Abstract
Nephropathic cystinosis is a rare and severe disease caused by disruptions in the CTNS gene. Cystinosis is characterized by lysosomal cystine accumulation, vesicle trafficking impairment, oxidative stress, and apoptosis. Additionally, cystinotic patients exhibit weakening and leakage of the proximal tubular segment of the nephrons, leading to renal Fanconi syndrome and kidney failure early in life. Current in vitro cystinotic models cannot recapitulate all clinical features of the disease which limits their translational value. Therefore, the development of novel, complex in vitro models that better mimic the disease and exhibit characteristics not compatible with 2-dimensional cell culture is of crucial importance for novel therapies development. In this study, we developed a 3-dimensional bioengineered model of nephropathic cystinosis by culturing conditionally immortalized proximal tubule epithelial cells (ciPTECs) on hollow fiber membranes (HFM). Cystinotic kidney tubules showed lysosomal cystine accumulation, increased autophagy and vesicle trafficking deterioration, the impairment of several metabolic pathways, and the disruption of the epithelial monolayer tightness as compared to control kidney tubules. In particular, the loss of monolayer organization and leakage could be mimicked with the use of the cystinotic kidney tubules, which has not been possible before, using the standard 2-dimensional cell culture. Overall, bioengineered cystinotic kidney tubules recapitulate better the nephropathic phenotype at a molecular, structural, and functional proximal tubule level compared to 2-dimensional cell cultures.
Original language | English |
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Article number | 177 |
Pages (from-to) | 1-18 |
Journal | Cells |
Volume | 11 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Jan 2022 |
Bibliographical note
Funding Information:Funding: This research received funding from the IMAGEN project, which is co‐funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate pub‐ lic–private partnerships (IMplementation of Advancements in GENetic Kidney Disease, LSHM20009; E.S.G., M.J.J. and R.M.).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Keywords
- 3‐ dimensional models
- Autophagy
- Hollow fiber membrane
- Lysosomal storage disease
- Nephropathic cystinosis