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 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.

A three-dimensional (3D) liver–kidney on a chip with a biomimicking circulating system for drug safety evaluation

“…In this paper, even though the 3D bio-printed liver lobule and renal proximal tubule recapitulate the structure and functions of normal tissues to some extent, still there is a gap between the engineered tissue and native ones, and the combination of organ on a chip with organoids, 46 which are mainly derived from stem cells and highly physiological relevant to human organs, could overcome the obstacles faced by each of them alone. Extensive studies on the proposed models should also be carried out to establish the standard for the transplantation from an organ-on a chip model to clinical applications.…”

Tubuloid culture enables long-term expansion of functional human kidney tubule epithelium from iPSC-derived organoids

“…Similar to tissue-derived tubuloids, the iPSCod tubuloid epithelium can be seeded not only on Transwells™, but also in more sophisticated organ-on-a-chip systems ( 33 ) to evaluate renal epithelial function in a physiological, tubular shape, with and without flow and with apical and basolateral access. These more advanced in vitro models will enable investigation of the interaction between different tissues (e.g., vasculature, interstitial cells) ( 60 , 61 ). Furthermore, application of the iPSCod tubuloid protocol on organoids from iPSCs with CRISPR-Cas9-induced knockouts or reporters will facilitate functional evaluation of the genetically modified tubular epithelium to study e.g., the function and membrane trafficking of specific (transport) proteins [e.g., NKCC2 ( 62 )] and induced diseases.…”

3D Printing Technologies in Personalized Medicine, Nanomedicines, and Biopharmaceuticals

“…However, 3D printing techniques, especially bioimprinting, can create 3D cell cultures and thus 3D models, also known, as organ-on-a-chip, that mimic human tissue much more closely and thus can mimic human response [ 10 , 11 ]. For example, the hepatic metabolism of drugs can be evaluated by printing well-defined hepatocyte architectures for testing, or similarly, the renal clearance can be reproduced by printing nephronlike structures [ 12 ]. Connecting these organ-on-chips in series can allow models to understand the overall permeability or clearance mimicking human data [ 13 , 14 ].…”