Drug testing evolved

Kyoto, Japan -- Developing advanced drug screening tools is crucial for the advancement of personalized medicine and the creation of more effective treatments. One organ receiving particular attention in this area is the kidney.

For example, the kidney's proximal tubules are essential for reabsorbing critical substances from the bloodstream before urine formation. However, traditional in vitro models have struggled to accurately replicate this, often failing to express key transport proteins like organic anion transporters -- OAT1/3 -- and organic cation transporter 2 -- OCT2.

A team at Kyoto University has now developed a human iPS cell-derived kidney organoid-based proximal tubule-on-chip -- OPTECs-on-Chip -- that mimics in vivo renal physiology more closely than ever before. This model exhibits enhanced expression and polarity of essential renal transporters, making it a powerful tool for assessing drug transport and nephrotoxicity.

"Our OPTECs-on-Chip demonstrates significant improvements in the expression and functionality of OAT1/3 and OCT2 transporters compared to previous models using immortalized cells," explains lead author Cheng Ma from KyotoU's Graduate School of Engineering.

This microphysiological system -- MPS -- utilizes two widely adopted differentiation protocols to derive kidney organoids, integrating them into a microfluidic system to form a proximal tubule model. This successfully maintains transporter expression, replicating the mechanisms of drug excretion in renal proximal tubules in vitro, mimicking the function of human epithelial tissue.

"Listening to the needs of pharmaceutical companies to develop the high-function kidney chip they require is the best way for us to integrate MPS technology into drug development," explains team leader Ryuji Yokokawa at KyotoU's Department of Micro Engineering.

"We demonstrated that our OPTECs-on-Chip not only assesses nephrotoxicity but also quantifies transcellular substrates transported specifically by OAT1, OAT3, and OCT2. This highlights the benefits of using iPS cell-derived cells and a microfluidic system to replicate in vivo cellular transport mechanisms," add co-author Minoru Takasato at the RIKEN Center for Biosystems Dynamics Research, together with Toshikazu Araoka of KyotoU's Center for iPS Cell Research and Application.

Yokokawa's team anticipates applying their MPS model as a screening tool for developing new drugs by evaluating the transport and nephrotoxicity of various membrane proteins.

"Our model has significant potential for drug screening and personalized medicine," notes Yokokawa. "By incorporating patient-derived stem cells, we can develop personalized assessments for renal transport and disease modeling."

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The paper "Efficient Proximal Tubule-on-Chip Model from hiPSC-Derived Kidney Organoids for Functional Analysis of Renal Transporters" appeared on 18 August 2024 in the journal iScience with doi: 10.1016/j.isci.2024.110760

About Kyoto University

Kyoto University is one of Japan and Asia's premier research institutions, founded in 1897 and responsible for producing numerous Nobel laureates and winners of other prestigious international prizes. A broad curriculum across the arts and sciences at undergraduate and graduate levels complements several research centers, facilities, and offices around Japan and the world. For more information, please see: http://www.kyoto-u.ac.jp/en