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
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...
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2022-11-01
|
| Series: | Journal of Extracellular Vesicles |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jev2.12280 |
| _version_ | 1828124088021811200 |
|---|---|
| author | Vivian V. T. Nguyen Shicheng Ye Vasiliki Gkouzioti Monique E. vanWolferen Fjodor Yousef Yengej Dennis Melkert Sofia Siti Bart deJong Paul J. Besseling Bart Spee Luc J. W. van derLaan Reyk Horland Marianne C. Verhaar Bas W. M. vanBalkom |
| author_facet | Vivian V. T. Nguyen Shicheng Ye Vasiliki Gkouzioti Monique E. vanWolferen Fjodor Yousef Yengej Dennis Melkert Sofia Siti Bart deJong Paul J. Besseling Bart Spee Luc J. W. van derLaan Reyk Horland Marianne C. Verhaar Bas W. M. vanBalkom |
| author_sort | Vivian V. T. Nguyen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T15:02:22Z |
| format | Article |
| id | doaj.art-0bfe9b51c350456fa7665cedf2f8b71f |
| institution | Directory Open Access Journal |
| issn | 2001-3078 |
| language | English |
| last_indexed | 2024-04-11T15:02:22Z |
| publishDate | 2022-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Extracellular Vesicles |
| spelling | doaj.art-0bfe9b51c350456fa7665cedf2f8b71f2022-12-22T04:16:54ZengWileyJournal of Extracellular Vesicles2001-30782022-11-011111n/an/a10.1002/jev2.12280A 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 vesiclesVivian V. T. Nguyen0Shicheng Ye1Vasiliki Gkouzioti2Monique E. vanWolferen3Fjodor Yousef Yengej4Dennis Melkert5Sofia Siti6Bart deJong7Paul J. Besseling8Bart Spee9Luc J. W. van derLaan10Reyk Horland11Marianne C. Verhaar12Bas W. M. vanBalkom13Department of Nephrology and Hypertension UMC Utrecht Utrecht The NetherlandsDepartment of Clinical Sciences Faculty of Veterinary Medicine Utrecht University Utrecht The NetherlandsDepartment of Nephrology and Hypertension UMC Utrecht Utrecht The NetherlandsDepartment of Clinical Sciences Faculty of Veterinary Medicine Utrecht University Utrecht The NetherlandsDepartment of Nephrology and Hypertension UMC Utrecht Utrecht The NetherlandsDepartment of Nephrology and Hypertension UMC Utrecht Utrecht The NetherlandsDepartment of Nephrology and Hypertension UMC Utrecht Utrecht The NetherlandsDepartment of Nephrology and Hypertension UMC Utrecht Utrecht The NetherlandsDepartment of Nephrology and Hypertension UMC Utrecht Utrecht The NetherlandsDepartment of Clinical Sciences Faculty of Veterinary Medicine Utrecht University Utrecht The NetherlandsDept of Surgery, Erasmus MC Transplant Institute University Medical Center Rotterdam Rotterdam The NetherlandsTissUse GmbH Berlin GermanyDepartment of Nephrology and Hypertension UMC Utrecht Utrecht The NetherlandsDepartment of Nephrology and Hypertension UMC Utrecht Utrecht The NetherlandsAbstract 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.https://doi.org/10.1002/jev2.122803RsEV‐based therapeuticsmicro‐physiological modelsrenal injury |
| spellingShingle | Vivian V. T. Nguyen Shicheng Ye Vasiliki Gkouzioti Monique E. vanWolferen Fjodor Yousef Yengej Dennis Melkert Sofia Siti Bart deJong Paul J. Besseling Bart Spee Luc J. W. van derLaan Reyk Horland Marianne C. Verhaar Bas W. M. vanBalkom 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 Journal of Extracellular Vesicles 3Rs EV‐based therapeutics micro‐physiological models renal injury |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | 3Rs EV‐based therapeutics micro‐physiological models renal injury |
| url | https://doi.org/10.1002/jev2.12280 |
| work_keys_str_mv | AT vivianvtnguyen ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT shichengye ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT vasilikigkouzioti ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT moniqueevanwolferen ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT fjodoryousefyengej ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT dennismelkert ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT sofiasiti ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT bartdejong ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT pauljbesseling ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT bartspee ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT lucjwvanderlaan ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT reykhorland ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT mariannecverhaar ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT baswmvanbalkom ahumankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT vivianvtnguyen humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT shichengye humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT vasilikigkouzioti humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT moniqueevanwolferen humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT fjodoryousefyengej humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT dennismelkert humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT sofiasiti humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT bartdejong humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT pauljbesseling humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT bartspee humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT lucjwvanderlaan humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT reykhorland humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT mariannecverhaar humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles AT baswmvanbalkom humankidneyandliverorganoidbasedmultiorganonachipmodeltostudythetherapeuticeffectsandbiodistributionofmesenchymalstromalcellderivedextracellularvesicles |