Differentiated kidney tubular cell-derived extracellular vesicles enhance maturation of tubuloids
Lindoso, Rafael Soares; Yousef Yengej, Fjodor A.; Voellmy, Franziska; Altelaar, Maarten; Mancheño Juncosa, Estela; Tsikari, Theano; Ammerlaan, Carola M.E.; Van Balkom, Bas W.M.; Rookmaaker, Maarten B.; Verhaar, Marianne C.; Masereeuw, Rosalinde
(2022) Journal of Nanobiotechnology, volume 20, issue 1
(Article)
Abstract
The prevalence of end-stage kidney disease (ESKD) is rapidly increasing with the need for regenerative therapies. Adult stem cell derived kidney tubuloids have the potential to functionally mimic the adult kidney tubule, but still lack the expression of important transport proteins needed for waste removal. Here, we investigated the potential
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of extracellular vesicles (EVs) obtained from matured kidney tubular epithelial cells to modulate in vitro tubuloids functional maturation. We focused on organic anion transporter 1 (OAT1), one of the most important proteins involved in endogenous waste excretion. First, we show that EVs from engineered proximal tubule cells increased the expression of several transcription factors and epithelial transporters, resulting in improved OAT1 transport capacity. Next, a more in-depth proteomic data analysis showed that EVs can trigger various biological pathways, including mesenchymal-to-epithelial transition, which is crucial in the tubular epithelial maturation. Moreover, we demonstrated that the combination of EVs and tubuloid-derived cells can be used as part of a bioartificial kidney to generate a tight polarized epithelial monolayer with formation of dense cilia structures. In conclusion, EVs from kidney tubular epithelial cells can phenotypically improve in vitro tubuloid maturation, thereby enhancing their potential as functional units in regenerative or renal replacement therapies. Graphical Abstract: [Figure not available: see fulltext.].
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Keywords: Bioengineered kidney tubules, Extracellular vesicles, Kidney tubuloids, Maturation, Organic anion transporter 1, Proteomics, Epithelial Cells, Kidney Tubules, Proximal/metabolism, Extracellular Vesicles/metabolism, Kidney/metabolism, Applied Microbiology and Biotechnology, Bioengineering, Molecular Medicine, Biomedical Engineering, Medicine (miscellaneous), Pharmaceutical Science, Journal Article
ISSN: 1477-3155
Publisher: BioMed Central Ltd.
Note: Funding Information: RSL, RM contributed to the conception and design of the project. KL RSL, FAYY, EMJ, TT, CMEA performed the experiments. RSL, FAYY, FV, MA, RM contributed to collection and/or assembly of proteomic data, data analysis and interpretation. RSL, RM contributed on the manuscript writing. All authors contributed to the revision and final approval of the manuscript. MV, RM were responsible for the financial support. All authors read and approved the final manuscript. Funding Information: We thank Hubrecht Organoid Technology (HUB), Utrecht, the Netherlands for providing the tubuloids. This work was supported by the partners of Regenerative Medicine Crossing Borders (Regmed XB). Powered by Health ~ Holland, Top Sector Life Sciences and Health; the Dutch Ministry of Education, Culture and Science; the Brazilian National Research Council (Grant Number 421916/2016-8); and the Carlos Filho Rio de Janeiro State Research Foundation (E-26/010.000981). Funding Information: We thank Hubrecht Organoid Technology (HUB), Utrecht, the Netherlands for providing the tubuloids. This work was supported by the partners of Regenerative Medicine Crossing Borders (Regmed XB). Powered by Health ~ Holland, Top Sector Life Sciences and Health; the Dutch Ministry of Education, Culture and Science; the Brazilian National Research Council (Grant Number 421916/2016-8); and the Carlos Filho Rio de Janeiro State Research Foundation (E-26/010.000981). Publisher Copyright: © 2022, The Author(s).
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