Human proximal tubule epithelial cells cultured on hollow fibers: living membranes that actively transport organic cations

Jansen, Jitske; Napoli, Ilaria; Fedecostante, Michele; Schophuizen, Carolien M. S.; Chevtchik, Natalia Vladimirovna; Wilmer, Martijn J.; Asbeck, Alexander H. van; Croes, H.J.E.; Pertijs, Jeanne; Wetzels, Jack F.M.; Hilbrands, Luuk B.; Heuvel, Lambertus P. van den; Hoenderop, Joost G. J.; Stamatialis, Dimitrios; Masereeuw, Rosalinde

doi:10.1038/srep16702

Cited by 97 publications

(128 citation statements)

References 52 publications

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“…We recently successfully developed a three-dimensional bioengineered tubule system27, which we here optimized and determined monolayer integrity by analyzing paracellular diffusion prior to transport experiments. The transepithelial barrier function was measured using a custom-made flow system and inulin as a leakage marker labeled with fluorescein isothiocyanate (FITC), allowing live imaging of hollow fiber membranes (HFM).…”

Section: Resultsmentioning

confidence: 99%

Bioengineered kidney tubules efficiently excrete uremic toxins

Jansen

Fedecostante

Wilmer

et al. 2016

Sci Rep

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119

146

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The development of a biotechnological platform for the removal of waste products (e.g. uremic toxins), often bound to proteins in plasma, is a prerequisite to improve current treatment modalities for patients suffering from end stage renal disease (ESRD). Here, we present a newly designed bioengineered renal tubule capable of active uremic toxin secretion through the concerted action of essential renal transporters, viz. organic anion transporter-1 (OAT1), breast cancer resistance protein (BCRP) and multidrug resistance protein-4 (MRP4). Three-dimensional cell monolayer formation of human conditionally immortalized proximal tubule epithelial cells (ciPTEC) on biofunctionalized hollow fibers with maintained barrier function was demonstrated. Using a tailor made flow system, the secretory clearance of human serum albumin-bound uremic toxins, indoxyl sulfate and kynurenic acid, as well as albumin reabsorption across the renal tubule was confirmed. These functional bioengineered renal tubules are promising entities in renal replacement therapies and regenerative medicine, as well as in drug development programs.

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Section: Resultsmentioning

confidence: 99%

Bioengineered kidney tubules efficiently excrete uremic toxins

Jansen

Fedecostante

Wilmer

et al. 2016

Sci Rep

Self Cite

119

146

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“…A number of 3D tissue engineering models have been developed that attempt to mimic the proximal tubule structure and function ((8, 16, 19, 20), for reviews see (5, 21)). A number of these systems utilize a monolayer of cells adhered to a microporous membrane coated with a thin layer of an ECM protein component, often collagen IV or laminin.…”

Section: Discussionmentioning

confidence: 99%

Development of a microphysiological model of human kidney proximal tubule function

Weber

Chapron

et al. 2016

Kidney International

226

218

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The kidney proximal tubule is the primary site in the nephron for excretion of waste products through a combination of active uptake and secretory processes, and is also a primary target of drug-induced nephrotoxicity. Here, we describe the development and functional characterization of a 3-dimensional flow-directed human kidney proximal tubule microphysiological system. The system replicates the polarity of the proximal tubule, expresses appropriate marker proteins, exhibits biochemical and synthetic activities, as well as secretory and reabsorptive processes associated with proximal tubule function in vivo. This microphysiological system can serve as an ideal platform for ex vivo modeling of renal drug clearance and drug-induced nephrotoxicity. Additionally, this novel system can be used for preclinical screening of new chemical compounds prior to initiating human clinical trials.

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“…A 2015 study showed that conditionally immortalized proximal tubule epithelial cells could be seeded onto the exterior surface of hollow fibres coated with an extracellular matrix, creating biofunctionalized hollow fibres with a monolayer of cells 144 (FIG. 2e).…”

Section: Preclinical Screens Of Nephrotoxicitymentioning

confidence: 99%

Advances in predictive in vitro models of drug-induced nephrotoxicity

et al. 2018

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In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants.

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Human proximal tubule epithelial cells cultured on hollow fibers: living membranes that actively transport organic cations

Cited by 97 publications

References 52 publications

Bioengineered kidney tubules efficiently excrete uremic toxins

Bioengineered kidney tubules efficiently excrete uremic toxins

Development of a microphysiological model of human kidney proximal tubule function

Advances in predictive in vitro models of drug-induced nephrotoxicity

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