REVIEW - Organogenesis in a dish, Modeling development and disease using organoid technologies
The making of bodies part by part
Mention of organoids, organlike structure growing in a Petri dish, might conjure up images of science fiction. However, the generation of organoids is very real, as is the increased understanding of organ form and function that comes from studying them. Lancaster and Knoblich review organoids as structures that include more than one cell type of an organ that exhibit structural and functional features of the natural counterpart. Knowledge of normal organ developmental pathways guides the formation of these structures. Organoids show great promise for modeling human development and disease and for biomedical research and regenerative medicine.
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Paper can be accessed here.
Background
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.
Graphic
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.
Advances
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.
Outlook
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 studies. Liver organoids, in particular, represent a system with high expectations, particularly for drug testing, because of the unique metabolic profile of the human liver. Finally, tissues derived in vitro could be generated from patient cells to provide alternative organ replacement strategies. Unlike current organ transplant treatments, such autologous tissues would not suffer from issues of immunocompetency and rejection.
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Another review of the same topic -
In vitro organogenesis in three dimensions: self-organising stem cells
Organ formation during embryogenesis is a complex process that involves various local cell-cell interactions at the molecular and mechanical levels. Despite this complexity, organogenesis can be modelled in vitro. In this article, we focus on two recent examples in which embryonic stem cells can self-organise into three-dimensional structures - the optic cup and the pituitary epithelium; and one case of self-organising adult stem cells - the gut epithelium. We summarise how these approaches have revealed intrinsic programs that drive locally autonomous modes of organogenesis and homeostasis. We also attempt to interpret the results of previous in vivo studies of retinal development in light of the self-organising nature of the retina.
