3
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发表时间：
2022-09-02
影响因子：
4.6
通讯作者：
Lewis, Jennifer A.
中科院分区：
文献类型：
--
作者：
Aceves, Jeffrey O.;Heja, Szilvia;Kobayashi, Kenichi;Robinson, Sanlin S.;Miyoshi, Tomoya;Matsumoto, Takuya;Schaffers, Olivier J. M.;Morizane, Ryuji;Lewis, Jennifer A.
药物筛选和疾病建模需要重现肾脏组织的三维器官芯片模型。在这里，我们报告了一种用于创建由从静态条件下成熟的肾类器官分离的上皮细胞组成的可灌注3D近端小管模型的方法。将这些类器官来源的近端小管上皮细胞（OPTEC）接种在完全嵌入细胞外基质的圆柱形通道中，在那里它们形成汇合的单层。将第二个可灌注通道放置在这些可重复使用的多路复用芯片内的每个近端小管附近，以模拟基底外侧药物转运和摄取。与基于永生化近端小管上皮细胞的对照芯片相比，我们的3D OPTEC芯片模型显示出有机阳离子（OCT 2）和有机阴离子（OAT 1/3）转运蛋白的显著上调，这导致药物摄取改善。因此，当暴露于已知的肾毒素、顺铂和马兜铃酸时，OPTEC小管表现出更高的标准化乳酸脱氢酶（LDH）释放，而添加OCT 2和OAT 1/3转运抑制剂后，这种释放会减少。我们的集成式多流体平台为药物筛选和疾病建模的个性化肾芯片模型铺平了道路。
Three-dimensional, organ-on-chip models that recapitulate kidney tissue are needed for drug screening and disease modeling. Here, we report a method for creating a perfusable 3D proximal tubule model composed of epithelial cells isolated from kidney organoids matured under static conditions. These organoid-derived proximal tubule epithelial cells (OPTECs) are seeded in cylindrical channels fully embedded within an extracellular matrix, where they form a confluent monolayer. A second perfusable channel is placed adjacent to each proximal tubule within these reusable multiplexed chips to mimic basolateral drug transport and uptake. Our 3D OPTEC-on-chip model exhibits significant upregulation of organic cation (OCT2) and organic anion (OAT1/3) transporters, which leads to improved drug uptake, compared to control chips based on immortalized proximal tubule epithelial cells. Hence, OPTEC tubules exhibit a higher normalized lactate dehydrogenase (LDH) release, when exposed to known nephrotoxins, cisplatin and aristolochic acid, which are diminished upon adding OCT2 and OAT1/3 transport inhibitors. Our integrated multifluidic platform paves the way for personalized kidney-on-chip models for drug screening and disease modeling.
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