A human kidney and liver organoid-based multi-organ-on-a-chip model to study the therapeutic effects and biodistribution of mesenchymal stromal cell-derived extracellular vesicles

Vivian V T Nguyen, Shicheng Ye, Vasiliki Gkouzioti, Monique E van Wolferen, Fjodor Yousef Yengej, Dennis Melkert, Sofia Siti, Bart de Jong, Paul J Besseling, Bart Spee, Luc J W van der Laan, Reyk Horland, Marianne C Verhaar, Bas W M van Balkom*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Mesenchymal stromal cell (MSC)-derived small extracellular vesicles (sEVs) show therapeutic potential in multiple disease models, including kidney injury. Clinical translation of sEVs requires further preclinical and regulatory developments, including elucidation of the biodistribution and mode of action (MoA). Biodistribution can be determined using labelled sEVs in animal models which come with ethical concerns, are time-consuming and expensive, and may not well represent human physiology. We hypothesised that, based on developments in microfluidics and human organoid technology, in vitro multi-organ-on-a-chip (MOC) models allow us to study effects of sEVs in modelled human organs like kidney and liver in a semi-systemic manner. Human kidney- and liver organoids combined by microfluidic channels maintained physiological functions, and a kidney injury model was established using hydrogenperoxide. MSC-sEVs were isolated, and their size, density and potential contamination were analysed. These sEVs stimulated recovery of the renal epithelium after injury. Microscopic analysis shows increased accumulation of PKH67-labelled sEVs not only in injured kidney cells, but also in the unharmed liver organoids, compared to healthy control conditions. In conclusion, this new MOC model recapitulates therapeutic efficacy and biodistribution of MSC-sEVs as observed in animal models. Its human background allows for in-depth analysis of the MoA and identification of potential side effects.

Original languageEnglish
Article numbere12280
JournalJournal of Extracellular Vesicles
Volume11
Issue number11
DOIs
Publication statusPublished - Nov 2022

Bibliographical note

ACKNOWLEDGEMENTS
The BIQMIMETICS collaboration project is co-funded by the PPP Allowance made available by Health-Holland, Top Sector Life Sciences & Health, to the Association of Collaborating Health Foundations (SGF) to stimulate public-private partnerships and by ZonMw (grant numbers LSHM20046-SGF and 114025102), the Dutch Kidney Foundation (grant number 19OP+007) and the Dutch Society for the Replacement of Animal Testing (Stichting Proefdiervrij). The REDUCE MORE! Project was funded by Health∼Holland TKI-LSH, grant number LSHM18045 (all to B.W.M. v.B.). This research was also funded by the Dutch Heart Foundation CVON2014-11 ‘RECONNECT’ and ‘RECONNEXT’ (to M.C.V.), the RECONNECT YTP ‘CHIPS’ grant and the Utrecht University 3Rs stimulus fund project “MOOI!” (to B.W.M.v.B.) grants; the EU H2020 research and innovation programme under Marie S. Curie Cofund RESCUE grant agreement No 801540 (to M.C.V.) and the Gravitation Program ‘Materials Driven Regeneration’, funded by the Netherlands Organization for Scientific Research (024.003.013) (to M.C.V.), China Scholarship Council (CSC201808310180) to (S.Y.), and Medical Delta program (Regenerative Medicine 4D) (to L.J.W.v.d.L.). We thank Dr Prins of the Gene and Cell Therapy facility of the UMC Utrecht for providing the MSC, Dr Verstegen for providing human liver organoids, and Dr Gremmels and Dr Maass for their help with data anaysis. The authors acknowledge the support of the partners of ‘Regenerative Medicine Crossing Borders’ (RegMed XB), Powered by Health∼Holland, Top Sector Life Sciences & Health.

© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.

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