A microfluidic bioreactor with integrated transepithelial electrical resistance (TEER) measurement electrodes for evaluation of renal epithelial cells

Ferrell, Nicholas; Desai, Ravi; Fleischman, Aaron J.; Roy, Shuvo; Humes, H. David; Fissell, William H.

doi:10.1002/bit.22835

Cited by 134 publications

(122 citation statements)

References 45 publications

(51 reference statements)

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“…[27][28][29] Similar results were obtained from three independent experiments. Different fractions of cells were analyzed: (1) the "unsorted" fraction, representing the trypsinized and replated EBs, and thus In KSP + cells fraction and mouse primary tubular cells TEER measurement was similar ( Figure 3).…”

Section: Transepithelial Electrical Resistance Measurement Confirms Tsupporting

confidence: 85%

Renal Cells from Spermatogonial Germline Stem Cells Protect against Kidney Injury

Chiara

Fagoonee

Bruno

et al. 2014

Journal of the American Society of Nephrology

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Spermatogonial stem cells reside in specific niches within seminiferous tubules and continuously generate differentiating daughter cells for production of spermatozoa. Although spermatogonial stem cells are unipotent, these cells are able to spontaneously convert to germline cell-derived pluripotent stem cells (GPSCs) in vitro. GPSCs have many properties of embryonic stem cells and are highly plastic, but their therapeutic potential in tissue regeneration has not been fully explored. Using a novel renal epithelial differentiation protocol, we obtained GPSC-derived tubular-like cells (GTCs) that were functional in vitro, as demonstrated through transepithelial electrical resistance analysis. In mice, GTCs injected after ischemic renal injury homed to the renal parenchyma, and GTC-treated mice showed reduced renal oxidative stress, tubular apoptosis, and cortical damage and upregulated tubular expression of the antioxidant enzyme hemeoxygenase-1. Six weeks after ischemic injury, kidneys of GTC-treated mice had less fibrosis and inflammatory infiltrate than kidneys of vehicle-treated mice. In conclusion, we show that GPSCs can be differentiated into functionally active renal tubular-like cells that therapeutically prevent chronic ischemic damage in vivo, introducing the potential utility of GPSCs in regenerative cell therapy. AKI is a common complication characterized by a rapid reduction in kidney function that results in failure to maintain fluid. AKI is a potentially reversible disease. However, some patients recover incompletely from AKI, and these patients either continue undergoing dialysis or progress to CKD. Moreover, development of CKD can lead to ESRD. One of the main causes of AKI is ischemia/reperfusion injury (IRI). 1 IRI is a pathologic condition characterized by an initial restriction of blood supply followed by the subsequent restoration of perfusion and concomitant reoxygenation that is frequently associated with an exacerbation of tissue injury and a strong inflammatory response. 2 The cells within the renal parenchyma that suffer the most damage upon kidney ischemia are the proximal tubular cells. This is likely due to the presence of a brush border on these cells that increases cell surface area and sensitizes them to damage.The recent discovery of the ability to reprogram adult cells into pluripotent stem cells (iPSCs) has profound therapeutic implications for diseases involving tissue damage and degeneration. Derivation of pluripotent stem cells from an adult source avoids several ethical concerns of obtaining such cells from embryos. However, efficient generation of iPSCs typically requires transduction of cells with reprogramming factors, including potent proto-oncogenes that can limit their therapeutic uses. 3 The existence of inherent epigenetic differences between iPSCs and regular embryonic stem cells (ESCs) can adversely affect iPSCs functionality. 4,5

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Section: Transepithelial Electrical Resistance Measurement Confirms Tsupporting

confidence: 85%

Renal Cells from Spermatogonial Germline Stem Cells Protect against Kidney Injury

Chiara

Fagoonee

Bruno

et al. 2014

Journal of the American Society of Nephrology

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“…However, the insertion of these electrodes lead to the contamination of the microfluidic platform, thus limiting its employment as a true in-line sensing system, to say nothing of the issues related to irreproducibility of chopstick electrode readings 32 . In literature, other kidney-on-a-chip type of device have been already reported 10,61,62 , but except from the work of Ferrell et al 62 their integration with in-line label-free sensors was not explored yet. For the latter, however, manual positioning of Ag/AgCl and silver wires in the microfluidics was needed to locate the recording electrode inside the bioreactor.…”

Section: Discussionmentioning

confidence: 99%

Organic transistor platform with integrated microfluidics for in-line multi-parametric in vitro cell monitoring

et al. 2017

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Future drug discovery and toxicology testing could benefit significantly from more predictive and multi-parametric readouts from in vitro models. Despite the recent advances in the field of microfluidics, and more recently organ-on-a-chip technology, there is still a high demand for real-time monitoring systems that can be readily embedded with microfluidics. In addition, multi-parametric monitoring is essential to improve the predictive quality of the data used to inform clinical studies that follow. Here we present a microfluidic platform integrated with in-line electronic sensors based on the organic electrochemical transistor. Our goals are twofold, first to generate a platform to host cells in a more physiologically relevant environment (using physiologically relevant fluid shear stress (FSS)) and second to show efficient integration of multiple different methods for assessing cell morphology, differentiation, and integrity. These include optical imaging, impedance monitoring, metabolite sensing, and a wound-healing assay. We illustrate the versatility of this multi-parametric monitoring in giving us increased confidence to validate the improved differentiation of cells toward a physiological profile under FSS, thus yielding more accurate data when used to assess the effect of drugs or toxins. Overall, this platform will enable high-content screening for in vitro drug discovery and toxicology testing and bridges the existing gap in the integration of in-line sensors in microfluidic devices.

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“…To determine whether binding sites for Gal-7 are limited, GST-Gal-7 binding and colocalization with the cilia-specific intracellular protein acetylated tubulin (20) were compared before and after endogenous Gal-7 was released by overnight pretreatment of the cells with 100 mM lactose in the culture medium. We observed similar levels of staining and perfect colocalization of GST-Gal-7 and acetylated tubulin regardless of whether endogenous Gal-7 was present, indicating that the ligands for Gal-7 binding are not limiting (Fig.…”

Section: Gal-7 Localizes To the Primary Cilia Of Polarized Mdck Cellsmentioning

confidence: 99%

Galectin-7 modulates the length of the primary cilia and wound repair in polarized kidney epithelial cells

Rondanino

Poland

Kinlough

et al. 2011

American Journal of Physiology-Renal Physiology

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Galectins (Gal) are β-galactoside-binding proteins that function in epithelial development and homeostasis. An overlapping role for Gal-3 and Gal-7 in wound repair was reported in stratified epithelia. Although Gal-7 was thought absent in simple epithelia, it was reported in a proteomic analysis of cilia isolated from cultured human airway, and we recently identified Gal-7 transcripts in Madin-Darby canine kidney (MDCK) cells (Poland PA, Rondanino C, Kinlough CL, Heimburg-Molinaro J, Arthur CM, Stowell SR, Smith DF, Hughey RP. J Biol Chem 286: 6780–6790, 2011). We now report that Gal-7 is localized exclusively on the primary cilium of MDCK, LLC-PK1 (pig kidney), and mpkCCDc14 (mouse kidney) cells as well as on cilia in the rat renal proximal tubule. Gal-7 is also present on most cilia of multiciliated cells in human airway epithelia primary cultures. Interestingly, exogenous glutathione S-transferase (GST)-Gal-7 bound the MDCK apical plasma membrane as well as the cilium, while the lectin Ulex europeaus agglutinin, with glycan preferences similar to Gal-7, bound the basolateral plasma membrane as well as the cilium. In pull-down assays, β1-integrin isolated from either the basolateral or apical/cilia membranes of MDCK cells was similarly bound by GST-Gal-7. Selective localization of Gal-7 to cilia despite the presence of binding sites on all cell surfaces suggests that intracellular Gal-7 is specifically delivered to cilia rather than simply binding to surface glycoconjugates after generalized secretion. Moreover, depletion of Gal-7 using tetracycline-induced short-hairpin RNA in mpkCCDc14 cells significantly reduced cilia length and slowed wound healing in a scratch assay. We conclude that Gal-7 is selectively targeted to cilia and plays a key role in surface stabilization of glycoconjugates responsible for integrating cilia function with epithelial repair.

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A microfluidic bioreactor with integrated transepithelial electrical resistance (TEER) measurement electrodes for evaluation of renal epithelial cells

Cited by 134 publications

References 45 publications

Renal Cells from Spermatogonial Germline Stem Cells Protect against Kidney Injury

Renal Cells from Spermatogonial Germline Stem Cells Protect against Kidney Injury

Organic transistor platform with integrated microfluidics for in-line multi-parametric in vitro cell monitoring

Galectin-7 modulates the length of the primary cilia and wound repair in polarized kidney epithelial cells

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