Human organoids: model systems for human biology and medicine

Abstract

The historical reliance of biological research on the use of animal models has sometimes made it challenging to address questions that are specific to the understanding of human biology and disease. But with the advent of human organoids - which are stem cell-derived 3D culture systems - it is now possible to re-create the architecture and physiology of human organs in remarkable detail. Human organoids provide unique opportunities for the study of human disease and complement animal models. Human organoids have been used to study infectious diseases, genetic disorders and cancers through the genetic engineering of human stem cells, as well as directly when organoids are generated from patient biopsy samples. This Review discusses the applications, advantages and disadvantages of human organoids as models of development and disease and outlines the challenges that have to be overcome for organoids to be able to substantially reduce the need for animal experiments.

Fig. 1. Comparison of organoids with other model systems.

The most common model organisms that are used in biomedical research are Caenorhabditis elegans, Drosophila melanogaster, Danio rerio and Mus musculus, along with patient-derived xenografts (PDX). These models, as well as 2D cell cultures and human organoids, are assessed here for their relative benefits and limitations. Relative scores are represented as being the best (dark green tick), good (light green tick), partly suitable (yellow tick) and not suitable (red cross).

Fig. 2. Process for the establishment of human PSC-derived and AdSC-derived organoids.

Pluripotent stem cell (PSC)-derived organoids are established following directed differentiation of PSCs, which requires a first step that involves germ-layer specification (endoderm, mesoderm or ectoderm), followed by induction and maturation, by culturing with specific growth and signalling factors to obtain the specific cell types that form the desired organ. Some PSC-derived organoids may contain cells from multiple germ layers to closely mimic the in vivo counterpart. Adult stem cell (AdSC)-derived organoid cultures require isolation of the tissue-specific stem cell population, which can then be embedded into an extracellular matrix (ECM) with defined, tissue-specific combinations of growth factors to allow propagation. AdSC-derived organoids, as shown here, are of epithelial origin and lack a mesenchymal or immune component unless it is added separately. Signalling components that are important for guided differentiation and niche function are shown; activated signalling pathways are shown in green, and inhibited ones in red. BMP, bone morphogenetic protein; EGF, epidermal growth factor; FGF, fibroblast growth factors; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; ROCK, RHO-associated protein kinase; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

Fig. 3. Reported human organoid systems by tissue of origin.

The chart provides information on the type (either pluripotent stem cell (PSC)-derived or adult stem cell (AdSC)-derived), biobanking status and use in disease modelling of the human organoid systems reported to date, summarized by organ.

Fig. 4. Potential applications of human organoids.

Two types of organoids are widely used, derived from either pluripotent stem cells (PSCs) or adult stem cells (AdSCs). Organoids can be used for (1) basic research, including studies of human biology aiming to understand developmental processes, responses to external stimuli and stress signals, cell-to-cell interactions and mechanisms of stem cell homeostasis; (2) biobanking, whereby samples obtained from patients can be used to generate patient-derived organoids and stored as a resource for future research; (3) disease modelling, to understand the mechanisms of human diseases such as infectious diseases, inheritable genetic disorders and cancer using various laboratory techniques, including omics and drug-screening analyses; and (4) precision medicine, in which patient-derived organoids can be used to predict response to drugs and as resources for regenerative medicine coupled with genetic engineering. ECM, extracellular matrix.