Tamara Meijer obtained her bachelor’s degree in Pharmaceutical Sciences at the Vrije Universiteit Amsterdam (VU) in 2017. As her interest in the field of molecular toxicology grew, she then followed the master’s programme in Drug Discovery and Safety with the specialisation Drug Disposition and Safety Assessment and graduated in 2019. In 2020, Tamara joined the Molecular and Computational Toxicology group at the VU as a PhD candidate under supervision of Dr. Anja Wilmes. Her work focuses on the optimisation and characterisation of proximal tubular-like cells (PTL) differentiated from human induced pluripotent stem cells (iPSC) with the application for personalised toxicity testing. Her goal is to develop a more stable and matured PTL model equipped with a comprehensive range of functional transport systems to study and predict drug-induced nephrotoxicity. Tamara’s research interests revolve around the development of advanced human renal in vitro models, with a particular interest in renal transport and nephrotoxicity, aiming to ultimately replace traditional animal models for predicting proximal tubule injury.
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Application of human iPSC-derived proximal tubular-like cells for transport studies
The proximal tubule is a component of the nephron that plays a crucial role in the reabsorption of water and filtered solutes as well as in the elimination of xenobiotics and waste products into the tubular lumen. As a result of these tubular reabsorption and secretion processes, the proximal tubule may be exposed to elevated intracellular levels of harmful substances, making it a particularly susceptible target for toxicity. Drug-induced nephrotoxicity can play a contributing role in the development of acute and chronic kidney diseases. Hence, it is essential to develop a human in vitro renal model that replicates the characteristics of the human kidney and its in vivo processes to study and predict drug-induced nephrotoxicity.
At the Vrije Universiteit Amsterdam, we have developed a protocol to differentiate human induced pluripotent stem cells (iPSC) into renal proximal tubular-like cells (PTL) [1,2]. These iPSC-derived PTL cells express proximal tubular-specific markers, including megalin, and form a polarised monolayer expressing tight junction proteins, including ZO-3. Furthermore, PTL display functional properties of proximal tubule cells, including parathyroid hormone response, megalin-mediated albumin uptake, and functional ABCB1 transport activity. Further characterisation of renal transport is vital to develop a suitable model for drug discovery and toxicity studies.
To study functional transport activity, the renal proximal tubular epithelial cell line RPTEC/TERT1 and iPSC-derived PTL were cultured on microporous growth supports, which allows a separation between apical and basolateral compartments. Tight barrier formation was confirmed by lucifer yellow retention and transepithelial electrical resistance (TEER) measurements. Functionality of organic cation transporters was measured using the fluorescent substrate ASP. In both models, ASP was taken up from the basolateral side and could be inhibited by basolateral application of the inhibitor quinidine. These results show the suitability of the iPSC-derived PTL model for studying organic cation transport.
 Differentiation and Subculturing of Renal Proximal Tubular-like Cells Derived from Human iPSC. Meijer T et al. https://doi.org/10.1002/cpz1.850
 Generation and characterization of iPSC-derived renal proximal tubule-like cells with extended stability. Chandrasekaran V et al. https://doi.org/10.1038/s41598-021-89550-4