A Multicompartment Human Kidney Proximal Tubule-on-a-Chip Replicates Cell Polarization–Dependent Cisplatin Toxicity

Nieskens, Tom T.G.; Persson, Mikael; Kelly, Edward J.; Sjögren, Anita

doi:10.1124/dmd.120.000098

Cited by 42 publications

(37 citation statements)

References 57 publications

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“…Clinical dosing regimens for cisplatin vary significantly in concentration (15 to 100 mg/m 2 ) and frequency (five consecutive days to once every three weeks) depending on cancer type and patient-specific toxicity risk 44 , 45 . The concentrations of cisplatin applied in this study are similar to peak blood concentrations observed during a typical infusion 44 , 45 and on the low end of typical concentrations used for in vitro studies 16 , 22 , 26 , 46 , 47 .…”

Section: Discussionsupporting

confidence: 67%

Evaluation of rapid transepithelial electrical resistance (TEER) measurement as a metric of kidney toxicity in a high-throughput microfluidic culture system

Shaughnessey

Kann

Azizgolshani

et al. 2022

Sci Rep

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Rapid non-invasive kidney-specific readouts are essential to maximizing the potential of microfluidic tissue culture platforms for drug-induced nephrotoxicity screening. Transepithelial electrical resistance (TEER) is a well-established technique, but it has yet to be evaluated as a metric of toxicity in a kidney proximal tubule (PT) model that recapitulates the high permeability of the native tissue and is also suitable for high-throughput screening. We utilized the PREDICT96 high-throughput microfluidic platform, which has rapid TEER measurement capability and multi-flow control, to evaluate the utility of TEER sensing for detecting cisplatin-induced toxicity in a human primary PT model under both mono- and co-culture conditions as well as two levels of fluid shear stress (FSS). Changes in TEER of PT-microvascular co-cultures followed a dose-dependent trend similar to that demonstrated by lactate dehydrogenase (LDH) cytotoxicity assays and were well-correlated with tight junction coverage after cisplatin exposure. Additionally, cisplatin-induced changes in TEER were detectable prior to increases in cell death in co-cultures. PT mono-cultures had a less differentiated phenotype and were not conducive to toxicity monitoring with TEER. The results of this study demonstrate that TEER has potential as a rapid, early, and label-free indicator of toxicity in microfluidic PT-microvascular co-culture models.

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Section: Discussionsupporting

confidence: 67%

Evaluation of rapid transepithelial electrical resistance (TEER) measurement as a metric of kidney toxicity in a high-throughput microfluidic culture system

Shaughnessey

Kann

Azizgolshani

et al. 2022

Sci Rep

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show abstract

“…For cisplatin, disruption of barrier integrity, lactate dehydrogenase release, and apoptosis were observed at lower levels of 25-100 mM when PTECs were cultured in a two-channel microfluidic device (Jang et al, 2013;Nieskens et al, 2020). By contrast, a bioprinted proximal tubule model comprised of fibroblasts, HUVEC cells, and primary human PTECs detected cisplatin toxicity at concentrations below 5 mM (King et al, 2017).…”

Section: E Applications Of 3d Human Kidney Modelsmentioning

confidence: 98%

Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development—Current State-of-the-Art and Future Perspectives

et al. 2022

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“…62 A recent study using human RPTEC cells cultured on a chip reported improved polarized tight junctions, cilia formation in the apical brush borders, and OCT2 transporter expression on the basolateral membrane as compared to 2D cultures. 63 The kidney-on-a-chip method has many advantages including extended life, biocompatibility, higher gas permeability and sensitivity, and low cost. The major advantage of the kidney-on-a-chip is the ability to apply a nephrotoxicant to either the apical or basolateral surface of the epithelium, which is not currently possible in a hiPSC-derived organoid.…”

Section: Kidney-on-a-chip Microfluidic Systemsmentioning

confidence: 99%

Tissue Culture Models of AKI: From Tubule Cells to Human Kidney Organoids

Bejoy

Qian

Woodard

2022

JASN

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Acute kidney injury (AKI) affects approximately 13.3 million people around the world each year, causing chronic kidney disease and/or mortality. The mammalian kidney cannot generate new nephrons after postnatal renal damage and regenerative therapies for AKI are not available. Human kidney tissue culture systems can complement animal models of AKI and/or address some of their limitations. Donor-derived somatic cells, such as renal tubule epithelial cells or cell lines (RPTEC/hTERT, ciPTEC, HK-2, Nki-2, and CIHP-1), have been used for decades to permit drug toxicity screening and studies into potential AKI mechanisms. However, tubule cell lines do not fully recapitulate tubular epithelial cell properties in situ when grown under classic tissue culture conditions. Improving tissue culture models of AKI would increase our understanding of the mechanisms, leading to new therapeutics. Human pluripotent stem cells (hPSCs) can be differentiated into kidney organoids and various renal cell types. Injury to human kidney organoids results in renal cell type crosstalk and upregulation of kidney injury biomarkers that are difficult to induce in primary tubule cell cultures. However, current protocols produce kidney organoids that aren't mature and contain off-target cell types. Promising bioengineering techniques, such as bioprinting and "kidney-on-a17 chip" methods, as applied to kidney nephrotoxicity modeling advantages and limitations are discussed. This review explores the mechanisms and detection of AKI in tissue culture, with an emphasis on bioengineered approaches such as human kidney organoid models.

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A Multicompartment Human Kidney Proximal Tubule-on-a-Chip Replicates Cell Polarization–Dependent Cisplatin Toxicity

Cited by 42 publications

References 57 publications

Evaluation of rapid transepithelial electrical resistance (TEER) measurement as a metric of kidney toxicity in a high-throughput microfluidic culture system

Evaluation of rapid transepithelial electrical resistance (TEER) measurement as a metric of kidney toxicity in a high-throughput microfluidic culture system

Organotypic and Microphysiological Human Tissue Models for Drug Discovery and Development—Current State-of-the-Art and Future Perspectives

Tissue Culture Models of AKI: From Tubule Cells to Human Kidney Organoids

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