3D multicellular systems in disease modelling: From organoids to organ-on-chip

Abstract

Cell-cell interactions underlay organ formation and function during homeostasis. Changes in communication between cells and their surrounding microenvironment are a feature of numerous human diseases, including metabolic disease and neurological disorders. In the past decade, cross-disciplinary research has been conducted to engineer novel synthetic multicellular organ systems in 3D, including organoids, assembloids, and organ-on-chip models. These model systems, composed of distinct cell types, satisfy the need for a better understanding of complex biological interactions and mechanisms underpinning diseases. In this review, we discuss the emerging field of building 3D multicellular systems and their application for modelling the cellular interactions at play in diseases. We report recent experimental and computational approaches for capturing cell-cell interactions as well as progress in bioengineering approaches for recapitulating these complexities ex vivo. Finally, we explore the value of developing such multicellular systems for modelling metabolic, intestinal, and neurological disorders as major examples of multisystemic diseases, we discuss the advantages and disadvantages of the different approaches and provide some recommendations for further advancing the field.

Organoids are not organs: Sources of variation and misinformation in organoid biology

“…The proof of concept of this has been shown, for example, in studies in which intestinal epithelial cells originally cultured as organoids were seeded in a microphysiological device recapitulating the structure of the small intestine provided the basis for differentiation into even rare cell types ( Nikolaev et al., 2020 ). The aggregation of organoids representing different tissues—assembloids—is also enabling much more complex human models ( Goldrick et al., 2023 ; Miura et al., 2022 ). The generation of combination tissue models in which TSC- and PSC-derived cells are combined is also an evolving area of activity.…”

Stem cell-derived intestinal organoids: a novel modality for IBD

“…The cell sources of intestinal organoids include ISCs from intestinal crypts, PSCs, embryonic SCs (ESCs), and iPSCs [ 18 , 56 ]. In 2009, Hans et al reported for the first time in Nature the formation of murine intestinal organoids with intestinal epithelial crypt structure using Lgr5(+) ISCs from mouse intestinal crypt in vitro [ 6 ].…”

The Evolution of Technology‐Driven In Vitro Models for Neurodegenerative Diseases

“…[ 24 ] Contrarily to spheroids that are usually free‐floating, organoids are often maintained within an ECM structure that offers mechanical support to the cells. [ 25 ] Thanks to these characteristics, organoids can be exploited as an effective platform not only to evaluate drug response and efficiency, but also to develop personalized medicine approaches [ 26 ] or study brain aging phenomena in vitro. [ 27 ] A variety of NDD models have been developed using spheroid or organoid technologies and were able to secure accurate regulation over cell positioning and ECM material composition.…”

“…Despite all these advantages, they are still at an embryonic phase and massive efforts need to be directed toward the optimization of organoid generation. In fact, to achieve these goals, several limitations have to be overcome, [ 25 , 26 , 27 , 28 ] including: i) lack of standardization of complex protocols; ii) definition of growth factors and metabolites necessary to prolong the lifespan and self‐renewal of the organoids; iii) high costs and time consumption; iv) lack of vascularization, oxygen, and nutrient diffusion in the center of the organoid; and v) difficulties in replicating age‐related diseases.…”