An organoid is a miniaturised and simplified version of an organ produced in vitro in three dimensions that mimics the key functional, structural, and biological complexity of that organ. It is derived from one or a few cells from a tissue, embryonic stem cells, or induced pluripotent stem cells, which can self-organize in three-dimensional culture owing to their self-renewal and differentiation capacities. The technique for growing organoids has rapidly improved since the early 2010s, and The Scientist named it one of the biggest scientific advancements of 2013. Scientists and engineers use organoids to study development and disease in the laboratory, for drug discovery and development in industry, personalized diagnostics and medicine, gene and cell therapies, tissue engineering, and regenerative medicine.
History Attempts to create organs in vitro started in 1907 with one of the first dissociation-reaggregation experiments where Henry Van Peters Wilson demonstrated that mechanically dissociated sponge cells can reaggregate and self-organize to generate a whole organism. In the subsequent decades, multiple labs were able to generate different types of organs in vitro through the dissociation and reaggregation of organ tissues obtained from amphibians and embryonic chicks. The formation of first tissue-like colonies in vitro was observed for the first time by co-culturing keratinocytes and 3T3 fibroblasts. The phenomena of mechanically dissociated cells aggregating and reorganizing to reform the tissue they were obtained from subsequently led to the development of the differential adhesion hypothesis by Malcolm Steinberg in 1964. With the advent of the field of stem cell biology and the first isolation of pluripotent stem cells from mouse embryos in 1981, the potential of stem cells to form organs in vitro was realized early on with the observation that when stem cells form teratomas or embryoid bodies, the differentiated cells can organize into different structures resembling those found in multiple tissue types. The advent of the field of organoids started with a shift from culturing and differentiating stem cells in two dimensional (2D) media, to three dimensional (3D) media to allow for the development of the complex 3-dimensional structures of organs. Utilization of 3D media culture media methods for the structural organization was made possible with the development of extracellular matrices (ECM). In the late 1980s, Bissell and colleagues showed that a laminin rich gel can be used as a basement membrane for differentiation and morphogenesis in cell cultures of mammary epithelial cells. Since 1987, researchers have devised different methods for 3D culturing, and were able to utilize different types of stem cells to generate organoids resembling a multitude of organs. In the 1990s, in addition to their role in physical support, the role of ECM components in gene expression by their interaction with integrin-based focal adhesion pathways was reported. In 1998 scientists first isolated stem cells from human blastocysts and cultured them, while the reprogramming of mouse and human fibroblasts to generate Induced pluripotent stem cells (iPSC) was introduced later and greatly enhanced stem cell and organoid research. In 2006, Yaakov Nahmias and David Odde showed the self-assembly of vascular liver organoid maintained for over 50 days in vitro. In 2008, Yoshiki Sasai and his team at RIKEN institute demonstrated that stem cells can be coaxed into balls of neural cells that self-organize into distinctive layers. In 2009 the Laboratory of Hans Clevers at Hubrecht Institute and University Medical Center Utrecht, Netherlands, showed that single LGR5-expressing intestinal stem cells self-organize to crypt-villus structures in vitro without necessity of a mesenchymal niche, making them the first organoids. In 2010, Mathieu Unbekandt & Jamie A. Davies demonstrated the production of renal organoids from murine fetus-derived renogenic stem cells. In 2014, Qun Wang and co-workers engineered collagen-I and laminin based gels and synthetic foam biomaterials for the culture and delivery of intestinal organoids and encapsulated DNA-functionalized gold nanoparticles into intestinal organoids to form an intestinal Trojan horse for drug delivery and gene therapy. Subsequent reports showed significant physiological function of these organoids in vitro and in vivo. Other significant early advancements included in 2013, Madeline Lancaster at the Institute of Molecular Biotechnology of the Austrian Academy of Sciences established a protocol starting from pluripotent stem cells to generate cerebral organoids that mimic the developing human brain's cellular organization. Meritxell Huch and Craig Dorrell at Hubrecht Institute and University Medical Center Utrecht demonstrated that single Lgr5+ cells from damaged mouse liver can be clonally expanded as liver organoids in Rspo1-based culture medium over several months. In 2014, Artem Shkumatov et al. at the University of Illinois at Urbana-Champaign demonstrated that cardiovascular organoids can be formed from ES cells through modulation of the substrate stiffness, to which they adhere. Physiological stiffness promoted three-dimensionality of EBs and cardiomyogenic differentiation.
Properties Lancaster and Knoblich define an organoid as a collection of organ-specific cell types that develops from stem cells or organ progenitors, self-organizes through cell sorting and spatially restricted lineage commitment in a manner similar to in vivo, and exhibits the following properties:
it has multiple organ-specific cell types; it is capable of recapitulating some specific function of the organ (e.g. contraction, neural activity, endocrine secretion, filtration, excretion); its cells are grouped together and spatially organized, similar to an organ.
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