3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake

• Published in: Scientific reports 2022-09, Vol.12 (1), p.14997-14, Article 14997
• Main Authors: Aceves, Jeffrey O., Heja, Szilvia, Kobayashi, Kenichi, Robinson, Sanlin S., Miyoshi, Tomoya, Matsumoto, Takuya, Schäffers, Olivier J. M., Morizane, Ryuji, Lewis, Jennifer A.
• Format: Article
• Language: English
• Subjects: 631/532; 631/61; 639/166; Biological Transport - physiology; Epithelial Cells - metabolism; Humanities and Social Sciences; Kidney Tubules, Proximal - metabolism; Membrane Transport Proteins - metabolism; multidisciplinary; Organoids - metabolism; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-19293-3

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.