Safety evaluation of conditionally immortalized cells for renal replacement therapy

Mihajlovic, Milos; Hariri, Sam; Westphal, Koen C.G.; Janssen, Manoe J.; Oost, Miriam J; Bongiovanni, Laura; Heuvel, Lambertus P. van den; Bruin, Alain de; Hilbrands, Luuk B.; Masereeuw, Rosalinde

doi:10.18632/oncotarget.27152

Cited by 9 publications

(10 citation statements)

References 71 publications

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“…In addition, after an inflammatory insult (exposure to lipopolysaccharide and IFN-γ), we found increased, polarized secretion of pro-inflammatory cytokines into the extra luminal (filtrate) space compared with the intraluminal (blood) space, indicating the immunological safety of the system 103 . We also showed that ciPTECs do not exhibit tumorigenic and/or oncogenic potential in vitro or in vivo 106 . Current challenges for this system are upscaling the BAK to a clinically relevant size and developing a production process that would make the device affordable for maintenance dialysis.…”

Section: Bioartificial Kidney Systemssupporting

confidence: 52%

Portable, wearable and implantable artificial kidney systems: needs, opportunities and challenges

Ramada,

de Vries,

Vollenbroek

et al. 2023

Nat Rev Nephrol

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Haemodialysis is life sustaining but expensive, provides limited removal of uraemic solutes, is associated with poor patient quality of life and has a large carbon footprint. Innovative dialysis technologies such as portable, wearable and implantable artificial kidney systems are being developed with the aim of addressing these issues and improving patient care. An important challenge for these technologies is the need for continuous regeneration of a small volume of dialysate. Dialysate recycling systems based on sorbents have great potential for such regeneration. Novel dialysis membranes composed of polymeric or inorganic materials are being developed to improve the removal of a broad range of uraemic toxins, with low levels of membrane fouling compared with currently available synthetic membranes. To achieve more complete therapy and provide important biological functions, these novel membranes could be combined with bioartificial kidneys, which consist of artificial membranes combined with kidney cells. Implementation of these systems will require robust cell sourcing; cell culture facilities annexed to dialysis centres; large-scale, low-cost production; and quality control measures. These challenges are not trivial, and global initiatives involving all relevant stakeholders, including academics, industrialists, medical professionals and patients with kidney disease, are required to achieve important technological breakthroughs.

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Section: Bioartificial Kidney Systemssupporting

confidence: 52%

Portable, wearable and implantable artificial kidney systems: needs, opportunities and challenges

Ramada,

de Vries,

Vollenbroek

et al. 2023

Nat Rev Nephrol

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“…Silencing LaminB1 immediately leads to inhibition of proliferation and the induction of senescence ( Shimi et al, 2011 ). Our previous research regarding cell cycle analysis of ciPTEC-OAT1 at permissive and non-permissive temperatures ( Mihajlovic et al, 2019 ) has shown that ciPTEC-OAT1 when cultured at 37°C for 1 or 7 d exhibits significantly reduced proliferation (less cells in the S phase) and an increased number of cells in the G0/G1 phase of the cell cycle, indicating halted proliferation at a non-permissive temperature. This is in line with our current results.…”

Section: Discussionmentioning

confidence: 99%

A Human Conditionally Immortalized Proximal Tubule Epithelial Cell Line as a Novel Model for Studying Senescence and Response to Senolytics

et al. 2022

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Accumulating evidence suggests that senescence of kidney tubule epithelial cells leads to fibrosis. These cells secrete senescence-associated secretory phenotype (SASP) factors that are involved in diverse signaling pathways, influencing kidney fibrosis. Here, we investigated whether our previously established conditionally immortalized proximal tubule epithelial cell line overexpressing the organic anion transporter 1 (ciPTEC-OAT1) can be used as a valid in vitro model to study kidney senescence and senolytics response. CiPTEC-OAT1 proliferates rapidly at 33°C and exhibits a “senescence-like” arrest at 37°C, most likely due to suppression of SV40T expression and subsequent reactivation of the p53 and Rb pathways. To understand how permissive (33°C) and non-permissive (37°C) temperatures of the cell culture affect the senescence phenotype, we cultured ciPTEC-OAT1 for up to 12 days and evaluated the apoptosis and SASP markers. Day 0 in both groups is considered as the non-senescence group (control). Further, the potential of navitoclax, dasatinib, quercetin, and the combination of the latter two to clear senescent cells was evaluated. Maturation of ciPTEC-OAT1 at non-permissive temperature affected mRNA and protein levels of senescence markers. A remarkable upregulation in p21 gene expression was found in the non-permissive temperature group, whereas expression of Lamin B1 decreased significantly. SASP factors, including PAI-1A, IL-1β, CTGF, and IL-6 were upregulated, but no significant difference in Bcl-2 and Bcl-xl were found in the non-permissive temperature group. After culturing ciPTEC-OAT1 up to 12 days, cells in the non-permissive temperature group showed an upregulation in the apoptosis-associated proteins Bcl-2, BID, and Bax, and a downregulation in Mcl-1, Bad, Bak, and Bim at various time points. Further, Bcl-xl, Puma, Caspase 3, Caspase 7, and Caspase 9 showed initial upregulations followed by downregulations at later time points. The loss of Lamin B1, upregulation of SA-β-gal expression and increase in its activity, upregulation of p21 levels and downregulation of p53, along with the upregulation of SASP factors, confirmed that maturation at 37°C promotes senescence features. Finally, the senolytics response was evaluated by testing cell viability following exposure to senolytics, to which cells appeared dose-dependently sensitive. Navitoclax was most effective in eliminating senescent cells. In conclusion, culturing ciPTEC-OAT1 at 37°C induces a senescence phenotype characterized by increased expression of cell cycle arrest and anti-apoptosis markers, SASP factors, and responsiveness to senolytics treatment. Therefore, ciPTEC-OAT1 represents a valid model for studying kidney senescence by simply adjusting culture conditions.

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“…Baseline levels of injury marker KIM-1 were 20-fold higher in immortalized cells compared to primary cells (Sakolish et al 2018). In addition, immortalized cell lines often show chromosomal instability, as demonstrated for ciPTEC-OAT1 without affecting cell function or posing a tumorigenic risk (Mihajlovic et al 2019), and represent a homogenous population instead of a genetic diverse population. Therefore, new sources for kidney cells emerged in the past decade.…”

Section: Perspectives In In Vitro Models' Developmentmentioning

confidence: 97%

Kidney-based in vitro models for drug-induced toxicity testing

et al. 2019

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The kidney is frequently involved in adverse effects caused by exposure to foreign compounds, including drugs. An early prediction of those effects is crucial for allowing novel, safe drugs entering the market. Yet, in current pharmacotherapy, drug-induced nephrotoxicity accounts for up to 25% of the reported serious adverse effects, of which one-third is attributed to antimicrobials use. Adverse drug effects can be due to direct toxicity, for instance as a result of kidney-specific determinants, or indirectly by, e.g., vascular effects or crystals deposition. Currently used in vitro assays do not adequately predict in vivo observed effects, predominantly due to an inadequate preservation of the organs' microenvironment in the models applied. The kidney is highly complex, composed of a filter unit and a tubular segment, together containing over 20 different cell types. The tubular epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functioning and response to environmental signals. Cell polarity is dependent on communication between cells, which includes paracrine and autocrine signals, as well as biomechanic and chemotactic processes. These processes all influence kidney cell proliferation, migration, and differentiation. For drug disposition studies, this microenvironment is essential for prediction of toxic responses. This review provides an overview of drug-induced injuries to the kidney, details on relevant and translational biomarkers, and advances in 3D cultures of human renal cells, including organoids and kidney-on-a-chip platforms.

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Safety evaluation of conditionally immortalized cells for renal replacement therapy

Cited by 9 publications

References 71 publications

Portable, wearable and implantable artificial kidney systems: needs, opportunities and challenges

Portable, wearable and implantable artificial kidney systems: needs, opportunities and challenges

A Human Conditionally Immortalized Proximal Tubule Epithelial Cell Line as a Novel Model for Studying Senescence and Response to Senolytics

Kidney-based in vitro models for drug-induced toxicity testing

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