Because of their differentiation potential, pluripotent stem cells can generate virtually any cell type and, as such, can be used to model development and disease and even hold the promise of providing cell-replacement therapies. Recently, structures resembling whole organs, termed organoids, have been generated from stem cells through the development of three-dimensional culture systems.

Organoids are derived from pluripotent stem cells or isolated organ progenitors that differentiate to form an organlike tissue exhibiting multiple cell types that self-organize to form a structure not unlike the organ in vivo. This technology builds upon a foundation of stem cell technologies, as well as classical developmental biology and cell-mixing experiments. These studies illustrated two key events in structural organization during organogenesis: cell sorting out and spatially restricted lineage commitment. Both of these processes are recapitulated in organoids, which self-assemble to form the cellular organization of the organ itself.

Organoid generation and therapeutic potential. Organoids can be derived for a number of organs from human pluripotent stem cells (PSCs). Like organogenesis in vivo, organoids self-organize through both cell sorting out and spatially restricted lineage commitment of precursor cells. Organoids can be used to model disease by introducing disease mutations or using patient-derived PSCs. Future applications could include drug testing and even tissue replacement therapy.

Organoids have been generated for a number of organs from both mouse and human stem cells. To date, human pluripotent stem cells have been coaxed to generate intestinal, kidney, brain, and retinal organoids, as well as liver organoid-like tissues called liver buds. Derivation methods are specific to each of these systems, with a focus on recapitulation of endogenous developmental processes. Specifically, the methods so far developed use growth factors or nutrient combinations to drive the acquisition of organ precursor tissue identity. Then, a permissive three-dimensional culture environment is applied, often involving the use of extracellular matrix gels such as Matrigel. This allows the tissue to self-organize through cell sorting out and stem cell lineage commitment in a spatially defined manner to recapitulate organization of different organ cell types.

These complex structures provide a unique opportunity to model human organ development in a system remarkably similar to development in vivo. Although the full extent of similarity in many cases still remains to be determined, organoids are already being applied to human-specific biological questions. Indeed, brain and retinal organoids have both been shown to exhibit properties that recapitulate human organ development and that cannot be observed in animal models. Naturally, limitations exist, such as the lack of blood supply, but future endeavors will advance the technology and, it is hoped, fully overcome these technical hurdles.

The therapeutic promise of organoids is perhaps the area with greatest potential. These unique tissues have the potential to model developmental disease, degenerative conditions, and cancer. Genetic disorders can be modeled by making use of patient-derived induced pluripotent stem cells or by introducing disease mutations. Indeed, this type of approach has already been taken to generate organoids from patient stem cells for intestine, kidney, and brain.

Furthermore, organoids that model disease can be used as an alternative system for drug testing that may not only better recapitulate effects in human patients but could also cut down on animal …