Towards Multi-Organoid Systems for Drug Screening Applications

Abstract

A low percentage of novel drug candidates succeed and reach the end of the drug discovery pipeline, mainly due to poor initial screening and assessment of the effects of the drug and its metabolites over various tissues in the human body. For that, emerging technologies involving the production of organoids from human pluripotent stem cells (hPSCs) and the use of organ-on-a-chip devices are showing great promise for developing a more reliable, rapid and cost-effective drug discovery process when compared with the current use of animal models. In particular, the possibility of virtually obtaining any type of cell within the human body, in combination with the ability to create patient-specific tissues using human induced pluripotent stem cells (hiPSCs), broadens the horizons in the fields of drug discovery and personalized medicine. In this review, we address the current progress and challenges related to the process of obtaining organoids from different cell lineages emerging from hPSCs, as well as how to create devices that will allow a precise examination of the in vitro effects generated by potential drugs in different organ systems.

Keywords: body-on-a-chip; drug discovery; human pluripotent stem cells; multi-organ systems; organoids; personalized medicine.

Figure 1

From human pluripotent stem cells (hPSCs) to multi-organoid platforms. The use of hiPSCs brings the possibility to generate patient- and disease-specific organoids that will contribute to advances in the fields of personalized medicine and disease modeling. These cells can be first differentiated into lineage specific progenitor cells that in turn will be able to generate organoids representing the complex interactions that exist between cells in vivo. The integration of these organoids within a culture/analysis chip provides the necessary tools to analyze different parameters that may be altered in specific conditions, such as exposure to a drug. Moreover, a chip that contains different types of organoids fulfills the necessity of analyzing the systems as a whole, considering the different interactions between organoids and providing an integrated response to a specific stimulus.

Figure 2

Influence of hPSC aggregate size on pluripotency maintenance, lineage specification and inner diffusion rates. The initial diameter of hPSC aggregates will determine the efficiency of induction into a specific lineage, as well as influencing the expansion capability. Furthermore, as aggregates increase in size, they are subjected to diffusional limitations that may cause necrotic zones in the inner part of the aggregates.

Figure 3

Signaling pathways and morphogens that control lineage specification from hPSCs. hPSCs can be differentiated towards the different lineages by BMP and Activin/Nodal inhibition (Neuroectoderm), Wnt signaling modulation (mesoderm and mesendoderm), and further differentiated to definitive endoderm by Activin A activation to generate pancreatic and hepatic lineage-derived cells. BMP: bone morphogenic protein, FGF: fibroblast growth factor, HGF: hepatoblast growth factor.